Download Low potential of dobutamine and dopexamine to block intestinal

Low potential of dobutamine and dopexamine to block intestinal
peristalsis as compared with other catecholamines
Sonja Fruhwald, MD; Stefan Scheidl; Wolfgang Toller, MD; Thomas Petnehazy; Peter Holzer, PhD;
Helfried Metzler, MD; Heinz F. Hammer, MD
Objective: Catecholamines are frequently used in critically ill
patients to restore stable hemodynamics and to improve organ
perfusion. One effect of short-term or long-term administration of
catecholamines may be inhibition of propulsive motility in the
intestine. We therefore analyzed the effect of dopexamine, dobutamine, and dopamine on ileal peristalsis and compared their
action with that of epinephrine and norepinephrine, which have
long been known to suppress intestinal peristalsis.
Design: In vitro study on excised guinea pig ileum segments.
Setting: Laboratory for experimental studies at the University.
Subjects: Isolated guinea pig ileum.
Interventions: Segments of ileum excised from guinea pigs
were mounted in a tissue bath in Krebs-Henseleit solution and
bubbled with 95% oxygen/5% CO2. Luminal perfusion with the
same solution was performed at a rate of 0.35 mL/min. The bath
temperature was kept at 36.5°C. Peristalsis was recorded via
changes in the intraluminal pressure. The drugs under investigation (dopamine, epinephrine, norepinephrine, dobutamine, and
dopexamine) were added to the tissue bath.
C
atecholamines are frequently
used in critically ill patients
with low cardiac output syndrome to improve global hemodynamics and/or regional perfusion.
Their effects on the human splanchnic
region may be divided into indirect effects, which result from beneficial or detrimental impact on splanchnic perfusion,
and direct effects on intestinal motility.
Experimental and clinical research on the
effect of catecholamines on the gastrointestinal tract currently focuses primarily
on their indirect effects because of
changes in cardiac output and splanchnic
perfusion (1–7). Despite the beneficial ef-
From the Departments of Anesthesiology and Intensive Care (Drs. Fruhwald, Toller, Metzler), Internal
Medicine (Dr. Hammer, Mr. Scheidl, Mr. Petnehazy),
and the Institute of Pharmacology (Dr. Holzer), University of Graz, Graz, Austria.
Address requests for reprints to: Heinz F. Hammer,
MD, Associate Professor of Medicine, Medizinische
Universitaetsklinik, Auenbruggerplatz 15, A-8036 Graz,
Austria. E-mail: [email protected]
Copyright © 2000 by Lippincott Williams & Wilkins
Crit Care Med 2000 Vol. 28, No. 8
Measurements and Main Results: Low concentrations of each
catecholamine, except epinephrine, caused a decrease in the
pressure threshold, which reflects a stimulatory effect on peristalsis. Higher catecholamine concentrations caused a concentration-related increase in the threshold, cumulating in a complete block of peristalsis. The rank order of inhibitory potency was
epinephrine > norepinephrine > dopamine > dobutamine ⬃
dopexamine. Dobutamine and dopexamine were about 500-fold
less active than epinephrine in suppressing peristalsis.
Conclusions: This study shows that dobutamine and dopexamine have the least potential to block propulsive motility in the
intestine, whereas epinephrine demonstrates the most adverse
inhibitory effect. Because at low concentrations dobutamine and
dopexamine even stimulate peristalsis, these drugs appear to be
superior compared with other catecholamines with regard to their
direct effects on intestinal motility. (Crit Care Med 2000; 28:
2893–2897)
KEY WORDS: guinea pig; ileum; threshold; peristalsis; dopamine;
epinephrine; norepinephrine; dobutamine; dopexamine; motility
fects of catecholamines on cardiac output
and overall splanchnic circulation, catecholamines do not necessarily improve
blood flow to the gastrointestinal mucosa. Dopamine, for instance, increases
splanchnic perfusion but causes a redistribution of blood flow from the mucosa
to the muscularis, which may lead to
mucosal dysfunction, promote bacterial
translocation, and eventually give rise to
multiple organ failure (8, 9).
