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THE HEMODYNAMIC EFFECTS
OF AMINOPHYLLINE,
ADENOSINE, LOSARTAN AND
NITRIC OXIDE ADMINISTERED
SHORTLY AFTER RIGHT HEART
INFARCT IN A PORCINE MODEL
MIC HA EL
SPAL DING
Department of Anaesthesiology,
University of Oulu
O UL U 2 0 0 1
MICHAEL SPALDING
THE HEMODYNAMIC EFFECTS OF
AMINOPHYLLINE, ADENOSINE,
LOSARTAN AND NITRIC OXIDE
ADMINISTERED SHORTLY AFTER
RIGHT HEART INFARCT IN A PORCINE
MODEL
Academic Dissertation to be presented with the assent of
the Faculty of Medicine, University of Oulu, for public
discussion in the Auditorium 7 of the University Hospital
of Oulu, on August 17th, 2001, at 2 p.m.
O U LU N Y LI O P IS TO, O U L U 2 0 0 1
Copyright © 2001
University of Oulu, 2001
Manuscript received 7 May 2001
Manuscript accepted 10 May 2001
Communicated by
Docent Raimo Kettunen
Docent Juhani Rämö
ISBN 951-42-6401-0
(URL: http://herkules.oulu.fi/isbn9514264010/)
ALSO AVAILABLE IN PRINTED FORMAT
ISBN 951-42-6400-2
ISSN 0355-3221
(URL: http://herkules.oulu.fi/issn03553221/)
OULU UNIVERSITY PRESS
OULU 2001
Spalding, Michael, The hemodynamic effects of aminophylline, adenosine, losartan
and nitric oxide administered shortly after right heart infarct in a porcine model
Department of Anaesthesiology, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu,
Finland
2001
Oulu, Finland
(Manuscript received 7 May 2001)
Abstract
Right heart failure may be caused by several etiologic factors such as pulmonary embolism, post
coronary bypass, chronic obstructive pulmonary disease (COPD) and right heart infarction.
Traditionally, treatment has consisted of fluid loading (volume expansion) and the use of inotropic
agents. In the present series of studies, an experimental model of acute right heart failure was
developed using right heart infarct. Treatment with drugs chosen to specifically improve right heart
performance was then evaluated. The drugs used in this series were aminophlline, adenosine, nitric
oxide (NO) and losartan.
Aminophylline transiently improved cardiac index and pulmonary vascular resistance, but
simultaneously caused an increase in heart rate and a decrease in stroke volume. Although it may
reduce right heart afterload, aminophylline did not improve overall cardiac function in this
experimental model of right heart infarction.
Adenosine affected an increase in cardiac index during the adenosine infusion and in stroke index,
while pulmonary vascular resistance and mean pulmonary pressure were decreased. There was a
marked decrease in systemic vascular resistance as a result of the drug. Heart rate remained
unchanged by the infusion. Discontinuation of the drug resulted in a rapid reversal of the
hemodynamic changes. The continuous infusion of adenosine therefore appears to cause an effective
arterial vasodilation, with a consequent unloading of right heart afterload.
NO treatment significantly reduced right heart afterload. A significant deterioration was observed
in cardiac output as well as in left and right ventricle stroke work indices. The use of NO in this model
of right heart infarct affected a decrease in both right heart afterload and left heart preload, with an
overall deterioration in global hemodynamics.
Losartan was shown to decrease central venous pressure and wedge pressure, while cardiac
output, left ventricle stroke work and stroke volume all showed improvement. Compared to the
control animals, pulmonary vascular resistance, systemic vascular resistance and systemic pressures
were unaffected by the drug, as was heart rate. An inhibition of angiotensin II action may therefore
be of benefit in the treatment of right heart failure symptoms during the first hours after right heart
infarct.
Keywords: adenosine, losartan, right heart failure, cardiovascular pharmacology
This book is dedicated to my father and mother.
Acknowledgments
This research project was carried out during the years 1997 to 1999 in cooperation between
the Department of Anaesthesiology, the Department of Pharmacology and Toxicology, and
the Experimental Animal Research Laboratory, in the University of Oulu.
I owe a debt of gratitude to the Acting Head of the Department of Anaesthesiology,
professor Seppo Alahuhta, M.D., Ph.D., for supporting me in my research work over the
years. He provided me with support both moral and otherwise over the years.
I would like to sincerely thank my supervisor in this project, Tero Ala-Kokko, M.D.,
Ph.D., who first provided me with the impetus to study right heart failure. His support was
especially significant during the early stages of this work.
Kai Kiviluoma, M.D., Ph.D. also acted as a supervisor of my work and provided a great
deal of important feedback. This was particularly critical when I was formulating the first
reports of the results of this project. Thank you Kai, for your input in this respect.
I must also express my sincere gratitude to professor Heikki Ruskoaho, M.D., Ph.D.,
who helped in planning the research and was a co-author in all the original publications.
His expert input as a professor of pharmacology and toxicology was especially valuable, as
were his many insights into the planning of an experimental study.
Professor Tatu Juvonen, M.D., Ph.D. was particularily supportive in the latter phase of
the project, providing me with the clear voice of reason during some dark hours. I can
justifiably claim that – without our talks and his contribution to the publication on the use
of nitric oxide – this book would likely still be an unfinished manuscript in the bottom
drawer of my desk.
I am very grateful to Raimo Kettunen, M.D., Ph.D. and to Juhani Rämö, M.D., Ph.D. for
their contribution in reviewing this manuscript. Their insightful comments were of great
help in formulating this final publication.
I would very much like to thank Jarmo Lahtinen, M.D., who taught me the sternotomy
technique used in the study and gave me many helpful pointers on surgical technique that
eased my work in the beginning. His useful lessons on the maintenance of chainsaws have
also been much appreciated.
All the staff of the Experimental Animal Research Laboratory, University of Oulu
deserve my very special thanks, in particular Seija Seljänperä and Veikko Lahteenmäki
were of immense value in the everyday details of this research project. I am grateful to Pasi
Ohtonen, M.Sc., for the time he contributed by sitting with me and discussing the ins and
outs of biostatistics. His help made possible an otherwise overwhelming task.
Finally, I would like to thank my family both here in Finland and those back in Canada
for their forbearance, support and understanding over the last four years. In particular, my
lovely wife Heli and my children David, Thomas, Alec and Jonathan have been a constant
source of love and strength for me during these times which have - periodically - been
rather lackluster.
Kemi, May, 2001
Mike Spalding
Abbreviations
A
ACE
ACEI
ADP
AMP
ATP
ANOVA
ARDS
ARF
AT
B
CI
COPD
CVP
EDVI
ESVI
ET
HR
LV
LVSWI
MAP
MPAP
NO
NOS
NYHA
PCWP
PG
PVRI
REF
Adenosine receptor
Angiotensin converting enzyme
Angiotensin converting enzyme inhibitor
Adenosine diphosphate
Adenosine monophosphate
Adenosine triphosphate
Analysis of variance
Adult respiratory distress syndrome
Acute respiratory failure
Angiotensin receptor
Bradykinin receptor
Cardiac output index
Chronic obstructive pulmonary disease
Central venous pressure
End diastolic volume index
End systolic volume index
Endothelin
Heart rate
Left ventricle
Left ventricle stroke work index
Mean arterial pressure
Mean pulmonary artery pressure
Nitric oxide
Nitric oxide synthase
New York Heart Association
Pulmonary capillary wedge pressure
Prostaglandin
Pulmonary vascular resistance index
Right ventricle ejection fraction
RV
RVSWI
SI
SV
SVRI
Right ventricle
Right ventricle stroke work index
Stroke index
Stroke volume
Systemic vascular resistance index
List of original publications
This thesis was written based on the following original articles. These are referred to in the
text by their corresponding Roman numerals.
I
II
III
IV
Spalding MB, Ala-Kokko TI, Kiviluoma K, Ruskoaho H & Alahuhta S
(2000) The effect of aminophylline on right heart function in young pigs after
ligation of the right coronary artery. Pharmacol Toxicol 86(4): 192-6.
Spalding MB, Ala-Kokko TI, Kiviluoma K, Ruskoaho H & Alahuhta S
(2000) The hemodynamic effects of adenosine infusion after experimental
right heart infarct in young swine. J Cardiovasc Pharmacol 35(1): 93-9.
Spalding MB, Ala-Kokko TI, Kiviluoma K, Ruskoaho H & Alahuhta S
(2001) The hemodynamic effects of losartan after right ventricle infarct in
young pigs. Pharmacol Toxicol (in press)
Spalding MB, Ala-Kokko TI, Kiviluoma H & Alahuhta S Juvonen, T (2001)
Inhaled nitric oxide effectively decreases right heart afterload following right
heart infarct in pigs. Scan Cardiov J 35(1): 45-49
Contents
Abstract
Acknowledgements
Abbreviations
List of original publications
1 Introduction................................................................................................................15
2 Review of the literature..............................................................................................17
2.1 The anatomy and physiology of the right heart ......................................................17
2.1.1 Morphology.....................................................................................................17
2.1.2 Vascularisation................................................................................................18
2.1.3 Autonomic nervous system and the heart........................................................19
2.1.4 Physiology in the healthy state........................................................................19
2.2 Neurohumoral factors governing the cardiovascular system ..................................21
2.2.1 Angiotensin II .................................................................................................21
2.2.2 Nitric oxide .....................................................................................................24
2.2.3 Adenosine .......................................................................................................25
2.2.4 Other neurohumoral factors ............................................................................26
2.3 Right heart failure: its etiology and pathophysiology .............................................29
2.3.1 Treatment modalities for acutely reduced right heart function .......................30
2.3.2 Fluid loading ...................................................................................................32
2.4 Review of the drugs under study.............................................................................34
2.4.1 Aminophylline ................................................................................................34
2.4.2 Adenosine .......................................................................................................37
2.4.3 Losartan...........................................................................................................40
2.4.4 Nitric oxide .....................................................................................................43
3 Purpose of the present study ......................................................................................45
4 Materials and Methods...............................................................................................46
4.1 Experimental animals .............................................................................................46
4.2 Monitoring protocol................................................................................................47
4.3 Study protocol.........................................................................................................47
4.3.1 General............................................................................................................47
4.3.2 Controls...........................................................................................................48
4.3.3 Aminophylline ................................................................................................48
4.3.4 Adenosine .......................................................................................................48
4.3.5 Losartan...........................................................................................................49
4.3.6 Nitric oxide .....................................................................................................49
4.4 Statistical Analysis..................................................................................................49
5 Results .......................................................................................................................51
5.1 Aminophylline ........................................................................................................51
5.2 Adenosine ...............................................................................................................51
5.3 Losartan ..................................................................................................................52
5.4 Nitric oxide .............................................................................................................52
6 Discussion..................................................................................................................59
6.1 Aminophylline ........................................................................................................59
6.2 Adenosine ...............................................................................................................60
6.3 Losartan ..................................................................................................................61
6.4 Nitric oxide .............................................................................................................63
6.5 Methodological aspects...........................................................................................64
6.5.1 Animals ...........................................................................................................64
6.5.2 Anesthesia .......................................................................................................64
6.5.3 Choice of right heart infarct model .................................................................65
6.5.4 The open chest model......................................................................................66
6.6 An overview of the results obtained in the present study .......................................66
6.6.1 Inotropy...........................................................................................................66
6.6.2 Vasodilation ....................................................................................................67
6.6.3 Chronotropy ....................................................................................................67
6.6.4 Cardiac output .................................................................................................67
6.7 The ideal drug in the treatment of right heart failure (due to myocardial infarct) ..68
7 Summary and conclusions .........................................................................................69
8 References..................................................................................................................70
1 Introduction
Right heart failure is a clinically important pathological process resulting from one or more
of various cardiovascular and/or pulmonary diseases. Failure will present with gradually
decreasing cardiac performance accompanied with increases in pulmonary vascular
pressure and its concurrent development of pulmonary dysfunction.
Right heart failure may have various etiologies, the more common being failure due to
chronically increased pulmonary pressures. These in turn may be pulmonary venous
hypertension-caused due to cardiovascular disease (e.g. rheumatic mitral valve stenosis
(Setaro et al. 1992)) or pulmonary artery hypertension caused due to pulmonary diseases
(e.g. chronic obstructive pulmonary disease (Matthay et al. 1982, Matthay & Mahler 1986,
Matthay 1987)). Common to these mechanisms for right heart failure, however, is that they
are all chronic processes which will only result in changes in the right heart over an
extended period of time. The most common cause of right heart failure is likely left side
failure (Thompson & White 1936), which in turn will most probably be due to myocardial
infarct.
Right heart infarct, on the other hand, is a process which leads to both an acute decrease
in right heart function, as well as chronic compensatory anatomical remodelling.
Myocardial infarct of the right ventricle will be at its purest a blockage of branches of the
right coronary artery, which will cause little or no direct left ventricle involvement.
Occlusion of branches of the anterior interventricular branch of the left coronary will also
cause infarction of septal areas of the right ventricle, but this will cause more left ventricle
involvement as well.
Another clinically relevant cause of acute right heart failure is pulmonary embolism,
which will present with increases in pulmonary vascular resistance and right heart dilation
and subsequent impairment of left ventricle function (Lualdi & Goldhaber 1995). In
addition, acute right heart failure may be observed after open-heart surgery.
Typical findings in right heart failure are dilation of the right ventricle with a
subsequent shift of the intraventricular septum to the left. The pericardial space is reduced
and symptoms of tamponade may be evident (Squara et al. 1993). Pulmonary vascular
resistance will increase as will mean pulmonary arterial pressure without a concomitant
16
rise in wedge pressure. Finally, right ventricle stroke volume and cardiac output will be
decreased. Treatment of these symptoms of right heart failure is a clinically challenging
proposition due to the anatomical and functional differences between this form of heart
failure and the more common form of left heart failure. The more salient points of
difference between these two distinct processes are the differences in vascular resistance
between the pulmonary and systemic circulations and the differences in the muscle mass of
the right and left ventricles.
The administration of volume expansion has been prominent in the treatment of right
heart failure (Squara et al. 1993), based on its effect on global heart function. Stroke
volume - and consequently cardiac output - is increased, as is the mean arterial pressure.
According to the Frank-Starling mechanism, optimal ventricular performance can only be
assured in the presence of a sufficient preload. This will then stretch myocardial myocytes
to their optimal preload pressure, allowing them to contract with maximum force. This
results in an improvement in both the systemic and pulmonary circulation. Overloading the
right ventricle, however, will cause an increase in ventricular dilation and an attenuation of
flow forward through the pulmonary circulation, further impairing filling of the left
ventricle and decreasing cardiac output (Romand et al. 1995). Ideally, treatment of right
heart failure should be focused on specifically improving right heart function, as well as on
treating the cause of the failure if possible. In addition to preload optimization, treatment of
right heart failure consists of the use of inotropic agents such as noradrenaline and
dobutamine (Squara et al. 1993).
Doyle and associates (1995) summarized the properties desirable in an inotropic drug.
