(Hypertension. 1999;33:145-152.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Inotropic Effects of Endothelin-1
Interaction With Molsidomine and With BQ 610
From the Medizinische Klinik, Abt III, Eberhard-Karls-Universität, Tübingen, Germany.
Correspondence to Dr Martin E. Beyer, Medizinische Universitätsklinik, Abteilung III, Otfried-Müller-Str 10, 72076 Tübingen, Germany. E-mail martin-eberhard.beyer{at}dgn.de
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Abstract |
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Abstract—In vivo studies could not detect a positive inotropy of endothelin (ET)-1 as described in in vitro experiments. ET-induced direct positive inotropy, which seems to be mediated by ETB receptors, may be antagonized in vivo by an indirect cardiodepressive effect owing to an ET-induced coronary vasoconstriction via ETA receptors. This study compares the effects of a dose of 1 nmol/kg ET-1 alone on myocardial contractility and myocardial energy metabolism with the effects of 1 nmol/kg ET-1 after pretreatment with 5 mg/kg molsidomine or with 100 µg/kg of the ETA receptor antagonist BQ 610. We investigated the effects of ET-1 versus saline controls in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined by isovolumic registrations independent of peripheral vascular effects. We also studied the effect of ET-1 on myocardial high-energy phosphates. Pretreatment with molsidomine and BQ 610 attenuated the ET-induced reduction of cardiac output (ET-1: -62%; molsidomine+ET-1: -47%; BQ 610+ET-1: -27% different from controls). After a transient initial vasodilation, ET-1 raised total peripheral resistance (ET-1: +190%; molsidomine+ET-1: +171%; BQ 610+ET-1: +89%). BQ 610 was more effective in preventing ET-induced vasoconstriction. The increase of isovolumic peak first derivative of left ventricular pressure (ET-1: -2%; molsidomine+ET-1: +16%; BQ 610+ET-1: +19%) after pretreatment with molsidomine or BQ 610 indicates that these drugs unmask the positive inotropy of ET-1. ET-induced myocardial ischemia was abolished by molsidomine and BQ 610. Pretreatment with molsidomine or blockade of ETA receptors by BQ 610 can unmask the positive inotropy of ET-1 by preventing ET-induced myocardial ischemia. The positive inotropic effect of ET-1 seems to be mediated by ETB receptors.
Key Words: endothelin • BQ 610 • molsidomine • contractility • phosphates, high-energy • rats
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Introduction |
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The peptide endothelin (ET)-1 is the most potent vasoconstrictor known to date,1 and it is involved in the development of several diseases. Increased ET plasma concentrations have been reported in patients with angina,2 3 myocardial infarction,4 5 or heart failure.6 Drugs that antagonize or block the effects of ET-1 may consequently be of importance in the treatment of these diseases. Two different ET receptors have been characterized (the ETA7 and the ETB8 receptors), and many selective and nonselective ET receptor antagonists have been synthesized. Nevertheless, until now it has been unclear whether selective or nonselective ET receptor antagonists should be used in therapy.
In addition to its important vascular effects, several experiments with isolated cardiac tissues demonstrated a positive inotropic effect of ET-1.9 10 11 12 In isolated hearts13 14 and in in vivo studies,15 16 ET-1 showed a controversial effect on myocardial contractility. In a previous in vivo study with rats, we could not detect the described positive inotropy of ET-1.17 We supposed that the potent vasoconstrictive effect of ET-1 might cause myocardial ischemia with consecutive cardiodepression, thereby masking the described direct positive inotropic effect of ET-1 in vivo. Our hypothesis was confirmed by the fact that the combination of ET-1 with high doses of the potent vasodilator adenosine unmasked in the same animal model the positive inotropy of ET-1 in vivo.18 Activation of ETB receptors by the selective ETB agonist IRL 1620 also produced positive inotropy in our in vivo model.19
The present study examined the hemodynamic and inotropic effects of ET-1 under different conditions in the previously described open-chest animal model.17 18 19 In addition to measurements in the intact circulation, this model also permits isovolumic measurements to determine direct myocardial effects that are independent of peripheral vascular effects but dependent on myocardial perfusion. In the first part of the study we investigated whether a clinically used vasodilator could unmask the "beneficial" positive inotropic effect of ET-1. Therefore, the effect of ET-1 was studied after pretreatment with the nitric oxide (NO) donor molsidomine, which is used clinically for treatment of myocardial ischemia.20 The second part of the study examined the effect of ET-1 after selective blockade of the ETA receptors by the ETA receptor antagonist BQ 610.21 Additionally, the effect of ET-1 on coronary flow and on myocardial energy metabolism under different conditions was investigated by colored microsphere technique and by determination of the myocardial high-energy phosphates.
