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Effects of acute intravenous iloprost on right ventricular hemodynamics in rats with
chronic pulmonary hypertension
Author(s): Nabil S. Zeineh, Timothy N. Bachman, Hazim El-Haddad and Hunter C. Champion
Source: Pulmonary Circulation, (-Not available-), p. 000
Published by: The University of Chicago Press on behalf of Pulmonary Vascular Research Institute
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ORIGINAL RESEARCH
Effects of acute intravenous iloprost on right ventricular
hemodynamics in rats with chronic pulmonary hypertension
Nabil S. Zeineh,1 Timothy N. Bachman,1 Hazim El-Haddad,2 Hunter C. Champion1
1
Vascular Medicine Institute, Pulmonary Allergy and Critical Care Medicine, Cardiovascular Institute, University of Pittsburgh
Medical Center, Pittsburgh, Pennsylvania, USA; 2Department of Internal Medicine, Wake Forest University Medical Center,
Winston-Salem, North Carolina, USA
Abstract: The inotropic effects of prostacyclins in chronic pulmonary arterial hypertension (PAH) are unclear and may be important in directing patient management in the acute setting. We sought to study the
effects of an acute intravenous (IV) infusion of iloprost on right ventricular (RV) contractility in a rat model
of chronic PAH. Rats were treated with monocrotaline, 60 mg/kg intraperitoneally, to induce PAH. Six weeks
later, baseline hemodynamic assessment was performed with pressure-volume and Doppler flow measurements. In one group of animals, measurements were repeated 10–15 minutes after IV infusion of a fixed dose
of iloprost (20 μg/kg). A separate group of rats underwent dose-response assessment. RV contractility and
RV–pulmonary artery coupling were assessed by the end-systolic pressure-volume relationship (ESPVR) and
end-systolic elastance/effective arterial elastance (Ees/Ea). RV cardiomyocytes were isolated, and intracellular
cAMP (cyclic adenosine monophosphate) concentration was measured with a cAMP-specific enzyme immunoassay kit. Animals had evidence of PAH and RV hypertrophy. Right ventricle/(left ventricle þ septum)
weight was 0.40 0.03. RV systolic pressure (RVSP) was 39.83 1.62 mmHg. Administration of iloprost
demonstrated an increase in the slope of the ESPVR from 0.29 0.02 to 0.42 0.05 (P < .05). Ees/Ea
increased from 0.63 0.07 to 0.82 0.06 (P < .05). The RV contractility index (max dP/dt normalized
for instantaneous pressure) increased from 94.11 to 114.5/s (P < .05), as did the RV ejection fraction, from
48.0% to 52.5% (P < .05). This study suggests a positive inotropic effect of iloprost on a rat model of chronic
PAH.
Keywords: prostacyclin, contractility, right ventricle.
Pulm Circ 2014;4(4):000-000. DOI: 10.1086/677358.
I NT RO D UCT I ON
Pulmonary hypertension is a syndrome of increased pulmonary vascular resistance (PVR) that ultimately leads to
right ventricular (RV) failure.1-3 The treatment of patients
presenting with acute worsening of RV function in the context of chronic pulmonary arterial hypertension (PAH) is a
poorly tackled clinical issue and involves management of
preload, afterload, and coronary perfusion pressure and often involves addition of positive inotropes.4,5 For enhancing
RV myocardial contractility, dobutamine or dopamine6 has
been traditionally favored over milrinone because of the latter’s smaller impact on systemic vascular resistance.7 Inhaled nitric oxide8,9 and traditional vasodilator therapies
such as prostacyclins10 and intravenous phosphodiesterase-
5 inhibitors have been evaluated11 in their ability to reduce
pulmonary artery (PA) pressure and vascular resistance.
It has been shown that prostacyclin analogs (iloprost,
epoprostenol) improve ventriculoarterial coupling in animal models of acute rise in RV afterload.12,13 There have
been some conflicting reports regarding the inotropic effect of these agents on the right and left ventricles (RV
and LV, respectively), both in controls and in animal models of acute RV failure but not chronic RV failure. The
effect of intravenous prostacyclin administration on RV
contractility has not been studied in models of chronic pulmonary hypertension. We therefore sought to study the
effects of an acute intravenous infusion of a prostacyclin
Address correspondence to Dr. Hunter C. Champion. E-mail: [email protected].
Submitted January 14, 2014; Accepted February 18, 2014; Electronically published October 29, 2014.
© 2014 by the Pulmonary Vascular Research Institute. All rights reserved. 2045-8932/2014/0404-00XX$15.00.