According to their report, the drug should increase cardiac output through an increase in
stroke volume without increasing heart rate. It should be lusitropic and be vasodilative. It
should lower both left and right ventricle afterload through the vasodilation of systemic
and pulmonary vascular resistance. Although this may be desirable up to a point, it should
be kept in mind that lowering systemic vascular resistance will lead to decreases in
systemic pressures and hence reduced tissue perfusion, possibly causing problems in
ischemia-prone organs, such as the kidneys and the gastrointestinal tract. Another related
problem is that systemic vasodilation will reduce right heart preload somewhat with a
subsequent attenuation of cardiac output. Therefore, systemic vasodilation should be
avoided in the treatment of heart failure, while pulmonary vasodilation is desirable. To this
end, infusable drugs with a very short half-life might be more preferable due to their higher
selectivity for the pulmonary circulation. Of the drugs currently available for clinical usage
in the treatment of right heart failure, no single medication fulfills all of the above criteria.
The present study was undertaken to elucidate the effects of various treatment regimes
on right heart contractility and afterload, as well as on global hemodynamics in general. An
experimental model of right heart failure involving right heart infarct in young pigs was
developed. Utilizing this model, the effects of intravenous aminophylline (I), adenosine
(II), losartan (III), and of inhaled nitric oxide (IV) in fluid-optimized, experimental cases of
right-heart failure were examined.
2 Review of the literature
2.1 The anatomy and physiology of the right heart
Although traditionally viewed as being a passive conduit for blood passage between the
systemic and pulmonary circulation (Starr et al. 1943), the right ventricle has more recently
been shown to play an active role in systemic hemodynamics (Cohn et al. 1974). Many
studies since then have shown a decisive role of the right ventricle in overall
hemodynamics, which has been especially apparent in cases of right heart failure (e.g. Fisk
& Guilbeau 1987, Wingate et al. 1991, Goldstein et al. 1983, Sibbald & Driedger 1983).
Table 1. Morphological considerations of the human right heart (Ganong 1993, Frick et al.
1994).
Parameter
Ventricle volume
Right ventricle
Approximately 130 ml at rest
Left ventricle
Stroke volume
70-90 ml (at rest)
70-90 ml (at rest)
Ejection fraction
Approximately 65% at rest
Approximately 75-85% at rest
Ventricle pressure
15-30 mmHg systole
0-8 mmHg diastole
90-140 mmHg systole
4-12 mmHg diastole
2.1.1 Morphology
Anatomically, the right ventricle can be divided into an inflow area (including the tricuspid
valve), a central chamber and an outflow area (including the pulmonary valve) (Farb et al.
1992). This tends to present as more of a sac-shaped formation than as a symmetrical
chamber (see Figure 1).
18
Fig. 1. A graphical representation of the right ventricle. 1 = inflow area, 2 = main
chamber area, 3 = outflow area.
2.1.2 Vascularisation
The myocardium of the right heart receives its blood flow from the right main coronary,
the circumflex and the anterior descending (LAD) coronary arteries. The latter two mainly
feed the posterior wall (circumflex) and the interventricular septum (circumflex and LAD).
The right main coronary is responsible for blood flow to the free wall of the right ventricle
(Farb et al. 1992). The right coronary also gives off a small branch which supplies blood
flow to the sinoatrial node (see Figure 2).
19
Fig. 2. Anatomical distribution of the coronary arteries (Adapted from Wind &
Valentine 1991).
2.1.3 Autonomic nervous system and the heart
Activation of the sympathetic part of the autonomic nervous system has both positive
inotropic and chronotropic effects (Yousef et al. 2000). After infarct, sympathetic activity
will lead to ventricular hypertrophy and remodelling of the ventricle itself (Sugden 1999)
through activation of the renin-angiotensin system.
2.1.4 Physiology in the healthy state
The right ventricle (RV) is coupled in series with the left ventricle (LV) and ejects its
stroke volume (SV) into the pulmonary circulation (Lee 1992). Under steady-state
conditions the SV of both ventricles is the same, but the RV ejects its volume into a lowresistance system with a large degree of compliance (Pinsky 1993). Due to its thin freewall,
the RV is weak compared to the LV, but is well adapted to wide variations in preload (i.e.
compliance is good). Due to its weaker nature and crescent shape, however, the RV cannot
adapt to acute increases in pulmonary pressure (i.e. increased afterload), which is thus one
20
of the major causes of right heart failure (Lee 1992). Early researchers examining the
function of the right ventricle hypothesized that it plays only a minimal role in the
circulation and that even its total dysfunction will be well tolerated (Starr et al. 1943,
Bakos 1950). Not until later were the problems of right heart infarction (Cohn et al. 1974)
and right heart failure first begun to be recognized (Doyle et al. 1995).
2.1.4.1 Determinants of right heart function
The functionality of the right heart is governed by various factors, the most important of
which are preload, afterload, muscle compliance and muscle contractility. These in turn are
affected by previous illness, such as myocardial infarction, pulmonary hypertension or
pulmonary disease (e.g. COPD), oxygen availability and myocardial thickness.
Preload is defined as the force stretching the myocardium in a resting state to its
precontractile length. This is an experimentally derived figure and can best be
demonstrated using a model involving an isolated papillary muscle stretched to its
precontractile length by a weight attached to a lever. The weight necessary to stretch the
muscle to this length is therefore representative of preload. After this, the lever is
prevented of stretching the muscle any further by placing a stop above it, and additional
weight is added. When stimulated, the muscle can now contract only when it generates
sufficient force to overcome both the preload weight and the additional weight, which is
representative of afterload (Freeman et al. 1994). As muscle length can not effectively be
measured in vivo, an estimation must be made based on other measurements (Civetta
1999). A good estimate of these models can be obtained by translating them to the force
stretching (filling) the myocardium during diastole (preload) and the force against which
the myocardium must contract during systole (afterload). In a clinical situation, right
ventricle preload is determined by venous return and the distensibility of the RVs thin
myocardial walls. Right ventricle contractility depends on the degree to which the RV
walls are stretched during the diastole (preload). This in turn defines the ejection fraction
and the final right ventricle stroke volume (RVSV), which are important measures of RV
efficiency.
2.1.4.2 The Frank-Starling mechanism
The Frank Starling mechanism states that the energy of contraction is proportional to the
initial length of the cardiac muscle fiber (Patterson et al. 1914). In practice, this translates
into a curvilinear function (see figure below) as cardiac output will at first respond quickly
to increases in preload, but as the myocardium is stretched further and further, the response
will level off.
21
Fig. 3. The Frank-Starling relationship
In the normal state, the RV compensates for changes in preload through compliance,
which is the stretching of the muscle wall without loss of muscle contractility. A
permanent increase in afterload, however, can only be compensated for through an increase
in contractility achieved through hypertrophy of the muscle, which will eventually lead to a
decrease in compliance. Hypertrophy will also cause an imbalance in the muscle between
oxygen delivery and consumption, causing a decrease in contractility. Both of these factors
contribute to RV failure.
2.2 Neurohumoral factors governing the cardiovascular system
2.2.1 Angiotensin II
The best-known tissues affected by angiotensin II and the physiologic actions of the
hormone in those tissues are listed in Table 2.
22
Table 2. Actions of Angiotensin II (adapted from Goodfriend et al 1996)
Tissue affected
Artery
Action
Contraction, growth
Reference
(Griffin et al. 1991)
Adrenal zona
glomerulosa
Kidney
Aldosterone secretion
(Laragh et al. 1960)
Inhibits release of renin
Increases reabsorption of Na+
Stimulates vasoconstriction
Release of prostaglandin
Affect on embryogenesis
(Menard et al. 1991)
(Mitchell et al. 1992)
(Mitchell et al. 1992, Hall &
Granger 1983)
(McGiff et al. 1970)
(Aguilera et al. 1994)
(Saavedra 1992)
Brain
Sympathetic
nervous system
Heart
Stimulates thirst
Release of vasopressin
Sympathetic outflow
Peripheral sympathetic
transmission
Release of epinephrine
Improves contractility
Ventricular hypertrophy
(Saavedra 1992)
(Reid 1992)
(Foucart et al. 1991)
(Sadoshima & Izumo 1993,
Moravec et al. 1990, Kent et al.
1972)
Most of these actions support or increase arterial blood pressure and maintain
glomerular filtration. Actions of angiotensin II which might lower blood pressure if they
occurred in isolation, such as the stimulation of prostaglandin production, sustain the
perfusion of selected vascular beds despite the powerful vasoconstrictor action of
angiotensin II.
Vasoconstriction and the release of aldosterone in response to angiotensin II occur in
seconds or minutes, in keeping with their roles supporting the circulation after hemorrhage,
dehydration, or postural change. Other actions, such as vascular growth, ventricular
hypertrophy, and the pressor effect of very low doses of angiotensin II, take days or weeks
(Griffin et al. 1991, Dzau et al. 1991, Gorbea-Oppliger et al. 1994). The slower responses
are likely to be more important in the pathogenesis of chronic hypertensive cardiovascular
diseases.
2.2.1.1 Angiotensin Receptors
The receptor subtypes AT1 and AT2 are polypeptides containing approximately 360 amino
acids (Sasaki et al. 1991, Murphy et al. 1991, Mukoyama et al. 1993). Despite their similar
affinities for angiotensin II, AT1 and AT2 receptors are functionally distinct, with a genetic
sequence homology of only 30 percent (Szpirer et al. 1993, Koike et al. 1994).
23
Angiotensin receptors of the AT1 subtype bind angiotensin II in ways characteristic of
other hormone receptors on the cell surface: their structural specificity is high; they have
limited binding capacity; they bind angiotensin II with an affinity similar to its circulating
-10
concentration, about 10 M; they convert the interaction with angiotensin II into cellular
responses; and they are regulated by their rates of biosynthesis and recycling (Goodfriend
et al. 1971, Lin & Goodfriend 1970, Carini et al. 1991).
Specific, high-affinity binding of angiotensin II is determined by amino acids located on
or near the extracellular surface of the membrane-bound receptor, as well as by sequences
in the transmembrane domains (Hjorth et al. 1994). These regions are probably adjacent to
one another in the native receptor in which two disulfide bonds hold its helical domains
together.
2.2.1.2 Neurohormonal effects of angiotensin II
The AT1 subtype is the target of the new receptor antagonists (Goodfriend et al. 1996) such
as losartan. The binding of angiotensin II causes vascular changes, renal changes,
hormonal changes, as well as modulating activity in both the central and peripheral nervous
system (see Table 2).
Angiotensin II directly stimulates AT1 and AT2 receptors causing vasoconstriction,
sodium and water retention, cellular remodelling, (AT1 receptors) cell differentiation and
tissue repair (AT2 receptors). In an elegant study differentiating the action of AT1 and AT2
receptors, Smits and colleagues blocked AT1 receptors with losartan and then stimulated
AT2 receptors with an AT2-specific agonist DPMA. They found that stimulation of the AT2
receptors caused dose–related vasodilation in anesthetized rats (Smits et al. 1993). The
stimulation of AT2 receptors also exerts an antiproliferative effect (AT2 receptors), which
may be of consequence in angiogenesis (Willenheimer et al. 1999). In addition,
angiotensin II potentiates the actions of other neurohormonal systems, contributing to the
remodelling process. It facilitates the activation of the sympathetic adrenergic system,
thereby enhancing the release of vasopresin/anti-diuretic hormone, aldosterone and
endothelin (Jilma et al. 1997). In addition, it triggers the formation of free radicals, which
subsequentially accelerate the degradation of nitric oxide (Kumar & Das 1993).
Concomitantly, it increases the breakdown of bradykinin, which further reduces levels of
nitric oxide (Cody 1997).
24
2.2.2 Nitric oxide
2.2.2.1 Nitric oxide synthases
Nitric oxide is produced by the oxidation of L-arginine by a family of isoenzymes (nitric
oxide synthases NOS) that includes two constitutive isoforms, viz., endothelial NOS
(eNOS) and neuronal (or brain) NOS (nNOS), as well as an inducible isoform (iNOS)
(Bolli et al. 1998). eNOS produces nitric oxide via a complex reaction which is stimulated
by calcium and requires other co-factors. Nitric oxide synthase catalyzes the oxidation of
the terminal guanidino nitrogen of L-arginine (Steudel et al. 1999). The reaction consumes
oxygen and nicotinamide adenine dinucelotide hydrogen phosphate (NADPH) and
produces NO. NOS will not produce detectable levels of nitric oxide unless superoxide
dismutase is present. During conditions of L-arginine depletion, NOS generates O2 (Steudel
et al. 1999). The characteristics of the different synthases are depicted in Table 3.
Table 3. Adapted from Steudel et al. (1999). NOS = nitric oixde synthase
NOS
Tissues
Effects
Neuronal NOS
CNS, peripheral nerve system
Brain development, memory,
behavior, pain perception,
vasodilation of large cerebral vessels.
Regulates smooth muscle relaxation
in gastrointestinal, urogenital and
respiratory tracts. Modulates skeletal
muscle function.
Inducible NOS
Inflammatory cells, local
cells during infection
Promotes wound closing,
neovascularization, may cause
systemic arterial dilation, may cause
deterioration of inflammation.
Endothelial NOS
Vascular endothelial cells,
fetal lung cells
Modulates systemic and pulmonary
vascular tone, roles in lung
development and disease. Role in the
development of post-ischemic
conditioning.
25
2.2.2.2 Metabolism of nitric oxide
Once formed, nitric oxide has a short half-life in vivo of a few seconds and is inactivated
by its target molecules. The main metabolic pathways are the binding of nitric oxide to O2and to hemoglobin. In a study examining the uptake of inhaled nitric oxide (Young et al.
1996) it was shown that 90% is absorbed during inhalation. Almost 70% of this appears
within 48 hours in the urine as NO3-. The remainder is excreted as NO2- in the oral cavity,
some of which is further converted to nitrogen gas in the stomach and some to ammonia in
the intestine (Steudel et al. 1999).
2.2.2.3 Protection against ischemic injury
A well-documented effect of nitric oxide is its role in preconditioning against mild
ischemia (Bolli et al. 1998). This takes place in two phases, generally known as "early" and
"late" preconditioning. In their extensive studies on the subject, Bolli and coworkers (1998)
have elucidated the method through which this protective mechanism is triggered. In early
preconditioning, a brief ischemic stress causes a burst of nitric oxide production via eNOS.
This leads to a cascade chain of events involving tyrosine kinases - and probably other
kinases - with the ultimate formation of iNOS and an increased generation of nitric oxide
(late preconditioning) during subsequent ischemic challenge. According to this model,
nitric oxide plays two completely different roles in preconditioning: during the early stage
it initiates the development of the cardioprotective mechanism, whereas during the late
stage it protects against myocardial stunning.
2.2.2.4 Direct myocardial effects of nitric oxide
Although nitric oxide will effect hemodynamics through vasodilation, it has also been
speculated to have a direct effect on myocyte contractility (Michel & Smith 1993, Brady
1993, Brady et al. 1993). Later studies have, however, speculated that the observed effect
results from the activation of other mechanisms, and is not related to iNOS (UngureanuLongrois et al. 1995). Some studies have been reported on the myocardial effects of
inhaled nitric oxide (see section 2.4.4.1.).