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Methods |
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Hemodynamic Measurements
Animal experiments for this study were performed according to national regulations on the use of laboratory animals. The protocol was approved by the local committee on ethics in animal research.
The study was performed on 4-month-old normotensive male Wistar rats
(n=123; weight, 350 to 450 g). The procedure of the experiments
has been described in detail previously.19 In addition to
hemodynamic measurements in the intact circulation,
isovolumic measurements were performed to determine isovolumic left
ventricular systolic pressure (peak LVSP) and peak
first derivative of left ventricular pressure
(dP/dtmax) (Figure 1
) as indices of myocardial
contractility independent of preload and afterload
conditions.19
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ET-1 (1 nmol/kg) (Sigma) was dissolved in a final volume of 1 mL 0.9% NaCl solution and was infused over a period of 7 minutes with a precision pump (Braun). According to a previous study that examined the dose-dependent effect of ET-1 over a wide range,17 the dose of ET-1 in the present study was selected from the middle of this range. Control groups received 1 mL 0.9% NaCl solution for a period of 7 minutes. Preinfusion control data of auxotonic and isovolumic measurements were obtained 3 minutes before infusions were started. Auxotonic measurements were recorded every minute until termination of infusion and 5, 10, and 15 minutes after infusion. At termination of infusion and 5 and 15 minutes after infusion, isovolumic measurements were performed.
Two groups received 1 nmol/kg ET-1 (n=12) or NaCl (n=10) without any pretreatment. Two other groups received pretreatment with molsidomine. Therefore, 5 mg/kg molsidomine (Hoechst) was dissolved in a final volume of 1 mL NaCl solution and was infused over a period of 7 minutes. The dose of molsidomine was selected according a previous in vivo study in rats.22 Ten minutes after termination of molsidomine infusion, preinfusion control data were recorded, and 3 minutes later the ET-1 (n=10) or NaCl infusions (n=11) were started. To test the effect of ET-1 on ETB receptors, 2 other groups (ET-1: n=10; NaCl: n=10) were pretreated with the selective ETA receptor antagonist BQ 610. A dose of 100 µg/kg BQ 610 (Phoenix Pharmaceuticals) dissolved in 4% dimethyl sulfoxide solution was infused during 7 minutes. The following procedure was the same as after pretreatment with molsidomine. To evaluate whether the ET effects after BQ 610 infusion are mediated by ETB receptors, in addition to ETA blockade by BQ 610, 5 animals underwent an ETB blockade by infusion of 0.5 µmol/kg IV of the selective ETB antagonist BQ 788 (Phoenix Pharmaceuticals) before ET-1 infusion was started.23
Coronary Flow
Coronary flow cannot be measured directly in the in vivo
model that we used. Thus, the effect of ET-1 (without or with
pretreatment with molsidomine or BQ 610) on myocardial perfusion was
determined in further experiments by a colored microsphere
technique.24 Coronary flow was determined before
and 5 minutes after termination of infusion by injecting approximately
400 000 red or yellow microspheres (Dye-Trak, Triton
Technology) dissolved in 0.05% Tween 80 into the left ventricle within
20 seconds. Reference blood samples (0.6 mL) were withdrawn from 10
seconds before until 30 seconds after microsphere injection via
a femoral catheter from the abdominal aorta. At the end of the
experiments, the hearts were removed. The tissue samples of the heart
were digested in 4 mol/L KOH containing 0.05% Tween 80 and the blood
samples in 16 mol/L KOH containing 0.05% Tween 80. To isolate the
microspheres, the digested tissue solution was filtered through
a 10-µm filter (Millipore), and the microspheres were washed
twice with 99.9% ethanol. To recover the dye from the
microspheres, the dried filter paper was immersed into 500 mL
dimethylformamide (Sigma). After 3 minutes of
centrifugation at 2400g, the photometric
absorption of each dye solution was determined by a diode-array
spectrophotometer (model 84528, Hewlett Packard).
Coronary flow was calculated according the formula
Coronary Flow=(Absorbance per Heart Sample)x(Blood Reference
Withdrawal Rate)/(Absorbance per Blood Reference Sample).
Myocardial High-Energy Phosphates
In addition to the hemodynamic measurements, the
effects of ET-1 on myocardial high-energy metabolism under
different conditions were studied. The animals of this examination
underwent the same procedure described for the
hemodynamic experiments.