A well-established action of the older
catecholamines epinephrine and norepinephrine on the gut, which may limit
their therapeutic usefulness, is the inhibition of propulsive intestinal motility
(10 –13). This effect is primarily a result
of inhibition of acetylcholine release from
enteric neurons (11, 13, 14). New catecholamines, such as dobutamine and
dopexamine, have been introduced into
clinical routine. They are used alone or in
combination with traditional catecholamines with the aim of improving
regional hemodynamic effects (1, 6). It is
not known whether these catecholamines
also inhibit peristalsis and, if so, how the
potency of such effects compares with
that of epinephrine and norepinephrine.
We therefore set out to compare the
actions of catecholamines currently in
clinical use on peristalsis in the isolated
guinea pig ileum. The experimental
model, which uses a fluid-perfused segment of ileum, allows a quantitative assessment of direct drug effects on peristalsis independent of circulatory
changes (15, 16). To allow comparison of
the potency of five catecholamines (epinephrine, norepinephrine, dopamine, dobutamine, and dopexamine), concentration response curves were constructed for
each drug.
MATERIALS AND METHODS
Animals and Assay Arrangement. Guinea
pigs were obtained from the Central Research
Institute for Laboratory Animal Breeding, University of Vienna, Austria. The guinea pigs
were fasted overnight with free access to water. The animals were killed by decapitation
and the ileum was excised. Before the guinea
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Table 1. Composition of the Krebs-Henseleit solution
Substance
Concentration
(mM)
NaCl
KCl
CaCl2
MgSO4
NaHCO3
KH2PO4
Glucose
119
4.75
2.5
1.5
25
1.2
11
pigs were killed, all procedures for care were
executed in accordance with national and international guidelines for the care and use of
laboratory animals.
After cleaning, the ileum was first equilibrated in Krebs-Henseleit solution (Table 1)
and bubbled with 95% oxygen/5% CO2 for ⬃1
hr. In a second step, segments of ileum with a
length of 6 cm were taken and mounted in a
small volume (22 mL) tissue bath (Mayflower,
Hugo Sachs Electronics, Freiburg, Germany)
in Krebs-Henseleit solution, which was bubbled with 95% oxygen/5% CO2. The temperature of the tissue bath was kept at 36.5°C,
whereas the pH of the Krebs-Henseleit solution was kept between 7.35–7.45.
Peristaltic contractions of the mounted ileum segment were elicited by luminal perfusion with Krebs-Henseleit solution at a rate of
0.35 mL/min using a REGLO-Digital MS-4/6 –
100 roller pump (Ismatec, Germany) against
an aboral pressure of 5 cm H2O. The peristaltic
nature of the contractions was confirmed visually. Peristaltic contractions resulted in
complete emptying of the segment. In total,
70% to 80% of the ileum segments developed
repetitive peristaltic contractions and could be
used for our experiments. Segments that did
not show regular contractions were discarded.
After a 15-min control period, the test drug
was added to the organ bath and a 15-min test
period was recorded. For each test drug and
test concentration, a new segment was used.
Test Drugs. The drugs used in the study
were dobutamine (Dobutrex, Eli Lilly, Indianapolis, IN), dopamine (Dopamin, Fresenius,
Austria), dopexamine (Dopacard, Fisons plc,
Pharmaceutical Division, UK), epinephrine
(Suprarenin, Hoechst, Austria), and norepinephrine (Arterenol, Hoechst, Austria). Each
test substance was first examined at a concentration of 1 nM. In the following experiments,
the concentration was increased to evaluate
the effect of different catecholamine concentrations on intestinal motility. The drugs were
administered into the bath to the serosal surface of the ileum, in volumes not exceeding
1% of the bath volume.
Data Recording. Intraluminal pressure was
measured at the oral end of the segment with
a very low range differential pressure transducer (Validyne DP 45-XX, Hugo Sachs Electronics) and an amplifier (2-channel bridge
2894
amplifier, type 301, Hugo Sachs Electronics).
Contractions were recorded with a Multi-Pen
Recorder (R-OX, Hugo Sachs Electronics).
The pressure curves of the mounted ileum
segments were characterized by a slow initial
rise of pressure to a threshold at which a
peristaltic contraction was triggered (Fig. 1A).
Then the cycle started anew. An increase in
the threshold represents an inhibitory effect,
whereas a decrease in the threshold reflects a
stimulant action on peristalsis.