2.2.3 Adenosine
Adenosine is an endogenous nucleoside occurring in all cells of the body, whose exact
chemical formula is 6-amino-9-ß-D-ribofuranosyl-9-H-purine. Endogenous adenosine
appears to be produced both intra- and extracellularly through the catabolism of adenine
26
nucleotides by 5'-nucleotidases (ATP -> ADP -> AMP -> adenosine) (Bukoski et al. 1986,
Shryock & Belardinelli 1997). In blood, the half-life of endogenous adenosine is very
short, ranging from 1 to a few seconds (Moser et al. 1989). Interestingly, during
degradation, endogenous adenosine will more likely be “recycled” back to AMP (through
phosphorylation) than deaminated to inosine (Sparks & Bardenheuer 1986). Endogenous
adenosine acts as a “retaliatory metabolite” i.e. its activation and effect on adenosine
receptors causes an inhibition of the target cell (Shryock & Belardinelli 1997). As an
example of this action, adenosine will reduce the pacemaking rate of the sinoatrial cells in
the heart, thereby slowing heart rate and reducing cardiac work. As adenosine is produced
by its own target cell, adenosine formation therefore both signals an imbalance between
tissue oxygen supply and demand and initiates responses to correct the problem (e.g.
vasodilation, slowing of heart rate, etc.)(Mullane & Bullough 1995).
Adenosine receptors are present in most cells throughout the body and are divided into
four sub-groups: A1, A2A, A2B and A3 (Ralevic & Burnstock 1998). A1 receptors are mainly
found in the brain and spinal cord, in the testis and in other adipose tissues. They are also
found to a lesser extent in many other tissues, including kidney, heart and spleen.
Stimulation of A1 receptors will inhibit adenylyl cyclase, thereby attenuating the action of
catecholamines. A2A receptors are mainly found in the brain, while A2B receptors appear to
be located in the colon, esophagus and gastric antrum. Pharmacological studies indicate
that A2B receptors are likely present in the coronary arteries, but they have not yet been
located. The action of A2 receptors appears to stimulate adenylyl cyclase. In humans, A3
receptors have been identified in the lung and liver. Preliminary reports on this receptor
suggest that A3 receptors inhibit adenylyl cyclase activity (Strickler et al. 1996).
In their recent review of the clinical implications of adenosine and specific receptor
agonists/antagonists, Auchampach and Bolli concluded that the therapeutic exploitation of
our current knowledge of adenosine and its receptors will require a more specific tissue
targeting of specific adenosine receptor agonists or antagonists. This way, for example, the
positive inotropic effects of A2A receptor antagonists will not be offset by a concomitant
blocking of A2A receptor vasodilative activity in the coronaries (Auchampach & Bolli
1999).
2.2.4 Other neurohumoral factors
2.2.4.1 Endothelins
Endothelins (ET) are peptides produced in many cells and tissues. The vascular ET system
is represented mainly by ET-1 produced in endothelial cells. The mature peptide ET-1 acts
in a paracrine manner on smooth muscle cell ET(A) and ET(B) receptors to induce
contraction and growth, and in an autocrine or paracrine manner on endothelial cells to
induce the production of nitric oxide and prostacyclin (Schiffrin & Touyz 1998). ET has
also been shown to stimulate the release of atrial natriuretic peptides both in vitro and in
27
vivo (Stasch et al. 1989). ET receptors may be downregulated by ET, especially under
conditions in which large amounts of ET are being produced in the vasculature. This has
been demonstrated in some models of experimental hypertension and in some forms of
human hypertension (Schiffrin & Touyz 1998). Some of the effects of angiotensin II,
particularly growth of the smooth muscle media of blood vessels, have been shown under
some conditions to be mediated by ET-1 via ET(A) receptors. In their experimental study
in pigs with hypoxic pulmonary hypertension, Liska and coworkers (1995) found that at
low doses (10-25 ng/kg/min) endothelin-infusion caused a dose-dependent decrease in
pulmonary vascular resistance. At a higher dose (100 ng/kg/min) both systemic and
pulmonary vascular resistance was increased, while cardiac output was reduced.
2.2.4.2 Eicosanoids
Eicosanoids are the group of compounds including prostaglandins, thrombaxanes and
prostacyclin. Prostaglandins (PG) are cyclic compounds, of which PGH is the precursor for
PGE and PGF (Moncada et al. 1985). PGA-C is derived from PGE. In addition,
thrombaxane A (TXA) and prostacyclin (PGI2) are also formed from PGH. PGG is a
precursor of PGH.
Eicosanoids participate in the regulation of blood pressure as vascular tone is subject to
the continuous relaxing influence from endogenous vasodilating prostaglandins (PG’s A,
B, E and F) or related substances such as bradykinin (Moncada et al. 1985). Prostacyclin
(PGI2) decreases blood pressure with a concomitant increase in cardiac output and a
reduction of systemic vascular resistance related to the peripheral vasodilation. Splanchnic,
pulmonary and coronary vasodilation are also observed with increased blood flows in the
mesenteric, renal and coronary beds. These changes in regional blood flows have been
linked to the inhibition by PGI2 of the vasoconstrictor response to sympathetic stimulation
and pressor hormones (noradrenaline, angiotensin II). TXA exerts a strong vasoconstrictive
effect (Moncada et al. 1985). It appears that prostaglandins stabilize hemodynamics
through an increase in systemic vascular resistance (Vanlersberghe et al. 1992).
Eicosanoids potentiate the cardiovascular effects of bradykinin and are in fact generated
by bradykinin through the formation of arachidonic acid. In vascular tissue, most of the
available arachidonic acid is converted into vasodilator prostaglandins, i.e., prostacyclin
(PGI2) and prostaglandin E2 (PGE2). These prostaglandins are involved in vasodilator
actions of the kinins. The biological significance of kinin-related prostaglandin formation
becomes apparent after inhibition of kinin breakdown by ACE inhibitors. These
compounds prevent the generation of vasoconstrictor angiotensin II and stimulate
endothelial eicosanoid formation via local kinin accumulation. There is evidence
suggesting that kinin-induced prostaglandin generation contributes to the anti-ischemic,
inotropic, and blood pressure-lowering effects of the compounds (Schror 1992).
PG’s and TXA also participate in platelet release and aggregation in injury (Moncada et
al. 1985). Interestingly, PGE and PGD are inhibitors of platelet aggregation, while TXA2 is
a potent inducer of aggregation. PGI2 is also a potent inhibitor of platelet activity.
28
2.2.4.3 Kallikrein-kinin system
Kinins are peptides synthesized de novo at sites of tissue damage and function as
inflammatory mediators, participating in the acute inflammatory response and aiding in
tissue repair (Hall 1997). Bradykinin is the most common of the kinins and interact with
bradykinin receptors on the cell surface. Regoli and colleagues (1980) first described the
two subtypes of bradykinin receptors, B1 and B2, but it wasn’t until the 1990’s that specific
bradykinin antagonists have been developed (Hall 1992). The kinins mediate a great
variety of responses, including: contraction or relaxation of smooth muscle in the
gastrointestinal, the respiratory and the urogenital tracts, effects on blood pressure and
circulation (vasodilation) and a putative response in the central nervous system
(hyperalgesia). The most extensively researched area to date is bradykinin’s role in the
inflammatory response, where they act on the microvasculature to promote vasodilation
and the extravassation of plasma into the damaged tissue (Hall 1992). This response
appears to be a B2-mediated event. B1 receptors also contribute to the inflammatory
response, producing cytokinins. The response is unique in that both bradykinin and the B1
receptors involved in the event are synthesized de novo at the damage site (Marceau et al.
1997).
29
Table 4. Neurohumoral factors in the cardiovascular system and their more important
properties.
Factor/
properties
Adenosine
Effect on
myocardium
Attenuates
pacing
Attenuates
catecholamines
Effect on
vasculature
Vasodilation
Effect on
peripheral nerves
Mediates neurotransmitter release
Effect on CNS
T1/2
Mediates neurotransmitter
release
1–8
sec
Angiotensin
II
Potentates
contractility
Vasoconstriction
/ growth
Augments nerve
transmission
Stimulates thirst
Bradykinin
Potentates
betaadrenergic
activity
vasodilation
Promotes algesia /
hyperalgesia
Increases blood
pressure
Nitric oxide
none
vasodilation
none
Memory, pain
perception
~10
sec
Endothelin
No direct
action
vasoconstriction
none
none
1-2
min
Pain mediation?
Stimulant /
depressant
5-30
sec
Prostaglandins
Potentates
contractility
vasodilation
2.3 Right heart failure: its etiology and pathophysiology
Right heart failure is a comparatively common process which may be caused by several
etiologic factors (Matthay et al. 1982, Matthay 1987, Clauss & Ray 1968, Herity et al.
1994) (see Table 5). Typically, pulmonary vascular resistance will increase as will mean
pulmonary arterial pressure. Increasing pulmonary circulation resistance leads to overdistension of the right ventricle, which is clinically apparent as a reduction in right
ventricle stroke volume as well as in cardiac output (Squara et al. 1993).
The anatomical disposition and geometry of the right ventricle allow it to adapt very
well to wide variations in preload, but poorly to increases in afterload. In the presence of
increased afterload, RV stroke volume decreases linearly with increasing resistance and the
ventricle eventually dilates (Lee 1992). This dilation is then responsible for further RV
failure, due to decreased right coronary artery flow (from systolo-diastolic to diastolic
30
only) at a time when myocardial oxygen consumption is increased. Furthermore, RV
dilation shifts the interventricular septum to the left, decreasing left ventricular preload and
compliance and, hence, the cardiac output. An often-lethal vicious circle is induced. The
main therapeutic goals aimed at breaking this circle are restoration of adequate oxygen
delivery to the myocardium and diminution of RV afterload (Romand et al. 1995).
Table 5. Etiologic factors contributing to both acute and chronic right heart failure.
Cause of RHF
Mechanism
Ischemic damage
Infarct
Primary pulmonary hypertension
Unknown
Secondary pulmonary hypertension
Left heart failure, valve disorder
Pulmonary artery stenosis
Congenital
Pulmonary embolism
Thrombosis/Fat-embolism
Chronic pulmonary disease
Vasoconstriction through hypoxia
2.3.1 Treatment modalities for acutely reduced right heart function
Essential cornerstones in treating acute RV failure are the optimisation of preload and
afterload, and the use of inotropic agents to increase myocardial contractility.
2.3.1.1 Optimize preload
By optimizing the degree to which the right ventricle will stretch during diastole, the
RVSV can be increased. This is accomplished through the use of fluid infusion to increase
venous return. In this, as in all instances of fluid infusion, careful monitoring is necessary
to avoid a concomitant increase in afterload, impeding flow into the pulmonary circulation.
31
Fig. 4. The effects of myocardial compliance and contractility on the Frank-Starling
mechanism. Figure reproduced from Internal Medicine, 4th edition, 1994, W.B.
Saunders with permission
Over-stretching of the ventricle can also occur, at which point contractility will decrease
(Freeman et al. 1994) as can be seen from loading curves depicting the Frank-Starling
principle (see figures above). Another limiting factor in the use of fluid loading is the
pericardium surrounding the heart. As the pericardium is a relatively stiff and non-elastic
structure, it will form a barrier to expansion of the right ventricle. This in turn will cause an
increase in diastolic transmural pressure on the left ventricle, thereby reducing its
compliance (Doyle et al. 1995).
2.3.1.2 Reduce right heart afterload
Right heart afterload, i.e. the pressure gradient present in the pulmonary circulation is the
result of several different factors, namely the ability of the right heart to pump blood
forward, the ability of the left heart to move that blood on from the pulmonary circulation
into the main circulation, the degree of volume loading present in the total circulation at
any given time, as well as localised impediments in the pulmonary circulation (e.g.
pulmonary embolism, COPD, primary pulmonary hypertension) (Romand et al. 1995). The
main aim of reducing right heart afterload is to reduce pulmonary vascular resistance. This
can be accomplished, for example, by improving LV-function (contractility) through the
use of vasoactive medication (e.g. digitalis or an adrenergic drug such as dobutamine). This
has the benefit of increasing performance on both sides of the heart so that not only does
LV-function improve, but RV-function does, as well. Another important method is the use
of vasodilating drugs such as those counteracting α- and/or β-adrenergic actions,
angiotensin converting enzyme inhibitors (ACEI) or nitroglycerin-based drugs (see Figure
32
5, below). There are also some drugs which have both an adrenergic and a peripheral
vasodilating effect (e.g. milrinone, dobutamine) (McCall 1994).
Fig. 5. The effect of vasoactive drug treatment on output/pressure curves in heart
failure. Unloading of the heart and inotropic intervention improve cardiac
performance (displace the curve upwards). The area to the extreme right of the figure
indicates the left ventricular end diastolic pressure area at which symptoms of
2
pulmonary congestion appear. The bottom area (cardiac index less than 2.5 l/min/m )
indicates low cardiac output. Figure reproduced from Internal Medicine, 4th edition,
1994, W.B. Saunders with permission
2.3.2 Fluid loading
Treatment of right heart failure has traditionally consisted of fluid loading (volume
expansion) and the use of inotropic agents such as dobutamine (Squara et al. 1993). As
explained above, optimal ventricular performance can only be assured in the presence of
sufficient preload. This will then stretch myocardial myocytes to their optimal preload
pressure, allowing them to contract at maximum force. One limiting factor in the use of
preload optimization when treating heart failure is the resultant distension of the ventricle,
especially of the right ventricle. As the Frank-Starling principle shows, over-extension of
the myocytes will eventually result in an attenuation of myocardial contractile strength (see
Figure 6).
33
Fig. 6. The effect of fluid loading and lusitropy on stroke volume. Ea = effective
arterial elastance, Ees = left ventricular end-systolic elastance, EDV = end systolic
volume, ESP = end systolic pressure, EDV = end diastolic volume. A. Increasing
preload improves stroke volume (EDV-ESV). B. Increasing afterload decrease stroke
volume by increasing ESV more than EDV. C. Increasing contractility improves
stroke volume, arterial elastance is decreased. D. Increasing ventricular wall stiffness
results in a lower EDV and stroke volume. E. An increase in lusitropy improves
stroke volume by increasing EDV. (Adapted from Pinsky & Dhainaut 1993)
34
Perhaps the most detrimental sequela of fluid loading is the passage of intravascular fluid
into the extravascular space and the ultimate reduction in perfusion of both peripheral and
central (i.e. pulmonary) tissues which results. Due to these limiting factors, fluid loading
must be used with caution in the treatment of heart failure, and care must be taken to avoid
over-distension of the right ventricle and the exaggerated extravasation of the fluid.
2.4 Review of the drugs under study
2.4.1 Aminophylline
Theophylline is a methylxanthine which acts as a non-specific phosphodiesterase inhibitor,
thereby increasing tissue levels of cyclic-AMP. Chemically, theophylline is related to the
other methylated xanthines, caffeine and theobromine. Xanthine is a dioxypurine which is
structurally related to uric acid (Hardman et al. 1995). Theophylline itself is poorly soluble,
but solubility is much enhanced by the formation of complexes, the clinically most
important of these being the complex of theophylline and ethylenediamine, which forms
aminophylline. Given intravenously, aminophylline converts to theophylline at about a 70
to 85 percent rate of efficiency, with a half-life thereafter from 3.5 to 9 hours (Kaplan
1988).