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| Iloprost and RV contractility
Zeineh et al.
analog on RV contractility in a frequently used model of
chronic pulmonary hypertension.
METHODS
All experiments were approved by the University of Pittsburgh Institutional Animal Care and Use Committee. Ten
Sprague-Dawley rats weighing 250–350 g were treated
with monocrotaline (MCT) 60 mg/kg intraperitoneally
(IP). Six weeks later, they were brought to the animal physiology laboratory for hemodynamic assessment and iloprost infusion. Central venous access was obtained via
internal jugular venous cannulation using sterile PE-50
tubing. To obtain in vivo hemodynamic measurements,
rats were anesthetized with an IP injection of ketamine
(100 mg/kg) and acepromazine (5 mg/kg). The rats were
then ventilated by the insertion of a tracheal cannula attached to a rodent ventilator (Harvard Apparatus, South
Natick, MA) set to 90 breaths/min, with a tidal volume of
8 mL/kg body weight. The chest was opened with a midline
incision, and then a 4-electrode pressure-volume catheter
(Scisence, London, Ontario, Canada) was placed through
the RV apex to record chamber volume by admittance and
pressure micromanometry, as described previously.14,15
Data were acquired with IOX 2.0 (EMKA, Falls Church,
VA). Direct Doppler velocities of the pulmonary arterial
flow were obtained with a 20-MHz ultrasound probe (Indus
Instruments, Houston, TX). A silk tie was loosely placed
around the inferior vena cava (IVC), and a transient decrease in preload was achieved by a gentle constriction
of the tie. PA flow velocities and stroke distance were
obtained. A family of pressure-volume loops can thus be
generated that allows evaluation of the slope of the RV endsystolic pressure-volume relationship (ESPVR). In addition,
single-beat estimates of pulmonary arterial elastance (Ea)
and end-systolic elastance (Ees) allow for measurement of
ventricular-arterial coupling (Ees/Ea).16,17
After baseline hemodynamics had been obtained, iloprost (10 μg/mL) was infused to a total dose of 20 μg/kg
body weight over 5 minutes. Hemodynamic measurements
were repeated 10–15 minutes after completion of the infusion.
In a separate group of rats similarly treated with MCT
for 6 weeks (n ¼ 3), a dose-response relationship to intravenous iloprost was evaluated. The rats were first given a
volume of drug-free vehicle as control, followed by iloprost 10 μg/kg, and this was followed by a second bolus
of iloprost 10 μg/kg. Hemodynamic measurements were
obtained with a pressure-volume catheter at baseline and
10–15 minutes after each infusion (4 acquisitions in total
per animal).
Isolation of rat RV cardiomyocytes
Fifteen Sprague-Dawley rats (250–300 g) were treated
with MCT 60 mg/kg IP. Six weeks later, the animals underwent deep anesthesia with ketamine 150 mg/kg IP, a
thoracotomy was performed, and the hearts were rapidly
excised. Cardiomyocytes were isolated via enzymatic dissociation, as previously described.18,19 In brief, hearts were
retrogradely perfused with a buffer solution in a Langendorff apparatus at 37°C via the aorta, followed by enzymatic dissociation. RV free walls were carefully separated
from the LV and septum before mechanical dissociation.
RV cardiomyocytes were then plated in culture dishes
containing antibiotic-free bicarbonate-buffered medium
(Gibco, Gaithersurg, MD; pH 7.40 in 5% CO2–95% air at
37°C) for 24 hours.
Measurement of intracellular cyclic guanosine
monophosphate content
Cell-containing culture plates were exposed for 30 minutes
to control medium (n ¼ 3), [iloprost-1] (10 μg/mL; n ¼ 4),
[iloprost-2] (20 μg/mL; n ¼ 4), and [iloprost-3] (30 μg/mL;
n ¼ 4) at 37°C. RV cardiomyocytes were then centrifuged
at 100 g for 10 minutes at 4°C; the pellets were resuspended in 250 μL lysis reagent and shaken for 10 minutes
at room temperature. After centrifugation at 1,000 g for
3 minutes at 4°C to remove the debris, part of the cell
lysate was used to determine protein concentration via
the Bradford method (Bio-Rad, Hercules, CA), with bovine
serum album as the standard. The rest of cell lysate was
used for the adenosine monophosphate concentration measurement with a cyclic adenosine monophosphate (cAMP)
enzyme-immunoassay (EIA) kit (GE Health Care–Amersham,
Piscataway, NJ), according to manufacturer’s instructions.
Intracellular cAMP concentration was expressed in optical
density (OD)−1/μg protein.