Data Analysis. Each segment served as its
own control. Paired Student’s t-test was used
for statistical analysis. A p of ⬍ .05 was considered to be significant. The recordings were
analyzed for a shift in the pressure threshold
required for triggering a contraction. The effects of different catecholamine concentrations on peristaltic frequency were analyzed by
measuring the distance between two consecutive contractions.
RESULTS
We tested five different catecholamines in at least six different concentrations. Analysis of the concentration response curves for pressure threshold
showed significant qualitative and quantitative differences in the action of the
different catecholamines on peristalsis.
As shown in Figure 2, all catecholamines
had a concentration-related increase in
pressure thresholds, cumulating in a
complete block of peristaltic activity. Epinephrine was the most effective inhibitor
of peristalsis; significantly lower concentrations increased the pressure threshold
as compared with the other catecholamines. Dopexamine and dobutamine were the least potent inhibitors;
higher concentrations were necessary to
show an effect on the pressure threshold.
The highest concentrations of each catecholamine used in the study resulted in a
block of peristalsis. The concentration
that led to this block of peristalsis was
significantly lower for epinephrine and
norepinephrine as compared with the
other catecholamines (Fig. 2). Figure 2
also shows that all substances, except epinephrine, caused a small, but significant,
reduction in the pressure threshold in
their lower concentration ranges.
Effects of Different Catecholamines.
Table 2 summarizes concentrations of
maximum threshold reduction, halfmaximum catecholamine concentrations
and maximal inhibitory concentrations
(block of peristalsis).
Epinephrine. Concentrations ⬍5 nM
did not change the peristaltic activity of
the ileum segment. Higher concentrations of epinephrine resulted in a concen-
tration-dependent rise of the pressure
threshold (Fig. 1B). At 100 nM, peristalsis
was completely abolished (Fig. 1C). Epinephrine was the only catecholamine
that did not decrease the threshold at
lower concentrations (Fig. 2).
At lower epinephrine concentrations,
the frequency of peristaltic contractions
increased (Fig. 1A), whereas at higher
concentrations peristaltic frequency was
reduced (Fig. 1B).
Norepinephrine. Concentrations ⬍5
nM did not alter peristaltic motility. Concentrations between 5 and 25 nM led to a
significant reduction of the threshold
with a maximal effect at 10 nM. Higher
concentrations resulted in an increase in
the threshold and a complete blockade of
peristalsis at 1 ␮M. The frequency of peristaltic contractions was reduced at all
concentrations tested.
Dopamine. There was no effect on
peristalsis with dopamine concentrations
⬍75 nM. A concentration of 100 nM led
to a significant reduction of the threshold. Concentrations up to 5 ␮M resulted
in a small increase of the threshold,
whereas higher concentrations led to a
pronounced increase in the threshold,
which resulted in a complete block of
peristalsis at 50 ␮M. The frequency of
peristaltic contractions increased at dopamine concentrations between 10 and
25 nM. Higher concentrations of the drug
reduced peristaltic frequency.
Dobutamine. Dobutamine added to
the tissue bath at concentrations ⬍1 ␮M
did not influence peristaltic motility (Fig.
3A). Concentrations between 1 and 10
␮M caused a significant reduction of the
threshold. At bath concentrations of 15 to
25 ␮M, the drug caused a moderate concentration-related increase in the threshold. A concentration of 30 ␮M dobutamine led to a marked rise in the
threshold, and at 50 ␮M, a complete
block of peristalsis was seen (Fig. 3B, C).
The peristaltic frequency was reduced by
dobutamine at all concentrations tested.
Dopexamine. Dopexamine concentrations up to 1 ␮M did not alter peristaltic
motility. Concentrations between 1 ␮M
and 20 ␮M lowered the peristaltic pressure threshold. At 30 ␮M, no change in
the threshold was found, whereas higher
concentrations of the drug caused a
marked increase in the threshold, and 50
␮M dopexamine completely suppressed
peristalsis. All concentrations caused an
initial increase in the peristaltic frequency, whereas after a few minutes a
decrease of frequency was found.
Crit Care Med 2000 Vol. 28, No. 8
Figure 2. Concentration response curves of the effect of different catecholamines on the pressure
threshold of peristalsis. The effect of catecholamines on threshold is shown as the difference between
thresholds before and after administration of the test substance (⌬threshold). Mean ⫾ SEM from six
experiments performed at each concentration. Positive ⌬ threshold values represent inhibition of
peristalsis and negative values represent stimulation of peristalsis. *significant values as compared
with baseline.