In addition to its phosphodiesterase inhibiting effect, theophylline has also been shown
to exert other effects in vivo, the most important of these being its antagonist action on
adenosine receptors (Hendeles et al. 1985) and has a catecholaminic effect, acting as a
dopamine-agonist (Hillis & Been 1982). In addition, an increased binding of cAMP to
cAMP-binding protein has also been reported (Miech et al. 1979) and an action as a
prostaglandin antagonist (Hendeles et al. 1985). The end-point of the action as a
phosphodiesterase inhibitor, however, is an increase in intracellular calcium levels, which
in turn contributes to positive inotropy (Colucci et al. 1986). The proportional magnitude
of the mechanisms of action attributed to theophylline has not been ascertained, however,
and there is some disagreement as to whether the effects observed are the result of a mainly
phosphodiesterase inhibition or of a direct catecholaminic effect (Hillis & Been 1982,
Matthay et al. 1978, Falicov et al. 1973). There is also some controversy as to the degree
theophylline improves hemodynamics through an improvement in myocardial contractility
as compared to its effect on afterload via broncho- and vasodilatation in the pulmonary
circulation (Matthay 1987).
The pharmacologic effects of intravenous aminophylline include bronchodilation,
vasodilatation, positive chronotropy, positive inotropy as well as an increase in renal
activity. In addition, respiratory muscle strength has been reported to improve with
intravenous aminophylline (Siafakas et al. 1993), and diaphragmatic muscle fatigue to be
reduced (Aubier et al. 1981, Bukowskyj et al. 1984). An improvement in mucociliary
clearance has also been reported (Guyton 1991).
35
2.4.1.1 Cardiovascular effects of aminophylline
The earliest reports of the cardiovascular effects of aminophylline were from studies
conducted during the first decades of the 1900's (e.g. Thompson & White 1936, Marvin
1926, Starr et al. 1937, Howarth et al. 1947, Fowell et al. 1949, Werkö & Lagerlöf 1950,
Borst et al. 1957). The findings in these early reports showed a slight chronotropic effect, a
short-lived drop in venous pressures and (in post-Second World War studies) increases in
cardiac output. Parker and his associates conducted experiments on the cardiovascular
effects of aminophylline in various pathological states in the 1960's (Parker et al. 1967,
Parker et al. 1966, Parker et al. 1966). Their findings showed an increase in cardiac output
along with a decrease in the filling pressures of both right and left ventricles. Interestingly,
even though they used a rather large dose of aminophylline (1 gram infused intravenously
over 30 minutes), there was no change in heart rate in their patients with heart failure
(Parker et al. 1966), while a substantial increase was observed in those with chronic
obstructive pulmonary disease (Parker et al. 1967). Murphy and associates performed a
study (1968) based on observations concerning the inotropic effect of aminophylline in
various forms of heart disease. They showed that aminophylline effected no improvement
in cardiac output in twenty-one patients with valvular heart disease (both mitral and aortal),
even though there was an improvement in inotropy (dP/dt). They also observed significant
reductions in pulmonary vascular resistance, which they concluded was the most favorable
hemodynamic effect of the drug in this subset of patients who generally suffer from
concurrent pulmonary edema.
Rall and West (1963) demonstrated that theophylline potentiates contractility in isolated
cardiac preparations, and these findings have later been clinically supported (Falicov et al.
1973, Rutherford et al. 1981). Several studies in the 1970's and 1980's in humans indicated
that either aminophylline used intravenously or theophylline orally will improve
hemodynamics in right heart failure (Matthay & Mahler 1986, Falicov et al. 1973,
Conradson 1984). Other studies showed an improvement in both global myocardial
performance (Falicov et al. 1973, Rutherford et al. 1981) and right heart performance with
the use of intravenous aminophylline (Matthay et al. 1978, Bisgard & Will 1977).
Aminophylline and its effects on cardiovascular performance has still been the subject
of research in the 1980's and 1990's. Many of the more recent studies have concentrated
mainly on the consequential effects of per oral methylxanthines on hemodynamics
(Matthay & Mahler 1986, Matthay 1987, Dini et al. 1993, Matthay 1985, Ueno et al.
1990), showing improvement in pump function and reductions in systemic and pulmonary
vascular resistances.
Elliot and his coworkers (1985) examined the effect of intravenous aminophylline on
cardiac performance during tread-mill exercise in healthy human subjects, finding no
significant improvement after drug administration.
Conradson (1986) showed that theophylline only produced minor improvements in
healthy male human subjects, in his study on theophylline and enprofylline. He concluded
that with plasma concentrations of 3.8 to 12.6 mg/l of theophylline there was some degree
of vasodilation, but only weak inotropic response.
Gomez and associates (1988) examined the effect of blood oxygen saturation on the
hemodynamic response of aminophylline in dogs. They showed that aminophylline exerted
36
a positive inotropic effect under normoxic conditions as well as increasing stroke volume,
but had little effect on left ventricle performance during hypoxia. Hakim and coworkers
(1988) continued to examine the effects of aminophylline on hemodynamics during
hypoxia in their study using pigs and dogs. They found that therapeutic doses of
aminophylline (1-10 mg/kg) administered intravenously during hypoxia attenuated
pulmonary vascular resistance without effecting systemic vascular resistance. They
concluded that xanthines can only be effective as vasodilators when there is already some
vasoconstriction.
Schreiber and associates (1992) examined the response of preconstricted pulmonary
vascular smooth muscle to aminophylline in newborn lambs. They could show no
relaxation by the drug, however, and concluded that the proposed use as a vasodilator in
the treatment of persistent pulmonary hypertension in newborns could not be
recommended. In another study (Mols et al. 1993) showed a dose-dependency for inotropic
and vasodilator effects of aminophylline in COPD patients
Various studies on the effect of aminophylline on coronary blood flow have been
reported (Roig et al. 1996, Crea et al. 1994, Granato et al. 1990), with somewhat
conflicting results. Granato and companions (1990) found that aminophylline had no
significant effect on hemodynamics or coronary blood flow in an open-chest study using
dogs. Crea and associates (1994) performed a similar study on dogs examining the effects
of aminophylline on myocardial blood flow. They concluded that aminophylline may
improve myocardial ischemia through 1) an unloading of the left ventricle and 2)
constriction of subepicardial vessels with a consequent redistribution of flow to the
subendocardium. They did not observe any improvement in total coronary flow. More
recently, Roig and coworkers (1996) ascertained an improvement in coronary flow by
aminophylline in patients with coronary occlusion. Exercise-induced ischemia was delayed
by the drug through an improvement in the collateral circulation. Despite the ambiguous
results reported above, aminophylline is regularly used to dilate coronary arteries during
medical imaging (Nahser et al. 1996, Johnston et al. 1995, Kahn et al. 1990, Miller et al.
1989, Mohiuddin et al. 1992).
In a study in open-chest dogs Minamino and coworkers (1995) were recently able to
ascertain that aminophylline had a biphasic action in myocardial ischemia. They found that
the drug (0.8 mg/kg infused over 10 minutes intravenously) improved mild ischemia but
worsened severe ischemia. They attributed this finding to the fact that aminophylline acts
through both an increase in plasma catecholamine concentrations and a blockade of
adenosine receptors. They conclude that the administration of aminophylline may result in
a worsening of myocardial ischemia through inhibition of adenosine receptors because
adenosine mediates cardioprotection in the ischemic and reperfused myocardium.
Aminophylline has been used to decrease pulmonary arterial pressure and increase
cardiac performance in chronic pulmonary hypertension (Matthay 1985, Maskin et al.
1984, Panuccio et al. 1984). Several studies have shown it to be an effective reducer of
pulmonary pressures (Matthay et al. 1978, Parker et al. 1966, Parker et al. 1966, Panuccio
et al. 1984), while some more recent studies have put this into question (Mols et al. 1993).
Although other, more specific phosphodiesterase inhibitors are available (i.e. amrinone,
milrinone, enoximone), aminophylline is still in use in some centers as a pulmonary
37
vasodilator. Due to its positive inotropic and vasodilative effects, this type of drug would
appear to be a natural choice for the treatment of right heart failure.
2.4.2 Adenosine
2.4.2.1 Cardiovascular effects of adenosine
Adenosine has long been recognized as a clinically effective anti-arrhythmic agent
(Belhassen & Pelleg 1984, Parker & McCollam 1990, Faulds et al. 1991, Rankin et al.
1992) and has been used to produce controlled hypotension (Sollevi et al. 1984).
Wainwright and Parratt (1993) reported on the effects of the administration of a selective
A1 adenosine agonist (R-PIA) during left main coronary occlusion in an open-chest pig
model. They reported a high incidence of ventricular fibrillation (70%) in animals not
receiving the drug, the incidence being 20% to which it was given. They concluded that the
A1 adenosine agonist markedly reduced the incidence and severity of ischemic arrhythmias.
They also concluded that the A1 adenosine agonist was a much more powerful
antiarrhythmic agent than a similar A2-specific adenosine agonist reported in an earlier
study (Wainwright & Parratt 1991).
Wang and coworkers (1994) examined the effects of adenosine on guinea pig atrial
myocytes, showing that the mechanism involved in the negative inotropic effect of the
agent is a potassium current on the cell membrane activated by adenosine type A1 receptor
stimulation which hyperpolarizes the cell membrane and shortens the action potential in
supraventricular tissues. This leads to negative dromotropy, negative chronotropy and,
ultimately, negative inotropy. No similar effect on ion currents has been demonstrated in
ventricular tissue, but attenuation of the effects of catecholamines on ion currents have
been reported (Belardinelli et al. 1995). Stimulation of A2 receptors causes vasodilation in
the coronaries, increasing coronary flow, appearing to act on both the endothelium and
vascular smooth muscle (Shryock & Belardinelli 1997).
Several researchers have reported on the cardioprotective potential of adenosine over
the past decade (Lasley & Mentzer 1995, Ely & Berne 1992, Belardinelli et al. 1989).
Current evidence suggests that stimulation of A1 and A2 receptors with exogenously
administered adenosine may enhance myocardial tolerance to ischemia and attenuate
damage to the myocardium during reperfusion of the stunned heart. The exact mechanism
involved is the subject of some discussion, but the activation of both A1 and A2 receptors
appears to be inherent in the phenomenon. Lasley and Mentzer (1993) reported on the use
of exogenous and endogenous adenosine in isolated rat hearts during low-flow ischemia.
Their findings indicated that the mechanism through which adenosine enhanced
myocardial tolerance to ischemia may be in part due to a modulation of glucose
metabolism. In a later study of theirs (Lasley & Mentzer 1995) using a different model,
they noted several important points on using adenosine in the stunned heart. First, the
degree of ischemia involved is of great importance when considering the mechanism by
38
which the adenosine will act. As an example, in their earlier study the model of ischemia
involved low-flow through the myocardial tissue, but not total ischemia, and a modulation
of glucose metabolism was found to be important. Second, the timing for administering the
adenosine is of critical importance, and must be begun before the ischemic event to achieve
maximal effect. They concluded that adenosine acts in the myocardium through A1
receptors, but also appears to modulate phosphorylation potential. The former takes place
during ischemia, while the latter occurs during reperfusion. It has been theorized (Shryock
& Belardinelli 1997) that the stimulation of A1 receptors causes an attenuation of pacing, a
slowing of cellular metabolism, an inhibition of catecholamine effects and of the cellular
release of noradrenaline, while A2 receptor stimulation causes inhibition of platelet
aggregation, the formation of protective superoxide anions and the activation of
neutrophils. De Jong and associates applied this to use in cardioplegia (de Jong et al. 1990)
and found that low-dose adenosine as an adjunct to potassium cardioplegia resulted in a
shortened arrest time in their model while improving post-ischemic recovery.
Adenosine is a vasodilator and will cause dilation of the coronary vessels as well. It has
therefore been used in coronary imaging (Marwick 1997, Ogilby 1997) to identify vessels
which are occluded as opposed to those with low flow due to constriction. One of the
pitfalls associated with this method, however, is the coronary steal sometimes associated
with a vasodilatation extending to the systemic circulation. In addition, ischemia may also
occur during adenosine infusion due to a decrease in distal coronary perfusion, causing
collapse of the vessel at the site of the stenosis (Ogilby et al. 1993). Anderson and
coworkers (1997) therefore recommended that the adenosine infusion be titrated to suit the
individual patient in their examination of hemodynamic response to adenosine infusion
before and after coronary bypass surgery.
Iskandrian and associates (1997) reported on the use of adenosine as an aid in coronary
imaging. They administered a 140 µg/kg/min infusion to patients unable to participate in
exercise stress tests due to difficult symptoms of angina pectoris. They concluded that the
infusion was well tolerated, although mild side-effects such as flushing, shortness of
breath, dyspnea and chest pains were quite common (70-80%). Dysrhythmias such as first
or second degree AV block were well tolerated and transitory. The report concluded that
this method of myocardial perfusion imaging is a viable alternative to exercise stress-tests.
2.4.2.2 Pulmonary effects of adenosine
Jolin and associates (Jolin et al. 1992) examined the effects of a continuous infusion of
adenosine on pulmonary hemodynamics and fluid filtration in isolated rat lungs with either
no damage or an ARDS-simulating fat emulsion-induced injury. They found that the drug
effected a decrease in both the intact and the injured lung in pulmonary vascular resistance,
as well as modulating the fluid filtration rate in the lung tissue. Öwall and companions
(1991) demonstrated a similar effect on pulmonary vascular resistance in anesthetized pigs
with hypoxia-induced pulmonary hypertension, as well as an increase in cardiac output.
The prostaglandin prostacyclin was also used in that experiment and was shown to be a
more effective vasodilator than adenosine, while adenosine increased cardiac output more.
39
Konduri and coworkers (1992) also demonstrated that adenosine infusion caused an
effective decrease in pulmonary hypertension in hypoxic newborn lambs.
Schrader and coworkers (1992) demonstrated a significant reduction in pulmonary
vascular resistance (37%) in patients with pulmonary hypertension of varied etiology. They
also showed that adenosine increased cardiac output by as much as 57%. Compared to the
calcium channel blocking agent nifedipine, adenosine proved to be the more effective
pulmonary vasodilator. In a later study (Inbar et al. 1993), the same authors examined the
combination of calcium channel blockers (nifedipine or diltiazem) and an adenosine
infusion (mean 180±63 µg/kg/min). They concluded that adenosine could further decrease
pulmonary vascular resistance in patients already receiving an optimum dose of a calcium
channel blocker. Of five patients not responding to the calcium channel blocking agent
with a decrease in pulmonary vascular resistance, three did respond to the adenosine
infusion.