Myocardial ATP, ADP, AMP, and creatine phosphate were determined by bioluminescence (for details, see Reference 18 ). The energy charge according to Atkinson25 was calculated as an index of myocardial energy metabolism, as follows: Energy Charge=[ATP+(ADP/2)]/(ATP+ADP+AMP).
Statistical Analysis
All data are expressed as mean±SEM. Hemodynamic
data were normalized to the individual preinfusion control data (100%
at the beginning of the ET or NaCl infusion). Statistical
analyses were performed at the end of infusion and 5 and 15
minutes after termination of infusion. We compared normalized data from
each of the 3 ET groups with the respective control group using a
2-tailed version of the Student's t test modified according
to the Bonferroni-Holm correction for multiple comparisons.
Additionally, the effect of ET-1 without pretreatment was compared with
the effect of ET-1 after pretreatment with molsidomine or with BQ 610
by ANOVA followed by Dunnett's test and the Bonferroni-Holm
correction. (No significant difference between the control group
without pretreatment and the control groups with pretreatment was
detectable with this test.) This test was also used to compare the data
of the coronary flow measurements, the high-energy phosphates,
and the isovolumic measurements of all ET groups with 1 control group.
P<0.05 was accepted as the level of significance.
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Results |
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Hemodynamic and Inotropic Effects of Molsidomine
Molsidomine caused a slight fall of blood pressure: mean aortic pressure was reduced
9.6% at the beginning of NaCl infusion and
11.2% at the beginning of ET-1 infusion. Heart rate and cardiac
output were not affected by molsidomine. Total peripheral
resistance was reduced by molsidomine (NaCl group, -7.5%; ET group,
-6.0%). The data of the isovolumic measurements were not changed by
molsidomine (peak LVSP: NaCl group, -3.4%, ET group, -2.6%; peak
dP/dtmax: NaCl group, -1.2%; ET group,
+0.5%).
Hemodynamic and Inotropic Effects of BQ
610
BQ 610 caused a slight decrease of blood pressure (mean aortic
pressure: NaCl group, -4.9%; ET group, -5.8%). Although heart rate
was not influenced by BQ 610, cardiac output was slightly increased
(NaCl group, +7.1%; ET group, +7.0%) associated with a reduction of
total peripheral resistance (NaCl group, -9.3%; ET group,
-2.6%) by BQ 610. The isovolumic maxima were not affected by BQ 610
(peak LVSP: NaCl group, -0.3%; ET group, 1.2%; peak
dP/dtmax: NaCl group, +5.8%; ET group,
+1.2%).
Hemodynamic Effects of ET-1
The hemodynamic and inotropic effects of
molsidomine and BQ 610 are excluded in the following section because
the data were normalized to the individual preinfusion control data at
the beginning of the ET or NaCl infusion (for absolute values, see
Table 1). At that time a steady state
after molsidomine or BQ 610 infusion was obtained.
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The results of the hemodynamic measurements in the
intact circulation are shown in Table 2.
ET-1 caused a transient decrease followed by a sustained increase of
LVSP. This biphasic blood pressure response was even more pronounced
for mean and diastolic aortic pressure, reflecting the
peripheral vascular effects of ET-1. Pretreatment with
molsidomine or BQ 610 had no effect on the ET-induced biphasic blood
pressure response. The ET-induced initial fall of blood pressure was
abolished after additional blockade of the ETB
receptors by BQ 788.
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A dose of ET-1 alone had no chronotropic effect. In the molsidomine and
the BQ 610 groups, ET-1 caused an increase of the heart rate of 10%
after termination of infusion. In both of these groups the positive
chronotropic effect of ET-1 was identical.
ET-1 caused a significant fall of stroke volume (5 minutes after infusion: 45.5±4.7% versus 102.8±3.4%; P<0.001). An identical effect was seen after pretreatment with molsidomine (5 minutes after infusion: 46.8±4.2% versus 98.4±2.2%; P<0.001). Blockade of the ETA receptors by BQ 610 prevented in part the ET-induced fall of stroke volume (5 minutes after infusion: 70.5±3.3% versus 101.8±2.4%; P<0.001).
Because of the effects on stroke volume and heart rate, ET-1 caused a
significant reduction of cardiac output (Figure 2A). Molsidomine influenced this effect
of ET-1 only to some degree (Figure 2B), whereas pretreatment
with BQ 610 reduced the ET-induced effect on cardiac output by 50%
(Figure 2C). Comparable effects can be shown for the ejection
fraction (Table 2
).
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P<0.001 compared with respective control group;
§P<0.05, ||P<0.01,
¶P<0.001 compared with ET group without
pretreatment.