Table 2. Relevant catecholamine concentrations
Figure 1. Effects of epinephrine on peristalsis in
guinea pig ileum. The figures show original pressure recordings before and after administration
(s) of epinephrine. Note the pressure threshold
(T) at which peristaltic contractions were elicited. At 25 nM, the peristaltic frequency was increased. At 50 nM, the threshold increased markedly and the frequency decreased. At 100 nM,
peristalsis was completely blocked, an effect that
was irreversible during the test period (15 mins).
DISCUSSION
Our results demonstrate that catecholamines that are currently used in
critically ill patients because of their cardiovascular effects differ markedly in
their inhibitory and stimulatory actions
on the peristaltic motility of guinea pig
ileum in vitro. Dobutamine and dopexamine are ⬃500 times less potent in inhibiting peristalsis than epinephrine,
which was the most active compound
among the catecholamines tested. The
rank order of inhibitory potency was as
follows: epinephrine ⬎ norepinephrine ⬎
dopamine ⬎ dobutamine ⬃ dopexamine.
The relative potency of epinephrine
and norepinephrine corresponds with the
potency reported by Mc Dougal and West
(10). To our knowledge, the effects of the
Crit Care Med 2000 Vol. 28, No. 8
Catecholamine
Maximum
Threshold
Reduction
Half-Maximum
Catecholamine
Concentration
Block of
Peristalsis
0.01
0.1
10
20
0.065
0.250
25
39
40
0.1
1
50
50
50
Epinephrine
Norepinephrine
Dopamine
Dobutamine
Dopexamine
All concentrations given in ␮M.
other catecholamines on peristaltic motility have not been tested. The low inhibitory potency of dobutamine (␤1-adrenoceptor agonist) and dopexamine (␤2adrenoceptor agonist and dopamine
receptor agonist) is, however, consistent
with the finding that ␣-adrenoceptor agonists are more active in inhibiting acetylcholine release from enteric neurons and
suppressing peristalsis than ␤-adrenoceptor agonists (13, 17, 18).
Other differences among the catecholamines concern the observation that
all substances, except epinephrine, decreased the peristaltic pressure threshold
at low subinhibitory concentrations,
which means that they facilitated peristalsis at this concentration range. The
relevance of this finding to propulsive
motility in vivo remains to be determined.
Another difference relates to the
steepness of the concentration-response
curves for peristaltic inhibition. The
curves for norepinephrine and dopamine
were flatter than those for the other
tested substances, which is likely to reflect the involvement of different receptors and/or mechanisms.
There were also differences in the catecholamine-induced changes of peristaltic frequency. Epinephrine, dopamine,
and dopexamine increased the frequency,
at least at subinhibitory concentrations.
The increase in pressure thresholds at
higher catecholamine concentrations was
associated with a reduction of frequency.
This was not evaluated further because
peristaltic frequency in vitro is a complex
variable dependent on infusion rate, intestinal compliance, peristaltic pressure
threshold, and the efficiency of emptying.
2895
D
obutamine and
dopexamine have
the least potential
to block peristalsis; at low
concentrations they even
stimulate peristalsis. These
drugs appear to be superior to
other catecholamines with regard to their adverse effects
on intestinal motility.
Figure 3. Effect of dobutamine on peristalsis in
guinea pig isolated ileum. The figures show original pressure recordings before and after administration (s) of dobutamine. Note the pressure
threshold (T). At 100 nM, there is no influence on
peristaltic contractions. A concentration of 30
␮M of dobutamine led to a marked increase in
pressure thresholds, whereas at 50 ␮M, peristalsis is completely blocked.
2896
Interpretation of frequency changes is
therefore controversial (19). Furthermore, in contrast to changes in thresholds, which were constant during the
whole observation period for each of the
catecholamine concentrations tested, influences on peristaltic frequency were not
constant.