Adenosine and prostacyclin were compared with respect to reductions in pulmonary
vascular resistance and cardiac output in a study by Nootens and coworkers (1995)
involving patients with primary pulmonary hypertension. They showed that the two agents
produced similar reductions in pulmonary vascular resistance and increases in cardiac
output, with no untoward effects on systemic or pulmonary pressures. They concluded that
– due to its short half-life – adenosine is not suitable as a therapeutic agent in these
patients, but may be useful as a test for patient suitability for prostacyclin treatment in this
disorder. They further theorized that prostacyclin as a second vasodilating agent may be
useful in cases where calcium channel blocking alone does not produce sufficient
reductions in pulmonary hypertension, referring to Inbar and associates’ earlier publication
(Inbar et al. 1993).
Another effect of adenosine in the pulmonary circulation is to protect the pulmonary
tissue from injury such as that induced by ARDS (Jolin et al. 1992, Jolin et al. 1994,
Adkins et al. 1993). Adkins and coworkers (1993) demonstrated that pretreatment with an
infusion of adenosine or of an A2 agonist completely prevented the hemodynamic changes
(increase in pulmonary vascular resistance and in capillary permeability) seen in lung
injury associated with phorbol myristate acetate (PMA) challenge. Jolin and associates
(1994) showed that adenosine infusion also helped to preserve the morphological
ultrastructure of lung tissue after fat emulsion injury.
Adenosine has lately been the cause of considerable interest due to its vasodilative and
cardiac protective properties. Studies have been performed in recent years on its use in
such diseases as pulmonary hypertension (Fullerton et al. 1996, Haywood et al. 1992,
Morgan et al. 1991, Reeves et al. 1991) and reperfusion injury (Mullane & Bullough 1995,
Ely & Berne 1992, Randhawa et al. 1993, Engler 1994, Granger 1997, Lee & Lineaweaver
1996) and have shown that it causes a clear reduction in pulmonary vascular resistance. Its
effect on right heart and global hemodynamics, however, is still the subject of some
controversy (Haywood et al. 1992). As an effective vasodilating drug with a very short
half-life, adenosine is drug of a good deal of theoretical interest with respects the treatment
of right heart failure. It can be centrally infused and its infusion rate titrated to render its
effects specific to the pulmonary circulation. Its negative chronotropic and dromotropic
effects may also be of benefit.
40
2.4.3 Losartan
Losartan ((DuP 753), 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphe
nyl-4-yl)methyl]imidazole) is a specific angiotensin II type 1 receptor (AT1 receptor)
inhibitor. It acts as an angiotensin II inhibitor, mainly on AT1 receptors. Losartan is
primarily metabolized through oxidation and glucuronidation (Lankford et al. 1997), with a
major oxidative product being the carboxylic acid metabolite EXP3174, which has been
shown to be approximately 33-41 times as potent an AT1 receptor inhibitor than is the
parent molecule, losartan. Lankford (1997) found the expression of this metabolite to be
species-dependent, with peak EXP3174 plasma concentrations in humans and rats being
twice that of losartan, while those in pig and dog are almost non-existent. The half-life of
losartan also shows inter-species variability, being about 2 hours in humans, with
EXP3174’s half life being 6.3 hours (Lo et al. 1995), while losartan’s T1/2 was only 40
minutes in pigs, with a mere 2% of that being oxidized to EXP3174 (Lankford et al. 1997).
2.4.3.1 Cardiovascular effects of losartan
Hypertension. Losartan was primarily developed for use in the treatment and control of
systemic arterial hypertension, and at present this is its only approved indication. The
inhibition of AT1 receptor expression causes vasodilation and stimulates renal excretion of
sodium and water. It also improves renal blood flow (Symons & Stebbins 1996).
Myocardial infarct. The effect of angiotensin II inhibition after myocardial infarct is the
subject of some debate. Hartman and coworkers reported (1993) that direct angiotensin II
stimulation or inhibition had no effect on the degree of infarct necrosis in an experimental,
open-chest rabbit model. They also reported that ACE inhibition using ramiprilat had a
protective effect. Capasso and associates (1994) performed a similar study comparing
captopril and losartan in rats with a large myocardial infarct of the left ventricle. They
found that both drugs improved cardiac performance, but through different mechanisms.
Whereas captopril reduced systemic pressures, thereby unloading the heart on both sides,
losartan was shown to improve myocardial contractility, with a consequential decrease in
ventricular workload. They also determined that losartan prevented ventricular remodelling
after infarct. They concluded that losartan may improve long-term survival after
myocardial infarct. Another study on the subject (Milavetz et al. 1996), found no
difference in the survival of infarcted rats receiving either captopril or losartan. No
differences were found in heart weight, left ventricular pressures, dP/dt, cardiac index or
left ventricular volume or dimensions. Sladek and associates (1996) performed an
experimental study on myocardial infarct of the left ventricle in rats, in which they were
able to ascertain that losartan improved cardiac performance, reduced right ventricle
loading and improved angiogenesis in the infarction area (38% improvement compared to
controls).
41
Heart failure. Fitzpatrick and coworkers (1992) induced heart failure in sheep with 7 days
of rapid ventricular pacing, after which intravenous losartan was given followed by
captopril on separate days. Their findings indicated that losartan was similar to captopril in
its efficacy in the treatment of heart failure with both drugs reducing systemic pressures,
while glomerular filtration and renal perfusion pressures were maintained. Dickstein and
coworkers (1994) examined the effects of per oral losartan in sixty-six patients with heart
failure (NYHA II-IV, ejection fraction <40%), observing favorable vasodilatory effects as
well as dose-related increases in plasma renin activity, angiotensin II levels and moderate
reductions in serum aldosterone and plasma noradrenaline levels. Crozier and others (1995)
reported a large, multicenter study on the use of per oral losartan in symptomatic heart
failure. Patients received 25 or 50 mg losartan. In addition to the neurohumoral effects
observed by Dickstein et al, these researchers were able to report beneficial changes in
systemic vascular resistance and blood pressure, as well as improvements in pulmonary
wedge pressure, cardiac index and heart rate after 12 weeks of drug administration. They
found the drug to be well tolerated, with the beneficial effects not diminishing over time.
Coronary circulation. Richard and coworkers reported (1993) on the effects of Exp3174 on
the coronary circulation in dogs. They measured regional myocardial blood flow using a
radioactive imaging technique, and found no improvement in coronary circulation after
administration of the metabolite. In a later study, Nunez and associates (1997) were able to
demonstrate an improvement in coronary hemodynamics either alone or in combination
with enalapril in spontaneously hypertensive rats. This was associated with a reduction in
cardiac mass and a reduction in systemic blood pressure. In that study, it was noted that
enalapril alone had no effect on coronary blood flow. Similarly, Kaneko and coworkers
(1996) showed that losartan decreased left ventricular mass and improved coronary blood
flow in a study on exercise in spontaneously hypertensive rats. In a study of exerciseinduced angiotensin II release (1996), Symons and associates showed that losartan
effectively increased blood flow and/or decreased vascular resistance during exercise in the
myocardium, as well as in the vasculature for the stomach, small intestine, and colon. It
also improved renal blood flow in their study using mini-swine running on treadmills.
Recently, Zhu and associates (1999) performed an interesting study to evaluate the
protection from reperfusion injury offered by losartan. They showed that losartan
significantly improved coronary flow and left ventricular developed pressure in isolated rat
hearts after 15 minutes of ischemia and 30 minutes of post-ishemic reperfusion.
Interestingly, they also found that this effect appeared to be bradykinin-dependent.
Pulmonary hypertension. Angiotensin II can contribute to the development and
exacerbation of pulmonary hypertension through several paths. Left ventricle ischemia will
result in elevated levels of angiotensin II, which cause vasoconstriction and ventricular
remodelling, leading to left heart failure. This impedes flow through the pulmonary system,
resulting in pulmonary hypertension and – ultimately – right heart hypertrophy and
insufficiency.
Morrell and associates (1995) examined the role of angiotensin II in the development of
hypoxia-induced pulmonary hypertension in rats. They found that the changes in these
animals after 14 days in a hypobaric hypoxic chamber (increased pulmonary artery
42
pressure, right ventricular hypertrophy, medial thickening and muscularization of the small
pulmonary arteries) could be attenuated using losartan or captopril. Furthermore, a
bradykinin B2 receptor inhibitor failed to reverse the protective effects of the ACE
inhibitor, indicating that its protective effects were mediated by reductions in angiotensin II
levels, rather than increases in levels of bradykinin. They also ascertained that AT2 receptor
expression did not contribute to the development of pulmonary hypertension.
Kiely and coworkers (1997) performed a clinical study in patients with hypoxemic cor
pulmonale and found that a 50 mg dose of per oral losartan significantly reduced MPAP
and TPR (total pulmonary resistance). MAP and SVR were also reduced, while cardiac
output was increased.
2.4.3.2 Losartan and right heart failure
To an increasing degree, angiotensin converting enzyme inhibitors (ACEI) have been one
of the mainstays in the treatment of heart failure after myocardial infarct (Capasso et al.
1994, Lindpaintner & Ganten 1991, Pfeffer 1991). Angiotensin II levels rise after
myocardial infarct (Lindpaintner & Ganten 1991, Baker et al. 1990, Hirsch et al. 1991,
Olivetti et al. 1990), causing a subsequent increase in systemic pressure and pulse (Yang et
al. 1997). The beneficial effects of ACEI consist of both their immediate improvement of
hemodynamics by decreasing the effects of angiotensin II and the long-term attenuation of
angiotensin II-induced cardiac remodelling (Smits et al. 1992). In addition, however,
ACEI’s also cause an inhibition of nitric oxide, bradykinin and prostaglandins
(Willenheimer et al. 1999), which effect may be detrimental in heart failure. Angiotensin II
type 1 receptor (AT1 receptor) antagonists have therefore been used for a more selective
blockade of the renin-angiotensin system by blocking the activated renin-angiotensin
system selectively and effectively at the receptor level (Milavetz et al. 1996, Pitt et al.
1997).
Earlier studies have demonstrated the beneficial effects of losartan in heart failure in
both acute (Fitzpatrick et al. 1992, Smits et al. 1992) experimental models and clinical
trials (Crozier et al. 1995, Dickstein et al. 1995) involving patients with chronic heart
failure. In an experimental model involving acute left-heart infarct in rats, Capasso et al.
(1994) studied losartan’s effects on cardiac pump performance, finding an improvement in
myocardial contractility as well as in afterload, with a resultant improvement in cardiac
output. Pit and coworkers (1997) found that the long-term use of losartan was associated
with a lower mortality than that for captopril in elderly patients with heart failure.
Therefore, with regards its vasodilative effects and attenuation of ventricular
remodelling, as well as its non-inhibition of the actions of prostaglandins and bradykinin,
losartan would appear to be a potentially effective drug for the treatment of post-infarct
right heart failure.
43
2.4.4 Nitric oxide
2.4.4.1 Cardiovascular effects of inhaled nitric oxide
Nitric oxide has effect on both early and late preconditioning of the myocardium (Bolli et
al. 1998) (see section 2.2.2.3.). With reference to right heart function, the administration of
inhaled nitric oxide in RV failure has been shown to dramatically reduce pulmonary
pressure, thereby improving right heart performance (Hillman et al. 1997). It has also been
shown that due to its short half-life, while decreasing pulmonary vascular resistance,
inhaled nitric oxide has little or no effect on systemic arterial pressure. This results in an
improvement in right ventricle performance without compromising systemic pressure
(Ziegler et al. 1998). Nitric oxide has been shown to effectively reduce pulmonary vascular
resistance (for example Snow et al. 1994, Chen et al. 1997, Rich et al. 1994, Semigran et
al. 1994). Adrie and coworkers (1996) showed that inhaled nitric oxide improves coronary
blood flow. Several studies have concentrated on the treatment of pulmonary vascular
hypertension such as persistent pulmonary hypertension in the newborn (PPHN) (Kinsella
et al. 1992, Roberts et al. 1992, Roberts et al. 1997, Kinsella et al. 1997). Although these
studies have demonstrated clinical improvement in the patients, as well as a reduced need
for extracorporeal membrane oxygenation (ECMO), overall survival was not improved.
Ishibashi and associates (1998) examined the roles of potassium channels, adenosine
receptors and nitric oxide in coronary vasodilation. They found that vasodilation by nitric
oxide was reduced to approximately one quarter of its normal exercise-induced level in the
presence of K+(ATP) channel and adenosine receptor blockade. Their conclusion was that
K+(ATP) channels are critical for maintaining coronary vasodilation at rest and during
exercise but that when K+(ATP) channels are blocked, both adenosine and nitric oxide act
to increase coronary blood flow during exercise.
Several studies have been published in recent years concerning the effects of exogenous
nitric oxide on the myocardium. Prendergast and coauthors (1998) reported that nitric
oxide enhanced the inotropic response of isolated preparations of the guinea-pig heart to
dobutamine. Somewhat in contrast to these findings, however, there is a growing body of
evidence that nitric oxide exerts a depressive effect on the myocardium (Baigorri et al.
1999, Goldstein et al. 1997). Some studies have associated the use of inhaled nitric oxide
with increases in pulmonary capillary wedge pressure which the authors have attributed to
an attenuation in left ventricular function (Bocchi et al. 1994, Kelm et al. 1997), while
others feel that this change is merely the result of changes in pulmonary vasodilation and
not of changes in myocardial contractility (Loh et al. 1999).
2.4.4.2 Pulmonary effects of inhaled nitric oxide
The clinical use of inhaled nitric oxide has concentrated mainly on its use in the treatment
of pulmonary disorders such as adult respiratory distress syndrome (ARDS) (Benzing et al.
44
1997, Bigatello et al. 1994) Matthay and cowriters (1998) reported in their editorial on the
subject that the consensus of trials concerning the use of nitric oxide in ARDS was that the
treatment was of little or no benefit. They concluded that inhaled nitric oxide may still be
of value as a rescue therapy for some patients with refractory hypoxemia. Nitric oxide has
also been clinically tested in other conditions such as chronic pulmonary arterial
hypertension (Sitbon et al. 1995), COPD (Högman et al. 1993), lung transplantation (Date
et al. 1996) and heart surgery (Curran et al. 1995).
More recent reports on the clinical use of nitric oxide have been less optimistic than
those published in the early 1990’s. Manktelow and cowriters (1997) reported that ARDS
patients were less likely to respond to nitric oxide-treatment (60-70% being
hyporesponsive). They attributed this phenomenon to the increased levels of endogenous
nitric oxide and of systemic and infused catecholamines present in these subjects due to
septic vasodilation.
In their exhaustive review of the use of inhaled nitric oxide, Steudel and cowriters
concluded that the clinical usefulness of inhaled nitric oxide remains unclear. In their paper
they established that the use of inhaled nitric oxide in the treatment of ARDS has not
improved mortality rates, but whether this is due to the complexity and broad spectrum of
the disease, inappropriate dosing, inappropriate study design, inefficacy of nitric oxide or
even to the counterbalancing toxic effects of nitric oxide is unknown (Steudel et al. 1999).
At present, nitric oxide therapy has its main clinical use in the treatment of neonatal
respiratory distress syndrome (Kinsella et al. 1997).