After an initial vasodilation (maximum in the second minute of
infusion), ET-1 caused a tremendous increase of the calculated total
peripheral resistance (Figure 3A). Pretreatment with molsidomine had no
effect on the initial vasodilation, but the following increase of total
peripheral resistance was less pronounced (Figure 3B). Blockade of the ETA receptors by BQ
610 clearly diminished the ET-induced increase of total
peripheral resistance (Figure 3C). Additional
ETB blockade by BQ 788 completely prevented the
initial vasodilative effect of ET-1 (total peripheral
resistance in the second minute of ET infusion: 107.3±4.1%).
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Inotropic Effects of ET-1
The effect of ET-1 on the isovolumic peak
dP/dtmax as a function of left
ventricular end-diastolic volume 5 minutes
after termination of infusion is shown in Figure 4. Although a dose of ET-1 alone had no
effect on peak dP/dtmax (Figure 4A),
pretreatment with molsidomine (Figure 4B) or BQ 610 (Figure 4C) caused a significant increase of peak
dP/dtmax by ET-1. This effect was more pronounced
after blockade of the ETA receptors by BQ 610.
The preload values from which the isovolumic maximal beats were
obtained tended to a lower range. Peak LVSP also was significantly
increased by ET-1 after molsidomine or BQ 610 infusion (Figure 5, Table 2). The increase of both
indices of myocardial contractility reached a maximum 5
minutes after termination of ET infusion. Pretreatment with the
ETB antagonist BQ 788 in addition to
the ETA receptor blockade by BQ 610 significantly
attenuated the inotropic response to ET-1 (5 minutes after termination
of ET-infusion: peak LVSP, 101.1±4.1%, P<0.05 versus ET-1
after BQ 610; peak dP/dtmax, 91.4±6.7%,
P<0.01 versus ET-1 after BQ 610), and both indices of
myocardial contractility were no longer significantly
different from those of the control group.
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P<0.01,
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Myocardial High-Energy Phosphates
A dose of ET-1 alone caused a significant reduction of
myocardial ATP content (3.35±0.10 versus 4.44±0.23 µmol/g wet
weight; P<0.01) with an insignificant increase of
ADP and AMP levels. Myocardial creatine phosphate content was also
significantly reduced by ET-1 (4.66±0.27 versus 7.73±0.61
µmol/g wet weight; P<0.01). Pretreatment with molsidomine
tended to abolish the ET-induced effects on myocardial high-energy
phosphates. In comparison with the control group, the ADP and AMP
levels were still increased, but the ATP level (4.18±0.29
µmol/g wet weight) was no longer reduced significantly; creatine
phosphate levels did not differ from those of control (8.73±1.05
µmol/g wet weight). After blockade of the ETA
receptors by BQ 610, the effects of ET-1 on myocardial high-energy
phosphates were completely abolished (ATP, 4.51±0.19 µmol/g wet
weight; creatine phosphate, 7.60±0.62 µmol/g wet weight).
The calculated energy charge as an indicator of myocardial energy level
(Figure 5) shows that a dose of ET-1 alone caused a significant
decrease. This ET-induced decrease was antagonized in part by
molsidomine and was even completely abolished by blockade of the
ETA receptors by BQ 610.
Coronary Flow
Figure 5 shows the results of the coronary
perfusion measurements 5 minutes after termination of infusion. In
parallel to the changes of the energy charge, the coronary flow
was significantly reduced by a dose of ET-1 alone by 50%. The
ET-induced reduction of coronary perfusion was slightly reduced
after pretreatment with molsidomine and was even less pronounced after
ETA receptor blockade by BQ 610.
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Discussion |
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The effects of ET-1 on ventricular function have been controversial: in vitro experiments in animal9 11 12 and in human11 cardiac tissues showed a positive inotropic effect of ET-1, while experiments with isolated hearts or in vivo experiments could not detect such a positive inotropy13 14 or even described a cardiodepressive effect of ET-1.15 16 Our previous in vivo experiments on rats also could not detect an ET-induced effect on myocardial contractility.17 We supposed that the described direct positive inotropy of ET-1 was counterbalanced in our experiments by a cardiodepressive effect as a result of a coronary constrictive effect of ET-1 with consecutive myocardial ischemia. Indeed, the administered dose of ET-1 caused myocardial ischemia, and pretreatment with the vasodilator adenosine unmasked the positive ino- tropy of ET-1 by preventing myocardial ischemia.18 To unmask the positive inotropy of ET-1, rather high doses of adenosine were necessary, which themselves have impressive hemodynamic effects.