The opposite effects of low and high
concentrations of four of the five tested
catecholamines on motility are most
likely attributable to stimulation of different receptors. Stimulation of different
receptors at different catecholamine dosages has been demonstrated for the effect
of dopamine on blood vessels. Low-dose
dopamine (ⱕ3 ␮g/kg/min) has a vasodilatory effect because of a stimulation of
dopaminergic receptors. Doses ⬎5 ␮g/
kg/min cause a stimulation of ␣-receptors and a vasoconstriction. In the
present study, we have also observed
dose-dependent switches of direct catecholamine effects. Except in the case of
epinephrine, lower concentrations
caused a reduction of the pressure
threshold, and therefore a stimulation of
intestinal contractility.
The present observations concerning
the peristaltic pressure threshold indicate
that dobutamine and dopexamine have
the least potential to block propulsive
motility in the gut. This low potency in
suppressing intestinal propulsion favors
the use of dobutamine and dopexamine in
critically ill patients, although this recommendation is only based on their effects on intestinal motility and does not
take their effects on gut perfusion into
account. Milder disturbances of intestinal
motility are frequently seen in the intensive care setting. Serious abdominal complications are known to occur in 1.4% of
patients after cardiac surgery and have a
total mortality of 14.5% (20). Risk factors
for severe abdominal complications in
cardiac surgery include advanced age,
prolonged aortic cross-clamping time,
low cardiac output, and multiple organ
failure.
In experimental studies of pharmacologic effects on intestinal motility, addition of a pharmacologic substance to the
organ bath rather than through the mesenteric vessels is commonly performed.
Our data suggest that neither the timing
nor quantitative aspects of the actions of
catecholamines on the ileum are influenced by a possible diffusion barrier. As
shown in Figures 1 and 3, the catecholamines had an immediate effect on
peristaltic activity, which suggests that
the time that is needed for diffusion of
the catecholamine to their receptors was
not a limiting factor of our preparation.
In addition, as shown in the Figures 1
and 3, the catecholamine effect did not
increase during the observation time,
which suggests that there was no diffusion barrier which would have been overcome with time and which might possibly
have influenced the quantitative aspect of
the catecholamines.
Although caution must be observed
when our data from the guinea pig are
applied to intensive care patients, some
comparisons may shed light on potential
clinical implications. Arterial plasma
concentrations reach 23.9 nM in healthy
volunteers after infusion of epinephrine
at a rate of 0.2 ␮g䡠kg⫺1䡠min⫺1 (21). In
guinea pig ileum, comparable concentrations of epinephrine resulted in a stimulation of peristaltic frequency (Fig. 1A).
There was no marked effect on the
threshold of peristalsis at this concentration, but because the concentrationresponse curve of epinephrine is very
steep, only slightly higher concentrations
already cause a considerable inhibition of
peristaltic contractility of the guinea pig
ileum (Fig. 2). Infusion of norepinephrine in humans at a rate of 0.2 ␮g䡠kg⫺1䡠
min⫺1 resulted in arterial plasma concentrations up to 44.1 nM (21). In the
guinea pig ileum, comparable concentrations caused a marginal increase of the
threshold. Because the concentration response curve of the effects of norepinephrine on motility is flatter, the margin of
safety for the therapeutic use of norepinephrine may be bigger as compared with
epinephrine.
Plasma concentrations of dobutamine
at an infusion rate of 10 ␮g䡠kg⫺1䡠min⫺1
reach about 0.6 ␮M, and plasma concentrations of dopexamine at an infusion rate
of 4 ␮g䡠kg⫺1䡠min⫺1 reach 0.4 ␮M (22,
23). As can be seen in Figure 2 these
concentrations have no effect on intestinal motility. Higher concentrations
would stimulate motility, before at even
higher concentrations inhibition of motility would occur. From the point of ileal
motility, our data therefore support the
suggestion of Meier-Hellmann et al. (4)
and Levy et al. (1) that a combination of
norepinephrine and dobutamine may be
preferable over an epinephrine monotherapy. This combination of drugs has
also recently been suggested to be used in
septic patients, by the Task Force of the
American College of Critical Care Medicine (24).
Crit Care Med 2000 Vol. 28, No. 8
In conclusion, our in vitro study compared the different effects of clinically
used catecholamines on intestinal motility. We demonstrated that these catecholamines differed profoundly in their
action on intestinal motility. Of the
tested substances, dobutamine and
dopexamine have the least potential to
block peristalsis; at low concentrations
they even stimulate peristalsis. These
drugs appear to be superior to other catecholamines with regard to their adverse
effects on intestinal motility.
7.
8.
9.
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