Data and statistical analysis
All values are reported as means SEM. Paired and unpaired analyses were performed with Student’s t test. Oneway ANOVA was used for multiple group comparisons in
the group of animals that underwent control drug-free infusion and dose-response assessment, as well as for comparing intracellular cAMP concentrations. All statistical
analysis was performed with Prism (ver. 5.04; GraphPad
Software, La Jolla, CA).
RES ULTS
MCT-induced changes
Six weeks after MCT injection, pulmonary hypertension
was confirmed: the RV systolic pressure (RVSP) was 39.83
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Pulmonary Circulation
1.62 mmHg, which was significantly higher than that
for controls (18.67 1.202 mmHg, n ¼ 3). Cardiac output
was 47.3 1.60 mL/min. The Fulton index, the ratio of
the RV weight to that of the (LV þ septum), is a measure
of RV hypertrophy and was measured in 9 animals. It was
0.40 0.03, the normal range being 0.2–0.25.
Influence of intravenous iloprost on RV function
under conditions of chronic PAH
Results from single-dose iloprost infusion are summarized in Table 1. Ten to 15 minutes after completion of
iloprost infusion, there was a non–statistically significant
increase in cardiac output, from 47.3 to 51.1 mL/min
(P ¼ .07), and the heart rate remained unchanged. There
was a nonsignificant decrease in peak RVSP, from 42.3 1.62 to 39.2 1.19 mmHg. Several measures of RV systolic function were significantly improved. The RV con-
Table 1. Parameters of global cardiovascular function after
single-dose iloprost infusion (20 μg/kg)
Parameter
Heart rate, bpm
RVSP, mmHg
RV contractility index,
1/sb
Cardiac output, μL/min
Stroke volume, μL
RVEDV, μL
Ejection fraction, %
ESPVR slope, mmHg/mL
Ees, mmHg/mL
Ea, mmHg/mL
Ees/Ea
ESPVR slope/ Ea
PVR, Wood units
PA flow mean velocity,
cm/s
Stroke distance, cm
Baseline
After infusiona
325 11
42.30 1.47
94.11 11.23
332 10
39.20 1.19
114.5 12.06*
47,341 1,596
146.0 3.5
318.0 21.0
47.98 3.73
0.292 0.017
0.205 0.012
0.330 0.019
0.633 0.067
0.897 0.090
0.502 0.025
13.91 4.229
51,129 2,395
153.8 5.2
298.1 20.4*
52.53 2.88*
0.424 0.026*
0.209 0.011
0.256 0.018*
0.827 0.064*
1.682 0.152*
0.337 0.027*
16.15 6.167
2.763 0.795
3.173 1.166
Note: Data are reported as means SEM. N ¼ 4 –10 rats.
Ea: arterial elastance; Ees: end-systolic elastance; ESPVR: endsystolic pressure-volume relationship; PA: pulmonary artery; PVR:
pulmonary vascular resistance; RV: right ventricular; RVEDV:
right ventricular end-diastolic volume; RVSP: right ventricular systolic pressure.
a
10 –15 minutes after infusion of 20 μg/kg iloprost.
b
Maximum dP/dt normalized for instantaneous pressure.
* P < .05.
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tractility index (max dP/dt normalized for instantaneous
pressure) increased from 94.11/s to 114.5/s (P < .05), as
did the RV ejection fraction, from 48.0% to 52.5% (P < .05).
The true measure of ventricular contractility is made
with the ESPVR, in which the slope of the ESPVR is measured during a reduction in ventricular preload. To achieve
this, we obtained pressure-volume data during a transient
IVC occlusion before and after iloprost administration.
Administration of iloprost demonstrated a significant increase in the slope of the ESPVR, from 0.29 0.02 to
0.42 0.05 (P < .05), in addition to concomitant increases
in ventricular-arterial coupling (using either single-beatderived Ees or the ESPVR slope), Ees/Ea, from 0.63 0.07
to 0.82 0.06 (P < .05), and in ESPVR slope/Ea, from
0.897 0.090 to 1.682 0.152 (P < .05). Moreover, PVR
decreased from 0.50 0.05 to 0.33 0.05 Wood units
(P < .05).
There was nonsignificant trend toward increased cardiac output in response to intravenous iloprost infusion,
as shown in Table 1. Direct cardiac output measurement,
from admittance-derived data, as well as Doppler derived
parameters (stroke distance, mean PA flow), were increased,
while there was no significant change in heart rate after
drug administration.
