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(Circulation. 1996;94:779-784.)
© 1996 American Heart Association, Inc.

Articles

Short-term Hemodynamic Effects of Endothelin Receptor Blockade in Dogs With Chronic Heart Failure

Hisashi Shimoyama, MD; Hani N. Sabbah, PhD; Steven Borzak, MD; Mitsuhiro Tanimura, MD; Serguei Shevlyagin, MD, PhD; Gloria Scicli, PhD; Sidney Goldstein, MD

the Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Mich.

Correspondence to Hani N. Sabbah, PhD, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202.

	Abstract

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Background Plasma endothelin levels are increased in heart failure and may contribute to the increased peripheral vasoconstriction that characterizes this disease state. In the present study, we examined the effects of intravenous bosentan, a nonpeptide, competitive endothelin-1 receptor antagonist, on hemodynamics in dogs with chronic heart failure.

Methods and Results Chronic heart failure was produced in 11 dogs by multiple sequential intracoronary microembolization. At the time of study, left ventricular (LV) ejection fraction was 25±2%. Hemodynamic and echocardiographic measurements were made at baseline and at 15, 30, and 60 minutes after a bolus injection of bosentan (10 mg/kg). Bosentan had no significant effect on heart rate or mean aortic blood pressure. At 60 minutes, bosentan reduced LV end-diastolic pressure (17±2 versus 11±2 mm Hg; P<.05) and systemic vascular resistance (3891±379 versus 3071±346 dyne·s·cm^-5; P<.05) compared with baseline and increased cardiac output (2.63±0.29 versus 3.33±0.46 L/min; P<.05), peak rate of change of LV pressure during isovolumic contraction and relaxation (1751±92 versus 2197±170 mm Hg/s; P<.05), and LV fractional shortening determined by echocardiography (30±2% versus 36±2%; P<.05).

Conclusions Short-term intravenous bosentan reduced systemic vascular resistance and improved overall LV performance in dogs with chronic heart failure. These results suggest that endothelin-1 receptor antagonists may be useful therapeutic agents in the treatment of heart failure.

Key Words: heart failure • endothelin • receptors

	Introduction

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The vascular endothelium plays an important role in the regulation of vascular tone. The endothelial cell produces vasodilators such as endothelium-derived relaxing factor and prostacyclin as well as vasoconstrictors such as thromboxane and ET.¹ Three isoforms of ET (ET-1, ET-2, and ET-3) have been identified,² but only ET-1 is produced by the vascular endothelium.³ ET-1 is a 21–amino acid vasoactive peptide that can cause potent and prolonged vasoconstriction.^{4 5} Two ET receptors, ET_A and ET_B, mediate the vascular effects of ET-1.⁶ Both receptors have been characterized, and their cDNA has been cloned.^{6 7} ET_A has a higher affinity for ET-1 than ET-3, whereas the ET_B receptor has the same affinity for all ET isoforms.⁷

ET-1 is a potent vasoconstrictor and is detectable in the plasma of healthy human subjects^{8 9 10} and in normal experimental animals.^{11 12 13} A role for ET has been proposed in a variety of cardiovascular disorders including cardiogenic shock,¹⁴ stable and unstable angina pectoris,¹⁵ acute myocardial infarction,^{16 17} and congestive heart failure.⁹ The plasma concentration of this potent vasoconstrictor has been shown to increase in patients with congestive heart failure^{9 10} as well as in several animal models of chronic heart failure.^{11 12 13 18 19} Despite the observed increase in plasma ET-1 in heart failure, a direct role for this vasoconstrictor in the pathophysiology of heart failure remains to be elucidated. The recent availability of ET-1 receptor antagonists allows for further investigation of the role of ET-1 in heart failure. In the present study, we examined the short-term hemodynamic effects of intravenous bosentan, a competitive, mixed ET_A and ET_B receptor antagonist, in dogs with chronic heart failure.