2.4.4.3 Systemic effects of inhaled nitric oxide
Högman and coworkers demonstrated that inhaled nitric oxide increases bleeding time by
inhibiting platelet function (Högman et al. 1994) in their study in a rabbit model of inhaled
nitric oxide. This same effect was also demonstrated by Adrie and associates (1996) in a
model using open-chest dogs. In that same study, the authors also reported that nitric oxide
improves healing of vascular injury.
2.4.4.4 Inhaled nitric oxide in the treatment of right heart failure
Inhaled nitric oxide may cause an unloading of the right heart, which should be of benefit
in cases of right heart failure. Its effects on right heart failure due to right ventricle
infarction have not previously been documented.
3 Purpose of the present study
The present study was undertaken to examine the hemodynamic effects of various drugs
after experimental right heart infarct. An open-chest porcine model was developed for the
experiment due to the similarities between the cardiovascular system of man and pigs and
the repeatability of this model. More specifically, the aims of the present study were as
follows:
1.
2.
3.
4.
To examine the effects of intravenous aminophylline on hemodynamics when
administered shortly after right heart infarct.
To examine the hemodynamic effects of a continuous intravenous infusion of
adenosine at four different infusion rates in a similar model.
To examine the effect of a bolus dose of the angiotensin II inhibitor losartan on
hemodynamics in this model, and
To examine the hemodynamic effects of progressive concentrations of inhaled nitric
oxide in this experimental model of right heart infarct.
4 Materials and Methods
4.1 Experimental animals
The animals used in the studies involved were young, healthy mongrel pigs of either sex
and of uniform size and age (27-31 kg, approximately 4 months of age). All animals
received humane care in compliance with the “Guide for the care and use of laboratory
animals” (NIH Publication no. 85-23, 1985). The local committee governing ethical
considerations in experimental animal studies approved the protocol involved in the four
separate parts of the study. All in all, 70 animals were anesthetized for the study, of which
ten were included in the aminophylline group, ten in the adenosine group, four in the
losartan group, ten in the nitric oxide group and seven in the control group. In addition, 5
animals were used in two separate pilot studies for the losartan protocol. The remaining 28
animals were lost during the experiment due to (in order of frequency): drug
incompatibility, early death (i.e. infarct too large), uncontrollable hemorrhage during
cannulation, previous illness (e.g. pericarditis, pneumonia), anesthesia-related malignant
hyperthermia, and other reasons (e.g. insufficient infarct).
All animals were treated similarly prior to the experiment. They were chosen from the
farm based on their size and apparent health and thereafter transferred to the Experimental
Animal Center of the University of Oulu’s Medical Faculty, where they were acclimatized
for approximately one week before the experiment. The animals were kept in separate pens
with unlimited access to water and were fed twice daily. On the morning of the experiment
the animals were sedated with intramuscular midazolam (1 mg/kg), ketamine (10 mg/kg)
and atropine 0,5 mg in their pens and then transferred to the operating theater. An
intravenous cannula was introduced into a peripheral vein, usually in the left ear.
Thiopental (100-150 mg) was administered intravenously and muscle relaxation induced
with 8 mg pancuronium, after which the animals were intubated. Mechanical ventilation
with the Siemens 730 ventilator (Siemens-Elema AB, Sweden) using 30% oxygen and
70% nitrous oxide was begun and maintained with normoventilation for the duration of the
experiment. Supplemental anesthesia was given in the form of inhaled enflurane at 1-2%,
intermittent bolus doses of pancuronium and a continuous intravenous infusion of
47
thiopental (5 mg/kg/h). An exception to these last two points was the nitric oxide group of
animals who were ventilated using the Dräger Evita-4™ respirator device (Drägerwerk
AG, Lübeck, Germany) with 30% oxygen in an oxygen/air mixture and maintained with
normoventilation for the duration of the experiment. Anesthesia was maintained in this
group using a total intravenous anesthesia (TIVA) technique via a continuous infusion of a
sodium thiopental-fentanyl-pancuronium mixture.
4.2 Monitoring protocol
Monitoring was carried out similarly in all studies using the Datex AS/3 anesthesia monitor
(Datex Inc., Espoo, Finland). Subsequent to the induction of anesthesia and intubation, the
femoral vein and artery were exposed and catheters introduced through them for the
monitoring of systemic pressures and drawing blood samples. A thermodilution ejection
fraction catheter (93A-43H-7.5 Baxter Health Care Co. Ltd., CA, USA) was then placed
via the right internal jugular vein for the measurement of heart function. Hemodynamic
measurements were performed at this point and thereafter at regular intervals. Values were
obtained and recorded for heart rate (HR), mean systemic arterial pressure (MAP), central
venous pressure (CVP), mean pulmonary arterial pressure (MPAP), pulmonary capillary
wedge pressure (PCWP) and cardiac index (CI). Right ventricle end-systolic volume index
(ESVI), right ventricle end-diastolic volume index (EDVI), left ventricle stroke volume
index (SI), pulmonary vascular resistance index (PVRI), systemic vascular resistance index
(SVRI) and right (RVSWI) and left (LVSWI) ventricle stroke work indices were then
calculated from the above (see Appendix I). An arterial blood-gas analysis was also
performed for the first time at this point and a total of eight times during the protocol to
ensure normoventilation.
4.3 Study protocol
4.3.1 General
Pre-sternotomy-level hemodynamic measurements were obtained after catheterization and
before any further intervention. Animals with a pulmonary capillary wedge pressure
outside the range of 8-10 mmHg received fluid loading at this point (100-200 ml
hydroxyethyl starch solution and/or Ringer’s solution 500 ml as needed), after which these
first measurements were performed again. A sternotomy was performed and hemodynamic
measurements taken, the results of which served as a baseline for later measurements.
Branches of the right coronary artery on the free wall of the right ventricle were then
ligated. Ligation was judged to be successful if a distinct blanching of the myocardial wall
could be observed.
48
New baseline measurements were performed 60 minutes later after allowing the
circulation to accommodate to the new hemodynamic state. A 250 ml infusion of a
hydroxyethyl starch solution (Plasmafusin®, Pharmacia AB, Sweden; average molecular
weight ~120.000 daltons) was then given over 15 minutes, with hemodynamic
measurements one half hour after the infusion.
A final bolus dose of 200 ml hydroxyethyl starch solution was given to the animals in
every group (including controls), followed by hemodynamic measurements, after which the
animal was exsanguinated. The heart was removed and the free wall of the right ventricle
was dissected and examined macroscopically to determine the extent of the infarct. All
animals included in the study were determined to have a transmural infarct of the free wall
of the right ventricle. No infarct extended to the septum.
4.3.2 Controls
Animals in the control group (N=7) were treated similarly to those in the study groups with
the exception that they received no drug during the post-loading period. All animals
received a continuous infusion of a 0.9% saline solution throughout the follow-up to
maintain the circulating volume.
4.3.3 Aminophylline
In contrast to the other groups, post-infarct loading was performed in this group of
experimental animals (N=10) in five aliquots of a hydroxyethyl starch solution
(Plasmafusin®, Pharmacia AB, Sweden, average molecular weight ~120.000 daltons), 50
ml each (i.e. 250 ml) at ten-minute intervals. Hemodynamic measurements were performed
after each injection. A final measurement of hemodynamics and blood gases was
performed 30 minutes after the fluid loading.
Aminophylline was subsequently administered intravenously at 30 minute intervals in
graduating doses of 50, 100, and 200 mg and its effects on hemodynamics observed with
measurements every 15 minutes.
4.3.4 Adenosine
In study II (N=10), an adenosine infusion (Adenocor®, adenosine 3 mg/ml, SanofiWinthrop AB, Helsinki, Finland) was begun as a continuous infusion at 25 µg/kg/min via
the atrial port of the pulmonary catheter subsequent to loading. The infusion rate was
subsequently raised at one half hour intervals to 50, 75 and 100 µg/kg/min. Hemodynamic
measurements were performed during this time at 15 minute intervals. After adenosine had
49
been infused at 100 µg/kg/min for 30 minutes, the infusion was discontinued and
hemodynamics followed for another half hour with measurements at 15 minute intervals.
One animal was excluded from the final analysis due to a high HR (> 180/minute), as
this made calculations for REF impossible. A further three animals were excluded due to
insufficient (less than 25%) changes in REF, CI and PVRI subsequent to right heart infarct,
in spite of significant macroscopic changes being observed in the free wall of the right
ventricle. This left six animals in the study group.
4.3.5 Losartan
In this group (N=5), a bolus dose of losartan (30mg/kg) was administered intravenously.
This dose had been calculated using the literature available (Lankford et al. 1997) and
information obtained in two pilot studies performed by our group previously (animals
received a 50 mg and a 30 mg/kg dose in the two studies). This dose was shown to
effectively block all angiotensin receptor activity for at least 45 minutes. After
administration of the drug, hemodynamic measurements were performed at 15-minute
intervals for one hour.
4.3.6 Nitric oxide
In the study animals (N=10) of study IV, nitric oxide gas was introduced into the inhaled
gases at progressive concentrations (5, 10, 15 and 20 ppm) for 30-minute periods at each
concentration. Hemodynamic measurements were performed during this time at 15-minute
intervals. After nitric oxide had been inhaled at 20 ppm for 30 minutes, the insufflation was
discontinued and hemodynamics followed for another half hour with measurements at 15minute intervals.
4.4 Statistical Analysis
It was intended that an analysis of variance (ANOVA) for repeated measurements would
be performed on data from each group in order to minimize type II error. Due to the small
groups, however, this was not possible in the losartan part of the study (III) (four animals
in the drug group), and the Mann-Whitney U-test for non-parametric data was performed in
that group. Data from all other groups (I, II, IV) was examined using ANOVA.
Bonferroni's t-procedure (II) and Scheffe's multiple comparison (IV) were used for a post
hoc examination of the ANOVA results. All statistical analyses were performed using the
StatView for Macintosh™ software package (SAS Institute Inc, North Carolina, U.S.A.,
version 5.0). A p-value less than 0.05 was considered to denote statistical significance.
50
Differences between post-infarct and post-fluid loading hemodynamic values were
examined using the two-tailed t-test. A p-value less than 0.05 was considered statistically
significant.
5 Results
5.1 Aminophylline
Aminophylline had no significant effect on any hemodynamic parameters at the 50 mg
dose (I), although slight and transitory changes were seen in CI (p = 0.1097) and HR (p =
0.1382) (see Figure 7). The 100 mg dose effected a positive chronotropic effect (p =
0.0020), as well as causing a decrease in left heart afterload. This was reflected in
decreases in MAP (p = 0.0041) and SVRI (p = 0.0012) (see Figures 7 and 9). Again,
changes in CI (p = 0.1409) and PVRI (p = 0.2156) tended towards a clear, but transitory
improvement, which was not statistically significant and had reverted within 30 minutes of
the dose.
At 200 mg, the aforementioned changes were amplified, but the shift in CI (p = 0.0112)
and PVRI (p = 0.0460) were still short-lived. There was a significant positive chronotropic
effect (p < 0.0001), which remained even after the changes in CI and PVRI had reverted. A
transient, non-significant decrease was also observed in SVRI (p = 0.0653), but no change
in MAP.
The increase in HR was reflected in a gradual decrease in SI (see Figure 9), which
although not significant between adjacent measurements (i.e. after any single dose), had
decreased significantly between administration of the first and last dose (p < 0.0001).
5.2 Adenosine
Both right ventricle preload (CVP) and left ventricle preload (PCWP) remained unchanged
during the adenosine infusion (II). The following changes could be observed in the
parameters describing right ventricle afterload (MPAP and PVRI). MPAP was reduced by
the adenosine infusion, although this difference was not significant (p=0.3). PVRI was also
reduced, which change was statistically significant (p<0.01)(see Figures 7 and 8).
52
Similarly, the changes in left ventricle afterload were as follows. MAP was reduced by
the adenosine infusion, which was especially significant (p<0.01) at the 75 and 100
µg/kg/min infusion rates. ANOVA showed a significant decrease (p<0.01) in SVRI during
the infusion (see Figure 10).
There was a general improvement in pump performance during the adenosine infusion.
CI remained elevated after the fluid loading, while values in the control group dropped
back down to the baseline, indicating an inotropic effect of the infusion (see Figure 7). This
between-group difference was not, however, statistically significant. RVSWI remained
unchanged by the infusion, while a decrease was observed in LVSWI at the higher infusion
rates (Scheffe p<0.01, see Figure 9). An improvement was observed in SI (p<0.01). All
changes observed during the drug infusion reverted after cessation of the drug (p<0.01).
No change was observed at any infusion rate in HR, while it increased (p<0.01) after
cessation of the drug (See Figure 7).
5.3 Losartan
Right ventricle preload (CVP) exhibited a significant decrease (p<0.05) after the
administration of losartan (III) as did left ventricle preload (PCWP) (p<0.05), which latter
change had reverted, however, by the 45 minute mark. No change was affected in HR by
the drug in comparison to the control animals (see Figure 7).
Concurrently, no statistically significant changes were observed in the parameters
describing right ventricle afterload (MPAP and PVRI) (see Figures 7 and 9). Similarly, the
left ventricle afterload parameters (MAP and SVRI) were not significantly affected by the
bolus dose of losartan (see Figures 7 and 9).
A significant enhancement in cardiac performance took place after the administration of
losartan. CI, LVSWI and SI were all increased, remaining elevated for the first 30 minutes
of the follow-up period (see Figures 6 and 8).
5.4 Nitric oxide
Insufflation of nitric oxide decreased right ventricle (RV) preload (IV), which was seen as
a progressive drop in CVP (p<0.05 at 15 ppm), and in EDVI (p<0.01 at 15 ppm). A slight
and progressive decrease in left ventricle (LV) preload (PCWP) (p<0.05 at 15 ppm) was
observed during the nitric oxide treatment.
RV afterload was monitored through MPAP, PVRI and ESVI. A significant decrease
(p<0.01 at all levels of insufflation) was observed in MPAP during nitric oxide treatment
(see Figure 8). PVRI, on the other hand did not exhibit any significant changes during the
nitric oxide-insufflation (see Figure 10). This is likely due to the progressive deterioration
(p<0.05 at all levels) in cardiac index (PVRI = [MPAP-PCWP]x80/CI). ESVI remained
stable throughout the drug treatment.
53
The parameters characterizing LV afterload (SVRI, MAP) were in partial discord, as
MAP tended to decrease, especially at the higher levels (p<0.01 at 15 ppm), while SVRI
increased steadily (p<0.01 at 15 ppm) (see Figures 7 and 9).
The hemodynamic parameters characterizing inotropy (CI, SI, LVSWI, RVSWI)
displayed a progressive deterioration during the nitric oxide treatment (see Figures 6 and
8). This was statistically significant at all levels of the insufflation (p<0.05).
A slight rise in heart rate was observable during the drug inhalation (p<0.05 at 15 ppm)
(see Figure 7).