ET-1 acts via ETA and ETB receptors,7 8 26 and ET-induced vasoconstriction seems to be mediated mainly by ETA receptors.27 28 In additional experiments with the selective ETB agonist IRL 1620, we demonstrated that the ETB receptor might provide evidence for ET-induced positive inotropy.19 The present study examined whether the NO donor molsidomine, used clinically as a coronary dilating drug,20 might unmask the positive inotropy of ET-1 by attenuating ET-induced myocardial ischemia without affecting the hemodynamics as adenosine does. Furthermore, we tested how effectively selective blockade of ETA receptors by BQ 61021 is able to prevent ET-induced myocardial ischemia with subsequent depression of ventricular function.
In rats, ET-1 produces a biphasic blood pressure response, reflecting its vasoactive effects. ETB receptors on endothelial cells mediate ET-induced vasorelaxation by activating NO synthase to produce NO via increased endothelial [Ca2+]i.29 30 Our findings support the hypothesis that ET-induced vasorelaxation is mediated by ETB receptors because the initial fall of total peripheral resistance was still present after ETA receptor blockade by BQ 610 but was completely abolished after additional ETB receptor blockade by BQ 788. The vasorelaxatory effect of molsidomine was mediated by its active metabolite 3-morpholino-sydnonimine (SIN-1), which releases NO.31 The ET-induced initial vasodilation via endogenous NO was not abolished in our experiments after pretreatment with molsidomine. This is in accordance with a previous study in which the endothelium-dependent relaxation of human coronary arteries was not influenced by exposure to SIN-1.32 In contrast to minor effects of molsidomine on ET-induced increase of total peripheral resistance, the blockade of ETA receptors significantly reduced the vasoconstrictive effect of ET-1. It is known that ET-induced vasoconstriction in rats is mainly mediated by ETA receptors33 34 35 and that the blockade of ETA receptors reduces the vasoconstrictive effect of ET-1.27 35 36 In our experiments the vasoconstrictive effect of ET-1 was not completely prevented by BQ 610. This can be explained (in part or totally) by the fact that the activation of ETB receptors also causes vasoconstriction.26 28 37 38 Although our dosage of BQ 610 was high compared with other studies36 39 and the blocking effect of BQ 610 seems to be much more potent than that of the frequently used selective ETA antagonist BQ 123,36 we cannot exclude that there still were some ETA-mediated effects in our experiments after pretreatment with BQ 610.
While in vitro studies describe a positive chronotropic effect of ET-1,40 in vivo studies cannot demonstrate an ET-induced increase of heart rate.15 16 17 41 Mir et al42 suggest that a hypoxia-induced bradycardia antagonizes the direct positive chronotropic effect of ET-1. The positive chronotropic effect of ET-1 in our experiment after pretreatment with molsidomine or BQ 610 provides evidence for this hypothesis. The positive chronotropic effect of ET-1 after ETA receptor blockade clarifies that the ETB receptor is involved in the chronotropic effect of ET-1. This is in accordance with previous studies describing a positive chronotropic effect of ETB agonists.19 43
The reduction of cardiac output and ejection fraction by ET-1 was the consequence of an increased afterload because the cardiodepressive effects of ET-1 were not detectable in our experiments. Pretreatment with BQ 610 in particular diminished the ET-induced reduction of cardiac output.