	Methods

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The canine model of chronic heart failure used in the present study was described in detail previously.²⁰ In this experimental preparation, chronic LV dysfunction and failure are produced by multiple sequential intracoronary embolizations with polystyrene latex microspheres (70 to 102 µm in diameter), which leads to loss of viable myocardium. The model manifests many of the sequelae of heart failure seen in humans, including marked and sustained depression of LV systolic and diastolic function, LV hypertrophy and dilation, reduced cardiac output, increased LV filling pressures and increased systemic vascular resistance, enhanced activity of the sympathetic nervous system, and increased plasma concentration of ET-1.^{12 20}

In the present study, 11 healthy mongrel dogs (weight, 24 to 31 kg) underwent coronary microembolizations to produce heart failure. Embolizations were performed 1 to 3 weeks apart and were discontinued when LV ejection fraction determined angiographically was 35%. Microembolizations were performed during cardiac catheterization under general anesthesia and sterile conditions. The anesthetic regimen used in the present study consisted of a combination of intravenous injections of oxymorphone (0.22 mg/kg), diazepam (0.17 mg/kg), and sodium pentobarbital (150 to 250 mg to effect). This anesthesia regimen has been shown to be effective in preventing the tachycardia, hypertension, and myocardial depression seen with pentobarbital alone²¹ and does not alter LV function compared with the conscious state.²¹ Studies with bosentan were performed at an average of 3 months after the last coronary microembolizations. At the time of the study, LV ejection fraction was 25±2%. The progressive decline in LV ejection fraction over time is a characteristic feature of this canine model of heart failure.²¹ The study was approved by the Care of Experimental Animals Committee of our institution and conformed to the position of the American Heart Association on research animal use and the guiding principles of the American Physiological Society.

Study Protocol
On the day of the study, dogs were anesthetized as described above, intubated, and ventilated with room air. A femoral arteriotomy and phlebotomy were performed. A catheter-tip micromanometer (Millar Instruments) was advanced into the LV and a Swan-Ganz catheter was advanced into the pulmonary artery under fluoroscopic guidance. After baseline hemodynamic and echocardiographic measurements were obtained, bosentan (10 mg/kg) was injected (bolus) intravenously. Hemodynamic and echocardiographic measurements were repeated at 15, 30, and 60 minutes after injection of bosentan. In 8 of 11 dogs, venous blood samples were obtained at baseline and at 15, 30, and 60 minutes after bosentan for determination of plasma ET-1 concentration. Studies also were performed in 3 normal dogs to determine whether bosentan has a hemodynamic effect in normal animals. The protocol used in these 3 dogs was identical to that used in dogs with heart failure. Bosentan was provided courtesy of F. Hoffmann-La Roche, Ltd, Basel, Switzerland.

Hemodynamic and Echocardiographic Measurements
Aortic pressure was measured during pullback of the micromanometer catheter from the LV. Peak rates of change of LV pressure during isovolumic contraction (+dP/dt) and relaxation (-dP/dt) were derived from analog differentiation of the LV pressure waveform. We measured mean pulmonary artery wedge pressure using the Swan-Ganz catheter in conjunction with a P23 XL pressure transducer (Spectramed). Cardiac output was measured in duplicate by use of the thermodilution method. The variability in cardiac output between the two measurements, based on 44 pairs of measurements made in the study, was 0.12±0.01 L/min. Systemic vascular resistance was calculated as mean aortic pressure times 80 divided by cardiac output. The time constant of LV relaxation () was calculated as described by Weiss and colleagues.²²

Two-dimensional echocardiograms were performed with use of a model 77020A ultrasound system (Hewlett-Packard) with a 2.5-MHz transducer. Measurements were made with the dog placed in the right lateral decubitus position. Echocardiograms were recorded on a Panasonic 6300 VHS recorder for off-line analysis. An LV short-axis view at the midpapillary muscle level was recorded at each study time point. This view was used to calculate the percent LV fractional area of shortening, defined as the difference between the end-diastolic and end-systolic area divided by the end-diastolic area times 100.²³ The LV endocardial tracings used for this analysis were drawn to include the papillary muscles inside the outlines.²³