The final bolus fluid-loading dose effected an improvement in both right heart and
global cardiac performance (see Figure 7)
54
PVRI (%-change)
120
Drug administration
begins here
130
Controls
Losartan
Nitric Oxide
110
Aminophylline
100
Adenosine
90
80
0.0
0.0
0.5
1.0
1.5
2.0
Time (h)
130
Nitric Oxide
Losartan
110
100
90
80
70
Controls
Drug administration
begins here
SVRI (%-change)
120
Aminophylline
Adenosine
0.0
0.0
0.5
1.0
1.5
2.0
Time (h)
Fig.7. Percentual changes in cardiac index and rate heart in the drug and control
groups during the study period.
55
MAP (%-change)
110
Drug administration
begins here
120
Losartan
100
Controls
90
Aminophylline
Nitric Oxide
80
Adenosine
0.0
0.0
0.5
1.0
1.5
2.0
Time (h)
MPAP (%-change)
110
Drug administration
begins here
120
Controls
Losartan
Adenosine
Aminophylline
100
Nitric Oxide
90
80
0.0
0.0
0.5
1.0
1.5
2.0
Time (h)
Fig.8. Percentual changes in mean arterial pressure and mean pulmonary artery
pressure in the drug and control groups during the study period.
56
120
Losartan
Adenosine
100
90
80
Controls
Drug administration
begins here
SI (%-change)
110
Aminophylline
70
Nitric Oxide
0.0
0.0
0.5
1.0
1.5
2.0
Time (h)
LVSWI (%-change)
120
110
Drug administration
begins here
130
Losartan
100
Controls
90
Aminophylline
80
Adenosine
70
Nitric Oxide
60
0.0
0.0
0.5
1.0
1.5
2.0
Time (h)
Fig.9. Percentual changes in stroke volume and left ventricular stroke work indices in
the drug and control groups during the study period.
57
PVRI (%-change)
120
Drug administration
begins here
130
Controls
Losartan
Nitric Oxide
110
Aminophylline
100
Adenosine
90
80
0.0
0.0
0.5
1.0
1.5
2.0
Time (h)
130
Nitric Oxide
Losartan
110
100
90
80
70
Controls
Drug administration
begins here
SVRI (%-change)
120
Aminophylline
Adenosine
0.0
0.0
0.5
1.0
1.5
2.0
Time (h)
Fig.10. Percentual changes in pulmonary vascular resistance and systemic vascular
resistance indices in the drug and control groups during the study period.
58
Table 6. The qualitative effects of the drugs under study on different hemodynamic
parameters.
Aminophylline
Losartan
Adenosine
Nitric oxide
Loading
CI
↑ (50 mg)
↑
↑
↓ (10 ppm)
↑
CVP
↓ (200 mg)
↓
↔
↓ (15 ppm)
↑
EDVI
↓ (200 mg)
↔
↓ (75 µg/kg/min)
↓ (10 ppm)
↑
ESVI
↓ (200 mg)
↔
↔
↔
↑
HR
↑ (100 mg)
↔
↔
↑ (15 ppm)
↔
↑
↓ (75 µg/kg/min)
↓ (10 ppm)
↑
LVSWI ↓ (100 mg)
MAP
↓ (100 mg)
↔
↓ (75 µg/kg/min)
↓ (15 ppm)
↑
MPAP
↔
↔
↔
↓ (5 ppm)
↑
PCWP
↔
↓
↔
↓ (15 ppm)
↑
PVRI
↓ (200 mg)
↔
↓ (50 µg/kg/min)
↔
↓
↔
↔
↓ (5 ppm)
↑
RVSWI ↔
SI
↓ (50 mg)
↑
↑ (75 µg/kg/min)
↓ (15 ppm)
↑
SVRI
↓ (100 mg)
↔
↓ (50 µg/kg/min)
↑ (20 ppm)
↓
Minimal drug dosage at which the effect was statistically significant are given in
parentheses. See original articles I-IV. ↑ = increase, ↓ = decrease, ↔ = no change.
6 Discussion
6.1 Aminophylline
Several earlier studies in humans have indicated that aminophylline used intravenously or
theophylline orally will improve hemodynamics in right heart failure (Matthay & Mahler
1986, Falicov et al. 1973, Rutherford et al. 1981, Conradson 1984). Improvement in both
global myocardial performance (Matthay & Mahler 1986, Falicov et al. 1973, Parker et al.
1966, Rutherford et al. 1981, Matthay 1985) and right heart performance have been
demonstrated with the use of intravenous aminophylline (Matthay et al. 1978, Bisgard &
Will 1977). It is likely that the improvement observed in these earlier studies were to some
extent reliant on an improvement in left ventricle function, which will have subsequently
helped unload the right ventricle and thereby improved right ventricle performance.
Theophylline has been shown to improve hemodynamics to some extent through an
augmentation of myocardial contractility as well as through its effect on afterload via
broncho- and vasodilatation (Matthay 1987). The present study was therefore designed to
examine the effects of aminophylline on left and right heart separately. The results
demonstrated a decrease in overall cardiac performance induced by aminophylline, which
was seen as reductions in ventricular stroke work and stroke volume, and an increase in
heart rate. These can best be explained as reflecting a reduction in left-side preload through
pulmonary vasodilatation.
An important factor confounding an analysis of hemodynamic data in studies on right
heart failure is that the failure itself is often secondary to a concomitant respiratory disease
(COPD, ARDS, ARF) (Matthay 1985). The drop observed in PVR in these studies may
therefore be more a result of vasodilatation secondary to bronchodilation.
The results from some earlier studies on the use of aminophylline have demonstrated
either a decrease in PVR (Murphy et al. 1968, Bisgard & Will 1977) or no change (Rall &
West 1963, DiBianco et al. 1980, Harasawa & Rodbard 1961) in studies involving
pulmonary hypertension and/or chronic right heart failure. Matthay et al (1982) showed
that orally ingested theophylline moderately improved both right and left ventricle
performance in COPD patients. These changes were similar after long-term treatment
60
(Matthay 1987). More recent reports from studies performed in lambs (Schreiber et al.
1992, Konduri et al. 1992), however, suggest that aminophylline is a poor pulmonary
vasodilating agent and that it inhibits the pulmonary vasodilator effect of endogenous
adenosine. The present study employed animals with an otherwise healthy vasculature, in
which the wall of the pulmonary arteries contain very little muscle (Ganong 1993).
Some earlier studies have mirrored the findings from the present report that
hemodynamic changes only become apparent when using larger doses of aminophylline
(Mols et al. 1993). The results demonstrated an only modest decrease in pulmonary
vascular resistance and a similar increase in cardiac output at a 200 mg dose. These
changes were reflected in the systemic circulation as a decrease in systemic vascular
resistance. The effect of the previously healthy pulmonary vasculature on the response to
aminophylline can only be speculated on.
An interesting observation made in this study was how short-lived the effect of even a
relatively high bolus dose of aminophylline was. All improvements observed in
hemodynamic parameters were visible ten minutes after the dose, but – for the most part –
had reverted by 30 minutes from the dose. Heart rate remained elevated, however, through
to the end of the experiment. DiBianco (1980) made similar observations in his study
comparing aminophylline to sodium nitroprusside, showing that hemodynamic changes
had reverted within 60 minutes of cessation of its infusion.
The more recent studies of the drug have concentrated on its global hemodynamic
effects, not on specific models of right heart failure of infarct, nor has the examination of
the results been weighted towards right heart function. Brown and coworkers (1991)
examined the relative effects of noradrenaline, theophylline and dibutyryl cAMP on
isolated rat atria and ventricle tissue. Their findings indicated that, while each of the
substances had a similar chronotropic effect on the tissue, noradrenaline’s inotropic effect
was significantly more pronounced than that for theophylline or dibutyryl cAMP.
6.2 Adenosine
Due to adenosine’s extremely short half-life (approximately 10 seconds), the drug must be
infused centrally to obtain the desired effect on the pulmonary vasculature. By titrating the
infusion rate, its vasodilative effects can be localized in the pulmonary circulation without
concurrent systemic changes (Haywood et al. 1992, Morgan et al. 1991, Utterback et al.
1994). In these studies, the decrease in PVRI has been thought to be due to unloading of
the right heart, which has consequently lead to an increase in cardiac output. In Utterback’s
study (1994), however, the increase in cardiac output only occurred after a corresponding
decrease in mean arterial pressure. The maximum infusion rate without decreases in
systemic vascular resistance or blood pressure (i.e. a high transpulmonary extraction rate)
has been reported in the literature as varying between 30 (Morgan et al. 1991, Utterback et
al. 1994) and 100 µg/kg/min (Haywood et al. 1992). In the present study, a significant
decrease was observed in SVRI in all animals when the infusion rate was increased to 75
61
µg/kg/min (see figure in Results). Similar variations were observed in the reduction in
MAP, but not in the improvement in intropy.
Haywood’s results (1992) showed no change in pulmonary arterial pressure, but a
significant increase in wedge pressure and cardiac index, which in turn lead to the observed
decrease in PVR. No unloading of the right ventricle was observed in that study, as judged
by the figures given for right side preload. Interestingly, no change was observed in SVR
in that study, even at an infusion rate of 100 µg/kg/min adenosine. Fullerton, however,
demonstrated a distinct decrease in MPAP (right heart afterload) without a concomitant
decrease in MAP (systemic afterload) (Fullerton et al. 1996). This was accompanied by a
significant increase in cardiac output. In the present study, infusion rates above 50
µg/kg/min caused systemic vasodilation, which were apparent as decreases in MAP,
LVSWI and SVRI.
Adenosine has been shown to improve hemodynamics in other ways than through
decreasing afterload by vasodilation. According to Berne’s “adenosine hypothesis” (1963),
endogenous adenosine regulates coronary vasodilation in reduced myocardial oxygen
supply, increasing coronary flow. Although several other mediators of coronary flow have
been suggested (e.g. nitric oxide, bradykinin, endothelin), adenosine appears to be an
important factor in this respect (Mubagwa et al. 1996). Adenosine also exerts negative
chronotropic and dromotropic effects (Pelleg & Belardinelli 1993), which was apparent in
this study subsequent to the discontinuation of the infusion when a significant increase in
HR was observed.
Adkins and associates (1993) demonstrated in an isolated canine lung model that the
PVRI-attenuating effect of adenosine appears to be associated with the A2 receptors, which
is the main type of adenosine receptors in the pulmonary circulation (McIntyre et al. 1997).
Extrapolating these results to intact models or clinical situations is problematic, however,
as the isolated-lung model does not take into account the other hemodynamic effects
associated with adenosine. These may include improved pump performance (Öwall et al.
1991, Fullerton et al. 1996, Öwall et al. 1988, Reid et al. 1990), and the systemic
vasodilation observed at higher infusion rates, as observed in the present study.
6.3 Losartan
Despite the fact that the vasodilative effect of losartan is well documented (Smits et al.
1993, Duan et al. 1995), no changes were observed in our study in systemic or pulmonary
pressure or in systemic vascular resistance. Compensation must have taken place to
counteract the vasodilation in the form of an increase in cardiac output. In agreement with
this, Capasso and associates showed an improvement in inotropy (dP/dt) in animals treated
with losartan, but not in those treated with captopril or in the controls in their study on the
effects of losartan and captopril after left ventricle infarction in rats (Capasso et al. 1994).
In addition, while captopril caused a significant reduction in afterload, this was not
observed with losartan, which is also in agreement with our findings. Those authors
hypothesized that the improvement in inotropy might have been partially brought about by
62
a prevention of angiotensin II’s indirect negative inotropic effect on the heart (Capasso et
al. 1994), though the decrease in afterload will undoubtedly have also contributed to the
improvement in pump performance.
Smits and coworkers (1992) showed no improvement in cardiac output in their
experimental study of losartan in rats with myocardial infarct, although myocardial
remodelling was somewhat attenuated by the drug. Several other experimental studies have
also examined the effect of angiotensin II inhibition in different models of heart failure
(Richard et al. 1993, Nunez et al. 1997, Irlbeck et al. 1997, Stebbins & Symons 1995) and
found no improvement in myocardial contractility or cardiac output. These latter studies
examined non-infarct models, however, in which the circulating levels of angiotensin II
can be expected to differ from those in an infarct study model. Other studies have shown
varying degrees of improvement in cardiac output during losartan treatment (Fitzpatrick et
al. 1992, Dickstein et al. 1994, Crozier et al. 1995). In some of these (Dickstein et al.
1994, Crozier et al. 1995), however, a dose-dependent decrease in left heart afterload was
also observed, which was not observed in the present study. Dickstein (1994) concluded
that losartan should be of benefit to patients suffering congestive heart failure. The results
from the present study are in good agreement with Dickstein’s and Crozier’s studies with
respect to the maintenance of heart rate and left ventricle afterload as well as the increase
in cardiac output.
An interesting observation in this study was that while the increase in cardiac
performance was relatively short-lived (approximately 30 minutes), the decrease in right
heart preload (CVP) persisted for the entire 60 minute follow-up. It might be conjectured
that the higher levels of losartan circulating immediately after its injection caused a total
inhibition of angiotensin II action, thereby improving inotropy and inducing vasodilation.
As the level of circulating losartan decreased, it may be that - while there was not sufficient
angiotensin II inhibition to maintain the improvement in inotropy - perhaps that required to
cause vasodilation is sufficiently less for the effect to still be observable. In a recent study
(Lankford et al. 1997) examining the pharmacokinetics of losartan in pigs, it was
demonstrated that EXP3174, losartan’s most active metabolite in humans, was formed
from less than 2% of the losartan dose administered intravenously. In addition, while in
humans EXP3174 has a half-life three times that of losartan (2.1 vs. 6.3 hours), in swine
the two have a half-life roughly equal to each other, and are otherwise much shorter than in
humans (approximately 40-50 minutes). The consequence of this is that losartan has a
relatively short-lived effect in the pig, whereas in humans it is substantially longer.
One of the arguments for the use of a specific AT1-inhibitor is that even when adequate
ACE-inhibition is attained, circulating levels of angiotensin II are still found in some
patients, which may even attain pre-ACEI levels (Willenheimer et al. 1999). This
phenomenon has raised speculation of other enzymes capable of converting angiotensin I
to angiotensin II and human heart chymase has been suggested to be potentially important
in this respect (Urata et al. 1993). Another reason may be that tissue ACE may not be
effectively inhibited (Willenheimer et al. 1999). On the other hand, the use of AT1 receptor
blockers may be less efficient than ACE-inhibition due to not inhibiting the breakdown of
bradykinin with its inherent benefits to the cardiovascular system (Willenheimer et al.
1999). Some evidence exists, however, which indicates that bradykinin may cause an
increased release of noradrenaline from sympathetic nerves in the ischemic myocardium, in
63
which case increases in bradykinin levels would be deleterious (Seyedi et al. 1997). In
contrast to the above studies, Stauss and coworkers (1994) have presented evidence
supporting the use of ACE-inhibitors after infarct in their study on rats. They administered
an ACE-inhibitor or losartan to rats before and after experimental infarct and found a
decrease in infarct size, a prevention of any increase in cardiac weight and a decrease in
end-diastolic pressure in ACEI-treated rats compared to the losartan group. A similar study
by Hartman and coworkers (1993) came to the same conclusions.