ET-1 has a considerable effect on afterload. Thus, the measurement of myocardial contractility independent of changes in peripheral perfusion is important.44 45 The procedure of determining isovolumic measurements by cross-clamping the ascending aorta fulfills this criterion: the determined peak LVSP and the corresponding peak dP/dtmax are indices of myocardial contractility independent of peripheral vascular effects but dependent on coronary perfusion. Whereas the results of isovolumic measurements after a dose of ET-1 alone do not indicate a positive inotropic effect, pretreatment with molsidomine reveals the positive inotropic effect of ET-1. The same effect has been seen after pretreatment with adenosine18 : adenosine prevents ET-induced myocardial ischemia by vasodilating effects and consequently unmasks the direct positive inotropic effect of ET-1 in vivo. Although molsidomine (in contrast to adenosine) can antagonize the peripheral vascular effects of ET-1 only to some degree, the increase of the indices of myocardial contractility is significant. Additionally, the determination of coronary flow and of myocardial high-energy phosphates elucidates that molsidomine effectively prevents ET-induced myocardial ischemia. Molsidomine mainly dilates the coronary arteries32 46 and reduces the preload of the heart because of its venodilating effect.46 There is only a minor effect of molsidomine on peripheral resistance.46 In our experiments molsidomine prevented in part the vasoconstrictive effects of ET-1 on the coronary arteries. Pretreatment with BQ 610 also unmasked the positive inotropy of ET-1. The effects of ET-1 in combination with BQ 610 on total peripheral resistance, coronary flow, and myocardial high-energy phosphates show that the vasoconstrictive effects of ET-1 with consecutive myocardial ischemia are mainly mediated by ETA receptors. The positive inotropic effect of ET-1 was still present after administration of BQ 610 but was completely abolished after additional ETB blockade by BQ 788. In the same experimental model, an equipotent dose of the selective ETB agonist IRL 1620 caused a positive inotropic effect19 identical to that of ET-1 after pretreatment with BQ 610. The present results confirm our assumption that the positive inotropic effect of ET-1 is mediated in rats mainly (or totally) by ETB receptors. This is in accordance with other experimental studies that describe the significance of the ETB receptor for myocardial inotropy.47
In summary, our study verifies that the lack of positive inotropy of ET-1 in vivo is the result of ET-induced myocardial ischemia due to the coronary constrictive effect of the peptide with a resultant indirect cardiodepressive effect of ET-1. Whereas vasoconstriction is mainly mediated by ETA receptors, the direct positive inotropy of ET-1 is mediated by ETB receptors. The NO donor molsidomine reveals the positive inotropy of ET-1. This may be relevant in the future in terms of drug therapy. Molsidomine is used clinically to treat patients with angina pectoris.20 Increased ET levels can be detectable in these patients.2 3 On the other hand, these patients often suffer from heart failure, and they may profit from the ability of molsidomine to unmask the positive inotropic effect of endogenous ET-1. BQ 610 can also reveal the positive inotropy of ET-1. In the future, ET receptor antagonists may also be used for therapy. Further studies must examine whether selective ETA receptor antagonists or nonselective ET receptor antagonists should be used for therapy.
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Acknowledgments |
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This study was supported in part by a grant from the University of Tübingen (
Received July 31, 1998; first decision August 27, 1998; accepted September 16, 1998.
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References |
|---|
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent constrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411–415.[Medline] [Order article via Infotrieve]
2.
Toyo-oka T, Aizawa T, Suzuki N, Hirata Y, Miyauchi T,
Shin WS, Yanagisawa M, Masaki T, Sugimoto T. Increased plasma level of
endothelin-1 and coronary spasm induced in patients with
vasospastic angina pectoris. Circulation. 1991;83:476–483.
3. Qiu S, Theroux P, Marcil M, Solymoss BC. Plasma endothelin-1 levels in stable and unstable angina. Cardiology. 1993;82:12–19.[Medline] [Order article via Infotrieve]
4. Miyauchi T, Yanagisawa M, Tomizawa T, Sugishita Y, Suzuki N, Fujino M, Ajisaka R, Goto K, Masaki T. Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet. 1989;2:747. Letter.[Medline] [Order article via Infotrieve]
5. Stewart DJ, Kubac G, Costello KB, Cernacek P. Increased plasma endothelin-1 in the early hours of acute myocardial infarction. J Am Coll Cardiol. 1991;18:38–43.[Abstract]
6. Rodeheffer RJ, Lerman A, Heublein DM, Burnett JC. Increased plasma concentrations of endothelin in congestive heart failure in humans. Mayo Clin Proc. 1992;67:719–724.[Medline] [Order article via Infotrieve]
7. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990;348:730–732.[Medline] [Order article via Infotrieve]
8. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature. 1990;348:732–735.[Medline] [Order article via Infotrieve]
9. Hu JR, von Harsdorf R, Lang RE. Endothelin has potent inotropic effects in rat atria. Eur J Pharmacol. 1988;158:275–278.[Medline] [Order article via Infotrieve]
10.
Ishikawa T, Yanagisawa M, Kimura S, Goto K, Masaki T.
Positive inotropic action of novel vasoconstrictor peptide endothelin
on guinea pig atria. Am J Physiol. 1988;255:H970–H973.
11. Moravec CS, Reynolds EE, Stewart RW, Bond M. Endothelin is a positive inotropic agent in human and rat heart in vitro. Biochem Biophys Res Commun. 1989;159:14–18.[Medline] [Order article via Infotrieve]
12. Krämer BK, Smith TW, Kelly RA. Endothelin and increased contractility in adult rat ventricular myocytes: role of intracellular alkalosis induced by activation of the protein kinase C–dependent Na+-H+ exchanger. Circ Res. 1991;86:269–279.
13.