Plasma ET-1 and Norepinephrine Measurements
Venous blood samples for measurement of ET-1 plasma concentration were drawn from conscious dogs before any embolization (normal state) and were drawn again in the conscious state when dogs were in heart failure and before studies with bosentan were performed. Venous blood was also drawn during the study (anesthetized state) in 8 of 11 dogs at each study time point. In all instances, blood was collected in chilled tubes that contained inhibitors (2 mg EDTA and 100 U aprotinin per milliliter of blood), placed on ice, and immediately centrifuged at 4°C. Plasma was separated and frozen at -30°C until the RIA was performed. Before the RIA was performed, ET was subjected to solid-phase extraction by use of 3-mL C₂ Bond-Elute cartridges. The cartridges were washed with 2.8 mL methanol and 2.8 mL of water. After the plasma (7 mL) was applied, the cartridges were washed with 2 mL of water and 5 mL 0.1% TFA. ET was eluted with 3 mL 70% acetonitrile/water and 5 mL 0.1% TFA. The samples were evaporated to dryness and reconstituted for RIA. The recovery of the extraction procedure was 70% as determined by the addition of synthetic ET to plasma. ET-1, ET antiserum, and ¹²⁵I-ET were purchased from Peninsula Laboratories. In the 3 normal study dogs, venous blood samples were also obtained at baseline and at 30 and 60 minutes after injection of bosentan. Plasma norepinephrine concentration was determined from aluminum oxide absorption by high-performance liquid chromatography. In our laboratory, this technique for assessment of norepinephrine concentration has a variability of 47±6 pg/mL between duplicate samples.

Data Analysis
Hemodynamic, echocardiographic, and ET-1 measurements obtained at baseline and 15, 30, and 60 minutes after the administration of bosentan were examined by use of repeated measures ANOVA. For this test, the level of significance was set at =.05. If significance was attained, pairwise comparisons between measurements at baseline and 15, 30, and 60 minutes were performed by use of the Student-Newman-Keuls test. For this test, a value of P.05 was considered significant. All data are reported as mean±SEM.

	Results

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Findings in Normal Dogs
Hemodynamic and echocardiographic measurements obtained in three normal dogs after the administration of bosentan are shown in Table 1. Intravenous bosentan at a dose of 10 mg/kg had no effect on LV end-diastolic pressure, pulmonary artery wedge pressure, or cardiac output. Similarly, bosentan in normal dogs had no effect on LV systolic function, as evidenced by the lack of a change in LV fractional shortening, or on LV relaxation, as evidenced by the lack of a change in LV peak -dP/dt or (Table 1).

View this table: [in this window] [in a new window]   Table 1. Hemodynamics and Echocardiographic Measurements at Baseline and at 15, 30, and 60 Minutes After Injection of Bosentan in Three Normal Dogs

Findings in Dogs With Heart Failure
Hemodynamic, echocardiographic, and plasma ET-1 concentration measurements made in dogs with heart failure are shown in Table 2 and the Figure. Bosentan had no significant effect on heart rate or mean aortic pressure in comparison with baseline values. There was a modest but statistically significant decline in mean pulmonary artery wedge pressure (Table 2) and a marked, time-dependent decline in LV end-diastolic pressure (Figure). LV end-diastolic pressure decreased from 17±2 mm Hg at baseline to 11±2 mm Hg at 60 minutes after injection of bosentan (P<.05). The reduction of LV filling pressures was accompanied by a significant time-dependent increase in cardiac output and a significant time-dependent decrease in systemic vascular resistance (Table 2). At baseline, cardiac output was 2.63±0.29 L/min and increased to 3.33±0.46 L/min at 60 minutes after injection of bosentan (Figure). Bosentan significantly improved systolic LV function, as evidenced by a significant increase in peak LV +dP/dt and LV fractional shortening (Table 2). LV fractional shortening was 30±2% at baseline and increased to 36±2% at 60 minutes after injection of bosentan (Figure). The increase in LV fractional shortening was due to a decrease in LV end-systolic area without a change in LV end-diastolic area (Table 2). Bosentan also improved LV relaxation, as evidenced by a significant increase in peak LV -dP/dt and a significant decrease in (Table 2).