6.4 Nitric oxide
In other studies examine the effects of nitric oxide on pulmonary vascular resistance
Semigran and associates (1994) compared the inhalation of nitric oxide via a positive
expiratory end-pressure (PEEP) mask at 20, 40 and 80 ppm to the use of iv nitroprusside in
patients with NYHA III-IV (left-)heart failure symptoms awaiting consideration for heart
transplant. They showed that nitric oxide significantly reduced PVR at 80 ppm, this change
exceeding that obtained using nitroprusside at the maximum tolerated dose. They also
observed that the reduction in PVR was specific to the pulmonary circulation (i.e. no
concomitant reduction in left heart function), which was not the case for nitroprusside.
They concluded that it offers a viable alternative as a specific pulmonary vasodilator. At
present, however, significantly smaller doses of nitric oxide are in use in clinical practice,
with 20 ppm being generally recognized as the maximum used for patients with pulmonary
distress such as ARDS. One of the basic precepts of our protocol was that we wished to
only examine the hemodynamic effects of nitric oxide at clinically relevant doses. In their
recent study, Matsumoto et al (1997) came to similar conclusions using exercise capacity
during nitric oxide inhalation in patients with chronic heart failure. The doses used in that
study were 0, 10, 20 and 40 ppm.
Our results demonstrated a reduction in mean pulmonary pressure somewhat similar to
Semigran’s and Matsumoto’s, but with the important difference that this was accompanied
by a concomitant decrease in cardiac index. This change was even more pronounced than
that observed in the animals in the control group (see Figure 7). Unfortunately, the findings
from these two groups cannot be directly compared due to differences in the anesthesia
techniques used for the nitric oxide-treated animals and for all others in this study.
In a report by Bocchi et al (1994), the authors found that nitric oxide caused pulmonary
edema in cases of severe heart failure, possibly associated with an increase in pulmonary
capillary wedge pressure during nitric oxide-inhalation. They suggest that nitric oxide will
not cause any improvement in cardiac index, but may improve pulmonary ventilation and
hemodynamics. Other studies have also raised concern as to whether nitric oxide might
have a negative inotropic effect (Kelm et al. 1997), but Goldstein and associates (1997)
concluded that the drug does not impair ventricular contractility. Their study protocol
involved thrombaxane-induced pulmonary hypertension, however, and it might be argued
that any conclusions drawn from observations of the combined effects of these two
vasoactive neurohumoral drugs will be complicated at best. The results from the present
64
study tend to support a depressive effect for nitric oxide, especially with regards cardiac
index and the pulmonary circulation (MPAP).
6.5 Methodological aspects
In the study under review, the following points concerning methodological questions
should be considered.
6.5.1 Animals
The animals chosen for the study were young pigs (3-4 months old), of mixed sex and
breed. They were raised on a nearby farm for the purpose of meat production and the only
criteria for inclusion in this study was that they be of apparent good health and that they
weigh between 25 and 30 kilograms for the sake of conformity. The rationale behind
choosing the pig as a study animal is that - due to its many inherent physiological
similarities with man - this animal has been used with increasing frequency over the past
years in many fields of experimental medicine. The use of this animal therefore eases both
the comparison of results with other studies and the extrapolation of the data obtained to
clinical practice.
A species-specific drawback associated with the use of the pig was the very short
metabolism of losartan compared to that seen in humans. This is partially due to a shorter
half-life in pigs of losartan itself and partially due to the non-formation of EXP3174,
losartan’s active metabolite in humans (Lankford et al. 1997). The effect of an intravenous
bolus dose of losartan shown in our previous pilot study to completely block angiotensin II
activity therefore wore off within 30 to 45 minutes. A dose of similar effect in humans (50
mg orally) will be effective at least 8 hours (Lo et al. 1995).
Apart from these drawbacks, the pig proved to be a highly suitable animal for this study.
There is a high degree of similarity between the anatomy and physiology of the pig and
human cardiovascular systems. In addition, the animal is readily available, relatively
inexpensive to procure, and due to its large size can be monitored in a manner similar to
that used in the clinical monitoring of human subjects.
6.5.2 Anesthesia
The balanced anesthesia used in the present series of studies was that generally acceptable
in clinical practice. The use of intravenous bolus doses of a barbiturate (tiopentothal) will
cause some attenuation in cardiac performance (Rosenberg et al. 1995), but this will have
corrected itself by the start of the study - the first pre-sternotomy hemodynamic
65
measurements generally being performed one hour or more after the induction of
anesthesia. Care was taking in choosing the pre-induction drugs (ketalamine, midazolam
and atropine) that they would cause as little attenuation of hemodynamics as possible. The
use of enflurane is also associated with minimal changes in hemodynamics, although other
inhalational agents (e.g. sevoflurane) might have had less effect in this respect (Yamada et
al. 1994).
A different mode of anesthesia was necessary in the nitric oxide study, as the respiratory
device used in that study (the Dräger Evita-4˙ respirator device [Drägerwerk AG, Lübeck,
Germany]) did not allow the use of an inhaled anesthetic. This in turn rendered a
comparison between this group and the control group inexact and such a comparison was
therefore abandoned in that part of the study.
6.5.3 Choice of right heart infarct model
The purpose of this study was to examine the effects of various drugs on hemodynamics
during right heart failure. The choice of right heart infarct was made as this provided an
acute model of right heart failure in which the hemodynamic effects of the treatment
regimes could be examined in its very early stages. This in turn addresses a distinct clinical
subset of patients suffering from acute heart failure after right heart infarct, as opposed to
those with valvular or pulmonary disease, in whom the disease and symptoms will have
gradually developed over an extended period of time. This distinction is important when
considering the clinical implications of the results of this study, as the etiology and
morphology of acute and chronic heart failure differ from each other in important ways.
Perhaps the most important of these with regards overall hemodynamics are the changes in
the right heart and pulmonary blood vessels associated with heart failure. These include a
thickening of the right heart myocardium and an enlargement of the right ventricle. The
walls of the pulmonary arteries will thicken and become more muscular over time, until
they eventually resemble the systemic arteries. This allows for a higher degree of effect by
medication on both the right ventricle and the pulmonary vessels, resulting in, for example,
a more effective vasodilatation and unloading of the right heart by vasodilators and a
greater degree of inotropy by beta-adrenergic agents. While there are some reports
supporting the use of nitric oxide in cases without significant pulmonary hypertension (De
Backer et al. 1996), other studies suggest that pulmonary circulation will only benefit from
nitric oxide if a previous pathology exists (Snow et al. 1994, Rich et al. 1994, Bigatello et
al. 1994, Loh et al. 1994, Wilson et al. 1997). Our results show a decrease in mean
pulmonary arterial pressure and would thus appear to support this latter thesis.
In this model of acute right heart failure after right heart infarct, the animals included in
the final analysis were uniformly healthy prior to the study with normal right ventricles and
minimal vascular resistance in the pulmonary system. It must be assumed, that the drugs in
this study would likely have had more effect on the right heart and on the pulmonary
vasculature if the animals had had a larger muscle mass on which the drug to take effect.
66
Future studies might therefore be targeted to examine the effects of these treatment regimes
in a chronic model of right heart failure.
6.5.4 The open chest model
All animals in this study underwent sternotomy and pericardiotomy prior to induction of
right heart infarct. The chest and pericardium was subsequently left open, although the
sternum was covered with saline-solution-soaked cloths to prevent volume loss through
evaporation. It is important to recognize, however, that this model therefore avoids the
constricting effect normally exerted by the pericardium and the chest wall. In a clinical
situation, as right heart failure develops and the right ventricle expands, the pericardium
will cause growth restriction with signs of tamponade and a shifting of the septal wall over
to the left side, with a consequential deterioration in left ventricle performance (Romand et
al. 1995). In this experimental model, any expansion in the right ventricle would be
unimpeded and symptoms of tamponade and attenuation in left ventricle performance
would not appear. It is unlikely, on the other hand, that any such significant expansion in
ventricle size would have appeared in such a short period, but this mechanism should be
kept in mind when analyzing this data for any possible clinical extrapolations. The model
itself approximates the situation in which right heart failure occurs after open-heart surgery
when coming off perfusion.
6.6 An overview of the results obtained in the present study
The main criteria used for the choice of drugs used in the present study were their
pharmacological action with respect to vasodilation, inotropy, chronotropy and half-life.
The drug should improve right heart function through an increase in inotropy and a
decrease in pulmonary vascular resistance, but should not increase heart rate by any
significant degree. In addition, the drug should have a relatively short half-life to render it
pulmonary-specific, as vasodilation in the systemic circulation will lead to a decrease in
right heart preload, with its attendant attenuation of cardiac performance, as well as a
decrease in peripheral perfusion. Using these criteria as a measure, the following
conclusions can be drawn regarding the effectiveness of the drugs under study.
6.6.1 Inotropy
Of the four drugs examined, only aminophylline has been shown to exert any direct
inotropic effect (Hillis & Been 1982, Crea et al. 1994), while adenosine has been shown to
have a negative inotropic effect (Wang & Belardinelli 1994, Belardinelli et al. 1989). Of
67
the other two drugs under study, nitric oxide should have no effect on myocardial
contractility, while reports on the inotropic effects of losartan are somewhat conflicting.
Inhibition of angiotensin II should reduce myocardial contractility, and some studies have
reported results to this effect (Milavetz et al. 1996, Sladek et al. 1996). Capasso, on the
other hand (1994) reported that losartan improves myocardial contractility.
Inotropy (dP/dt) was not directly measured in the present study, but ventricular stroke
work indices will closely approximate this measurement (Nelson & Rutherford 1993).
Only losartan (III) could be shown to significantly and specifically improve ventricle
stroke work in this study (see Figure 9), the other drugs having no effect (I, II) or an
attenuating effect (IV) on LVSWI.
6.6.2 Vasodilation
All of the drugs examined in the present study have been shown to exert some degree of
vasodilation in previous studies (Matthay 1987, Steudel et al. 1999, Dickstein et al. 1994,
Mosqueda-Garcia 1992). The desired effect in this examination was a reduction in
pulmonary vascular resistance without a significant drop in systemic vascular resistance.
Theoretically, therefore, the drug with the shortest half-life should be the most preferable
in this respect. Adenosine and nitric oxide best fit this description and the former did in
fact effectively attenuate pulmonary vascular resistance. At higher infusion rates, however,
adenosine also had a significant effect on systemic vascular resistance. Aminophylline (200
mg dose) also reduced pulmonary vascular resistance in this study, causing a slight drop in
systemic vascular resistance at the same dose.
6.6.3 Chronotropy
With the exception of aminophylline, none of the substances used in this study have been
shown to exert a direct enhancing effect on heart rate. The results support this, with a
significant increase in heart rate only observed in the aminophylline group after the 100 mg
bolus dose.
6.6.4 Cardiac output
Concentrating on any single hemodynamic parameter can be a major pitfall in any
examination of the effects of a drug on hemodynamics. The end-point of any analysis of a
drug should concentrate on the overall well-being of the subject rather than on isolated
parameters. To illustrate this, the effect of simple vasodilation can be considered. If
system-wide vasodilation occurs, pulmonary vascular resistance will decrease, which
68
might well be considered a desirable outcome in cases of right heart failure. At the same
time, however, the attenuation of systemic vascular resistance will result in a reduction of
right heart preload, which – according to the Frank-Starling principle – will result in a
consequent reduction in myocardial contractile force. This can easily result in an overall
deterioration of hemodynamics. Of the hemodynamic parameters followed in this study,
cardiac output is widely regarded as best reflecting overall cardiac performance. Apart
from myocardial contractility, preload, afterload and heart rate also greatly effect cardiac
output. It is therefore appropriate to include this parameter as an indicator of overall
improvement or deterioration in cardiovascular performance in this study. Adenosine
infusion improved cardiac index, especially at the higher infusion rates. This despite the
drop in systemic vascular resistance observed at these same doses. Aminophylline and
losartan also improved cardiac output somewhat (see Figure 7), while cardiac output
deteriorated in the nitric oxide-treated animals.
6.7 The ideal drug in the treatment of right heart failure (due to
myocardial infarct)
In their exhaustive review of therapeutics in heart failure, Bonarjee and Dickstein (1996)
concluded that optimal therapy will consist of a combination of several drugs. This is due
to the wide range of effects desirable in a drug used for the treatment of heart failure.
Doyle and associates summed up the characteristics desirable in such a drug (1995),
including in this list (1) inotropy without chronotropy, (2) vasodilation and (3) lusitropy.
Based on the findings of the present study, the following recommendations can be
made.
1. The ideal drug should increase myocardial contractility and reduce afterload without
any increase in energy expenditure. In addition, it should improve myocardial
oxygenation through an improvement in coronary blood flow. To this end the drug
should be both inotropic and (preferably) lusitropic, as well as being a vasodilator.
2. The ideal drug should not decrease preload, nor should it be chronotropic as - while an
increase in heart rate will initially result in an increase in cardiac output (stroke
volume x heart rate) - contractility and therefore stroke volume will begin to suffer as
the pulse increases to 140-150 beats per minute (Freeman et al. 1994).
Of the drugs examined in the present study, none of them meet the above requirements.
It might be concluded that adenosine comes close, being a short-lived vasodilator with
negative chronotropic and dromotropic properties, and having been demonstrated to
improve coronary blood flow. It does not, however, exert any direct inotropic effect.
The angiotensin II inhibitor losartan also provides an interesting alternative in the
treatment of right heart failure. This drug is a potent vasodilator and appears to improve
inotropy as well. Its effect is not pulmonary-specific, however, and it has a relatively long
effective half-life in humans, which complicates its use in a titrated manner on the ICU.
7 Summary and conclusions
In this study of previously healthy young swine with experimental right ventricle infarct,
the following conclusions can be drawn:
1.
2.
3.
4.
Aminophylline was demonstrated to cause an appreciable transitory decrease in
pulmonary vascular resistance, and a similar short-lived increase in cardiac index.
Coupled with an increase in heart rate, however, the overall effect was a decrease in
left-side preload and subsequently in cardiac performance. It is recommended that
aminophylline be used with caution for pulmonary vasodilation in patients suffering
right heart failure due to infarct and that left-heart preload be carefully optimized in
these subjects.
A continuous infusion of adenosine at various rates was shown to effectively decrease
both systemic and pulmonary afterload and thereby improve cardiac output after right
heart infarct. The effects on pulmonary pressure were observable, but not as marked.
Discontinuation of the infusion led to an increase in both systemic and pulmonary
resistances, as well as a decrease in cardiac index. The infusion of adenosine therefore
appears to cause an unloading of the right heart and an improvement in inotropy. The
vasodilative effect extended to the systemic vasculature at higher doses.
Losartan induced a significant improvement in cardiac performance with a concurrent
reduction in both right and left heart preload. Of equal importance, both systemic
pressures and heart rate were maintained. Due to the longer half-life of this drug in
humans, it may be an effective regime in the treatment of heart failure after right heart
infarct.
Nitric oxide appears to effectively unload the right heart, even in subjects with normal
pulmonary vasculature. It also effects a decrease in left-side preload, however, as well
as a deterioration in cardiac pump performance and systemic pressures. When using
nitric oxide in a clinical situation, special attention should be paid to its effects on left
heart preload and myocardial performance.
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