Karwatowska-Prokopczuk E, Wennmalm Å. Effects of
endothelin on coronary flow, mechanical performance,
oxygen uptake, and formation of purines and on outflow of prostacyclin
in the isolated rabbit heart. Circ Res. 1990;66:46–54.
14. Neubauer S, Ertl G, Haas U, Pulzer F, Kochsiek K. Effects of endothelin-1 in isolated perfused rat heart. J Cardiovasc Pharmacol. 1990;16:1–8.[Medline] [Order article via Infotrieve]
15. Domenech R, Macho P, González R, Huidobro-Toro JP. Effect of endothelin on total and regional coronary resistance and on myocardial contractility. Eur J Pharmacol. 1991;192:409–416.[Medline] [Order article via Infotrieve]
16. Yang X-P, Madeddu P, Micheletti R, English E, Rossi R, Giacalone G, Benatti P, Bianchi G. Effects of intravenous endothelin on hemodynamics and cardiac contractility in conscious Milan normotensive rats. J Cardiovasc Pharamacol. 1991;17:662–669.[Medline] [Order article via Infotrieve]
17. Beyer ME, Nerz S, Krämer BK, Hoffmeister HM. Hemodynamic and inotropic effects of endothelin-1 in vivo. Basic Res Cardiol. 1994;89:39–49.[Medline] [Order article via Infotrieve]
18. Beyer ME, Nerz S, Kazmaier S, Hoffmeister HM. Effect of endothelin-1 and its combination with adenosine on myocardial contractility and myocardial energy metabolism in vivo. J Mol Cell Cardiol. 1995;27:1989–1997.[Medline] [Order article via Infotrieve]
19.
Beyer ME, Slesak G, Hoffmeister HM. Significance of
endothelinB receptors for myocardial
contractility and myocardial energy
metabolism. J Pharmacol Exp Ther. 1996;278:1228–1234.
20. Majid PA, DeFeyter PJF, Van der Wall EE, Wardeh R, Roos JP. Molsidomine in the treatment of patients with angina pectoris: acute hemodynamic effects and clinical efficacy. N Engl J Med. 1980;302:1–6.[Abstract]
21. Ishikawa K, Fukami T, Nagase T, Mase T, Hayama T, Nilyama K, Fuijita K, Urakawa Y, Kumagni U, Fukuroda T, Ihara M, Yano M. Endothelin antagonistic peptide derivates with high selectivity for ETA receptors. In: Schneider CH, Eberele AN, eds. Peptides. Leiden, Netherlands: ESCOM; 1992:685–686.
22. Cornet S, Teillot M, Pirotzky E, Braquet P. Cicletanine modulates endothelin-induced renal vasoconstriction in the rat. J Cardiovasc Pharmacol. 1991;17:S319–S321.
23.
Ishikawa K, Ihara M, Noguchi K, Mase T, Mino N, Saeki
T, Fukuroda T, Fukami T, Ozaki S, Nagase T, Nishikibe M, Yano M.
Biochemical and pharmacological profile of a potent and selective
endothelinB-receptor antagonist, BQ
788. Proc Natl Acad Sci U S A. 1994;91:4892–4896.
24.
Kowallik P, Schulz R, Guth BD, Schade A, Paffhausen W,
Gross R, Heusch G. Measurements of regional myocardial blood flow with
multiple colored microspheres. Circulation. 1991;83:974–982.
25. Atkinson DE. The energy charge of the adenylate pool as a regulatory parameter: interaction with feedback modifiers. Biochemistry. 1968;11:4030–4034.
26. Sakurai T, Yanagisawa M, Masaki T. Molecular characterization of endothelin receptors. Trends Pharmacol Sci. 1992;13:103–108.[Medline] [Order article via Infotrieve]
27. Fukuroda T, Nishikibe M, Ohta Y, Ihara M, Yano M, Ishikawa K, Fukani T, Ikemoto F. Analysis of responses to endothelins in isolated porcine blood vessels by using a novel endothelin antagonist, BQ-153. Life Sci.. 1992;50:PL107–PL112.[Medline] [Order article via Infotrieve]
28. Balwierczak JL. Two subtypes of the endothelin receptor (ETA and ETB) mediate vasoconstriction in the perfused rat heart. J Cardiovasc Pharmacol. 1993;22(suppl 8):S248–S251.
29.
Fujitani Y, Ueda H, Okada T, Urade Y, Karaki H. A
selective agonist of endothelin type B receptor, IRL 1620, stimulates
cyclic GMP increase via nitric oxide formation in rat aorta.
J Pharmacol Exp Ther. 1993;267:683–689.
30.