Results of control and dose-response data are summarized in Table 2. Infusion of drug-free vehicle did not
have any discernible effect on several indices of inotropy
and systolic function, as shown in Figure 1. A trend toward a dose-response relationship was observed with increasing doses of the study drug. The ESPVR slope
increased from 0.30 0.06 at baseline to 0.43 0.08 and
0.46 0.08 after infusion of iloprost at 10 and 20 μg/kg,
respectively. Similarly, the contractility index increased
from 154.0 13.53/s at baseline to 181.0 21.46 and
214.7 25.41/s on the same time line. Similar trends
were observed for heart rate response, stroke volume, and
cardiac output. There was a trend toward dose-response
increase in ESPVR slope/Ea, reflecting improvement in
ventricular-arterial coupling as well (Fig. 1d ).
Influence of Iloprost on cAMP levels
in isolated cardiac myocytes
After isolation of RV cardiomyocytes, the level of cAMP,
as measured by specific cAMP EIA, was 0.115 0.007
OD−1/μg protein. Iloprost induced a dose-dependent increase in cAMP in isolated RV cardiac myocytes. After
30 minutes of incubation in medium with a concentration of [iloprost-1], there was an approximately 25% increase in cAMP levels (0.145 0.019 OD−1/μg protein).
Similarly, levels of cAMP after incubation in medium with
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Table 2. Parameters of cardiovascular function after drug-free vehicle infusion and dose-response data
Parameter
Heart rate, bpm
RVSP, mmHg
RV contractility index, 1/sa
Cardiac output, μL/min
Stroke volume, μL
ESPVR slope, mmHg/mL
Ea, mmHg/mL
ESPVR slope/Ea
Baseline
Vehicle
Iloprost 10 μg/kg
Iloprost 20 μg/kg
262 18
33.33 3.33
154.0 13.5
42,965 5,770*
165.3 23.1
0.3 0.06
0.16 0.01
1.87 0.32
248 22
31.67 0.88
140.3 3.76
39,753 641*
162.7 11.1
0.28 0.07
0.18 0.02
1.58 0.42
313 17
35.33 2.19
181.0 21.5
69,195 10,573*
218.7 25.0
0.43 0.08
0.20 0.05
2.25 0.32
384 10
42 2.52
214.7 25.4
72,015 6,515*
187.0 13.1
0.46 0.08
0.18 0.04
2.63 0.39
Note: Data are reported as means SEM. N ¼ 3 rats. Ea: arterial elastance; ESPVR: end-systolic pressure-volume relationship;
RV: right ventricular; RVSP: right ventricular systolic pressure.
a
Maximum dP/dt normalized for instantaneous pressure.
* P < .05. by ANOVA.
Figure 1. In rats with chronic pulmonary arterial hypertension, the right ventricular end-systolic pressure-volume relationship
(ESPVR) slope, contractility index, and ESPVR slope/Ea showed a trend toward improvement after intravenous iloprost infusion.
Cardiac output was significantly improved. N ¼ 3 rats. Ea: arterial elastance.
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Pulmonary Circulation
Figure 2. Cyclic adenosine monophosphate (cAMP) levels in
isolated rats cardiomyocytes, measured by enzyme immunoassay (EIA). Dose-response relationship with increasing concentrations of iloprost (1–3) in the cell culture plates. OD: optical
density; 1: 10 μg/mL; 2: 20 μg/mL; 3: 30 μg/mL.
[iloprost-2] and [iloprost-3] were increased by 56% (0.179 0.015 OD−1/μg protein) and 107% (0.238 0.108 OD−1/μg
protein), respectively (Fig. 2).
D I S CU S S I O N
A number of studies have been published that tackled the
question of the direct inotropic effect of prostacyclins on
the myocardium.12,13,20-22 The importance of this issue is
due to the fact that prostacyclins are often used empirically in the acute setting of PAH decompensation, as well
as chronically 23,24 (with proven benefits on quality of life
and, sometimes, improved survival). It is unclear whether
inotropic effects play a role in the phenotypic responses
to treatment. The effects on contractility have been studied in various animal species, with different experimental
protocols. Older studies involving isolated atrial and ventricular cardiomyocytes have suggested a positive inotropic effect of prostacyclins, thought to be related to alterations in cAMP metabolism.25,26 In general, in vivo results
have been mixed. Studies involving dogs12 and pigs20,22
with acute pulmonary hypertension demonstrated a negative RV inotropic effect of prostacyclins, albeit with improvement in global hemodynamics. These favorable effects have
been ascribed to improved ventriculoarterial coupling as
well as to a known decrease in afterload. However, acute
infusion of prostacyclins in healthy pigs resulted in an
increase in left ventricular contractility.13 Similarly, results
from a study in 1998 among a cohort of patients with LV
failure and secondary pulmonary hypertension showed
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evidence of a positive LV inotropic effect during an infusion of epoprostenol.21
The conflicting nature of previously published results
seems to point toward a differential effect of prostacyclins
on inotropy, depending on the clinical scenario and disease conditions. To our knowledge, the effect of an acute
infusion of prostacyclin on an animal model of chronic
PAH with RV hypertrophy has not yet been reported.