View this table: [in this window] [in a new window]   Table 2. Hemodynamics, Echocardiographic Measurements, and Plasma ET Concentration at Baseline and at 15, 30, and 60 Minutes After Injection of Bosentan in Dogs With Heart Failure

View larger version (17K): [in this window] [in a new window]   Figure 1. LV end-diastolic pressure (LVEDP; top), cardiac output (CO; middle), and LV fractional shortening (LVFS; bottom) at baseline (BASE) and at 15, 30, and 60 minutes (m) after administration of bosentan in dogs with heart failure. *P<.05 relative to baseline.

In conscious dogs (8 of 11 study dogs), before any coronary microembolizations were performed (normal state), ET-1 plasma concentration was 1.3±0.1 pg/mL and increased to 3.4±0.7 pg/mL when dogs were in heart failure (P<.03, Student's paired t test). After anesthesia and at the time of study (8 of 11 study dogs), baseline ET-1 plasma concentration was 2.8±0.5 pg/mL (Table 2), which was slightly lower but not significantly different from ET-1 plasma levels measured in the conscious state when dogs were in heart failure. Only 15 minutes after administration of bosentan at a dose of 10 mg/kg, there was a nearly eightfold increase of plasma ET-1 concentration compared with baseline levels. Plasma ET-1 concentration increased further at 30 and 60 minutes after injection of bosentan (Table 2). In 3 dogs with heart failure in which plasma norepinephrine concentration was measured, bosentan did not increase norepinephrine concentration. Average plasma norepinephrine concentration was 156 pg/mL at baseline and 179 and 172 pg/mL at 30 and 60 minutes after administration of bosentan, respectively. These minor differences in plasma norepinephrine are within the range of variability of the method used to assess plasma norepinephrine.

	Discussion

Top Abstract Introduction Methods Results Discussion Acknowledgment References

 
The results of the study indicate that short-term administration of bosentan, a mixed ET_A and ET_B ET receptor antagonist, leads to overall improvement of systolic and diastolic LV function in dogs with chronic heart failure. The hemodynamic response to bosentan is characterized by an increase of cardiac output, a reduction in LV filling pressures, a reduction of systemic vascular resistance, an increase in LV fractional shortening, and an improvement in LV relaxation without significant changes of heart rate and mean aortic pressure. The observed, marked increase in plasma ET-1 concentration after administration of bosentan indicates that considerable ET-1 receptor blockade was achieved. In contrast to its response in dogs with heart failure, bosentan had no hemodynamic effect in normal dogs. This observation is consistent with studies by other investigators²⁴ that also showed that bosentan alone had no hemodynamic effect in normal, anesthetized, open-chest dogs.

The reported increase in the plasma concentration of ET-1 both in patients with heart failure^{9 10} and in animal models of heart failure^{11 12 13 18 19} has led to speculation that this potent vasoconstrictor plays an important role in the increased peripheral vascular resistance that is a hallmark of this disease state. Until the discovery of ET, the known endocrine systems believed to contribute to the increased systemic vascular resistance in heart failure included enhanced and sustained activation of the sympathetic nervous system,²⁵ the renin-angiotensin system,²⁶ and enhanced secretion of arginine vasopressin.²⁷ The findings of the present study that ET-1 receptor blockade improves overall cardiac performance in dogs with heart failure and reduces systemic vascular resistance support the hypothesis that ET may also play an important role in the pathophysiology of this disease state.

The factor or factors responsible for the increased production and release of ET-1 in heart failure are not fully understood. Several possibilities, however, merit consideration. It is well known that various factors, including thrombin, phorbol ester, ionomycin, and transforming growth factor-ß, induce the production of mRNA of ET in endothelium.^{1 28} Furthermore, administration of transforming growth factor-ß, angiotensin II, or arginine vasopressin into the incubation medium of cultured endothelial cells elicits release of ET from the cells.^{1 28} It is well known that the heart failure state is accompanied, at the very least, by increased angiotensin II and arginine vasopressin. In vitro studies²⁹ have also suggested that long-term, low-level shear stress that acts on cultured endothelial cells increases the mRNA for preproendothelin and the recovery of ET in the supernatant. The reduced cardiac output characteristic of the heart failure state is very likely associated with low shear stress that acts on the vascular endothelium. Increased plasma ET concentration has also been shown in patients with episodes of orthostatic hypotension, a condition characterized by decreased cardiac output.³⁰ Finally, in addition to increased secretion of ET, it is possible but by no means established that clearance of ET may be diminished in heart failure, which could lead to increased plasma concentration.¹⁰