Tsukahara H, Ende H, Magazine HI, Bahou WF, Goligorsky
MS. Molecular and functional characterization of the
non-isopeptide-selective ETB receptor in
endothelial cells: receptor coupling to nitric oxide
synthase. J Biol Chem. 1994;269:21778–21785.
31. Feelisch M, Noak E. Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur J Pharamacol. 1987;139:19–30.[Medline] [Order article via Infotrieve]
32. Kuhn M, Förstermann U. Endothelium-dependent vasodilation in human epicardial coronary arteries: effect of prolonged exposure to glyceryl trinitrate or SIN-1. J Cardiovasc Pharmacol. 1989;14(suppl 11):S47–S54.
33. Bigaud M, Pelton J. Discrimination between ETA and ETB-receptor mediated effects of endothelin-1 and [Ala1,3,11,15] endothelin-1 by BQ 123 in the anaesthetized rat. Br J Pharmacol. 1992;107:912–918.[Medline] [Order article via Infotrieve]
34. Douglas SA, Elliott JD, Ohlstein EH. Regional vasodilation to endothelin-1 is mediated by a non ETA receptor subtype in the anaesthetized rat: effect of BQ 123 on systemic haemodynamic responses. Eur J Pharmacol. 1992;221:315–324.[Medline] [Order article via Infotrieve]
35. Cornet S, Pirotzky E, Braquet P. Implication of different endothelin receptors in the vascular action of a hypertensive dose of ET-1 in rats. J Cardiovasc Pharmacol. 1993;22(suppl 8):S239–S242.
36. Han H, Neubauer S, Braeker B, Ertl G. Endothelin-1 contributes to ischemia/reperfusion injury in isolated rat heart-attenuation of ischemic injury by the endothelin-1 antagonists BQ 123 and BQ 610. J Mol Cell Cardiol. 1995;27:761–766.[Medline] [Order article via Infotrieve]
37. Shetty SS, Okada T, Webb RL, del Grande D, Lappe RW. Functionally distinct endothelin B receptors in vascular endothelium and smooth muscle. Biochem Biophys Res Commun. 1993;191:459–464.[Medline] [Order article via Infotrieve]
38.
Teerlink JR, Breu V, Sprecher U, Clozel M, Clozel J-P.
Potent vasoconstriction mediated by endothelin
ETB receptors in canine coronary
arteries. Circ Res. 1994;74:105–114.
39. Deng L-Y, Li J-S, Schiffrin EL. Endothelin receptor subtypes in resistance arteries from humans and rats. Cardiovasc Res. 1995;29:532–535.[Medline] [Order article via Infotrieve]
40. Ishikawa T, Yanagisawa M, Kimura S, Goto K, Masaki T. Positive chronotropic effects of endothelin, a novel endothelium-derived vasoconstrictor peptide. Pflügers Arch. 1988;413:108–110.
41. Kitayoshi T, Watanabe T, Shimamoto N. Cardiovascular effects of endothelin in dogs: positive inotropic action in vivo. Eur J Pharmacol. 1989;166:519–522.[Medline] [Order article via Infotrieve]
42. Mir AK, Berthold H, Scholtysik GE, Fozard JR. Cardiovascular effects of endothelin-1 in pithed spontaneously hypertensive rats: evaluation of its mechanism(s) of action. Naunyn-Schmiedebergs Arch Pharmacol. 1989;340:424–430.[Medline] [Order article via Infotrieve]
43. McMurdo L, Thiemermann C, Vane JR. The endothelin ETB receptor agonist, IRL 1620, causes vasodilatation and inhibits ex vivo platelet aggregation in the anaesthetised rabbit. Eur J Pharmacol. 1994;259:51–55.[Medline] [Order article via Infotrieve]
44. Schmidt HD, Scheer RD. Quantitative data on the afterload dependence of left ventricular dP/dtmax in isolated canine hearts. Basic Res Cardiol. 1981;76:89–105.[Medline] [Order article via Infotrieve]
45. Pfeffer MA, Pfeffer JM. Left ventricular hypertrophy and pressure generating capacity in aging genetically hypertensive rats. J Cardiovasc Pharmacol. 1985;7:41–45.
46. Bassenge E, Mülsch A. Anti-ischemic actions of molsidomine by venous and large coronary dilation in combination with antiplatelet effects. J Cardiovasc Pharmacol. 1989;14(suppl 11):S23–S28.
47.
Takanashi M, Endoh M. Characterization of positive
inotropic effect of endothelin on mammalian ventricular
myocardium. Am J Physiol. 1991;261:H611–H619.
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