This model is a closer analog of human PAH as encountered in clinical practice, since patients are typically diagnosed at a fairly advanced stage in the natural history
of their disease.27 In this study, we show that iloprost infused at a conventional dosing regimen of 20 μg/kg and a
low total infused volume (200–300 μL) improves RV hemodynamics, with evidence of a direct inotropic effect, in
addition to a drop in PVR. The ESPVR, as obtained from
a transient decrease in venous return, has been previously shown to be an index of contractility that is relatively independent from preload and afterload conditions.
In addition, other indices of contractility, such as ejection
fraction and the maximal change in pressure/change in
time (dP/dt max) normalized for instantaneous pressure,
show an increase after infusion of prostacyclin. Afterload
(PVR) decreased as well, a finding that correlates with the
known pharmacology of iloprost. Finally, we also show
that iloprost improves right ventriculoarterial coupling
(by measuring both Ees/Ea and ESPVR slope/Ea), most
likely reflecting the effect on the pulmonary vasculature
as well as on intrinsic ventricular contractility. In both
the systemic and the pulmonary arterial beds, ventriculoarterial coupling has been shown to reflect the system’s
efficiency,28,29 with higher ratios indicating improved bioenergetics. In other terms, an increase in afterload and
arterial system compliance (Ea) normally has to be met
by a concomitant increase in contractility (as estimated
by Ees and ESPVR slope), and vice versa. A decline in
RV–pulmonary arterial Ees/Ea has been shown to be an
indicator of developing RV failure and to portend a worse
prognosis in both animal models30 and in patients.31 In
addition to the inotropic responses observed in fixed-dose
experiments, there was a trend toward a dose-response
relationship when using subsequently higher doses of
iloprost.
On a molecular level, and using RV cardiomyocytes
from rats with chronic PAH, we have observed a dosedependent increase in intracellular cAMP concentration
after exposure to iloprost. The presence of prostacyclin
receptors in ventricular tissue has been shown in previous
studies,32 and cAMP is a known second messenger in
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| Iloprost and RV contractility
Zeineh et al.
the prostacyclin signaling pathway.32-35 Commonly used
positive inotropes, such as catecholamines, stimulate adenylate cyclase, production of cAMP, and increased contractility via Ca2þ-mediated facilitation in actin-myosin
complex binding with troponin C.36 We hypothesize that
the increase in cAMP in RV cardiomyocytes exposed to
iloprost might play a mechanistic role in the observed
increased inotropy in the model we used here. However,
further elucidating the molecular mechanisms underlying these observations is the subject of ongoing studies.
We think that our results do not contradict prior published works but rather complement the knowledge in
the field. The physiology of hypertrophied ventricles is
probably different from that of models in which acute
disease is induced or that when healthy control animals
are used. Our study model had evidence of RV hypertrophy, as demonstrated by a substantial increase in the Fulton index, and therefore in principle should have exhibited hemodynamic and morphologic changes similar to
those that occur in patients diagnosed with PAH. As
stated above, iloprost has been shown to have negative
effects on contractility in models of acute pulmonary hypertension, and the reasons underlying these different
responses are unclear at this time.
As with all studies, this study has some limitations. It
should be noted that we have not examined the effects of
iloprost on RV contractility in a model of acute decompensation in the setting of chronic PAH. Therefore, we
cannot infer that positive inotropy will occur in that setting, despite our findings here. Future studies will evaluate the effect of acute on chronic right heart failure in the
setting of pulmonary hypertension.
The practical clinical implications of these preliminary findings are not clear at this time, given the lack of
clinical end points assessed in our animal model (such as
mortality). Further studies will be needed to determine
the role of iloprost as adjunct inotropic support. Whether
the modest increase in various indices of myocardial contractility and systolic function may play a significant role
in the acute treatment of human PAH remains to be determined.
In conclusion, we report that in a model of chronic
PAH with RV hypertrophy, acute iloprost infusion exhibits positive inotropic effects. The evaluation of iloprost or
other prostacyclin analogs in the treatment algorithm of
acute PAH decompensation merits further study in the
clinical setting.
Source of Support: Nil.
Conflict of Interest: None declared.
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