We are aware of one study¹³ in which bosentan was used in a rat model of heart failure secondary to coronary artery ligation. Heart failure was defined as present only in rats in which LV end-diastolic pressure was >15 mm Hg. In rats with heart failure, bosentan administered by gavage at a dose of 100 mg/kg had no effect on heart rate but produced a significant reduction in mean arterial pressure.¹³ In the present study, intravenous bosentan had no significant effect on mean aortic pressure. The difference between the two studies in terms of arterial blood pressure changes may be due in part to the high dose of bosentan used in the rats (100 mg/kg) compared with that used in the dogs (10 mg/kg). The absence of a reduction of arterial pressure in the present study after the administration of bosentan may be explained on the basis of a simultaneous significant increase in cardiac output. The lack of a decrease in arterial pressure with bosentan may also be due to the nonselective blockade of this ET-1 receptor antagonist. There is evidence that suggests that the ET_B receptor, in contrast to the ET_A receptor, mediates vasodilation and, therefore, nonselective blockade might exert opposing effects on vascular tone.^{31 32} Other studies, however, have suggested that ET_B receptors, which can be specifically stimulated by sarafotoxin S6c, may also cause vasoconstriction.^{33 34} These findings suggest that the cardiovascular responses to ET-1 are complex and are probably due to actions at more than one receptor subtype.

In addition to the observations in the present study of the beneficial effects elicited by an ET-1 receptor antagonist in a canine model of chronic heart failure, this class of drugs has also been shown to modulate other pathophysiological conditions in animal models of human cardiovascular disease. In a rat model of neointimal formation after carotid artery balloon angioplasty,³⁵ the ET-1 receptor antagonist SB 209670 was shown to reduce neointimal formation by 50% compared with untreated controls, which suggests its possible use to attenuate the degree of vascular restenosis after coronary angioplasty. In anesthetized dogs with 90-minute occlusion of the circumflex coronary artery followed by 5 hours of reperfusion,³⁶ treatment with the ET-1 receptor antagonist BQ-123 produced a 40% reduction in infarct size compared with vehicle-treated dogs. On the basis of these findings, these investigators³⁶ suggested that ET-1 release during ischemia may be involved in the pathogenesis of myocardial infarction. This observation, however, is controversial, because others³⁷ have shown that ETs protect the ischemic myocardium. Studies in rats with LV hypertrophy secondary to aortic banding³⁸ also showed that treatment with BQ-123 blocked the increases in the ratio of LV weight to body weight and in the diameter of cardiomyocytes after 1 week of banding but that the effect was abolished after 2 weeks.³⁸ On the basis of these findings, the investigators³⁸ suggested that endogenous ET-1 may play a role in the mechanism of cardiac hypertrophy during the early phase of pressure overload in vivo.

Several studies^{39 40 41} suggested that ET-1 has a positive inotropic effect on cardiac muscle. ET-1 was shown to have a positive inotropic effect on guinea pig atria,³⁹ rat and rabbit papillary muscle preparations,⁴⁰ and isolated rat ventricular trabeculae.⁴¹ These studies would suggest that ET-1 may be a factor in the regulation of contractility of cardiac muscle. In the present study, the use of an ET-1 receptor antagonist did not have a negative inotropic effect on the heart. To the contrary, overall LV performance improved after administration of bosentan in dogs with heart failure. It is possible that ET-1 has a positive inotropic effect on cardiac muscle and that its blockade at the receptor site might elicit a negative inotropic effect but that this effect, at least in the setting of heart failure, is overridden by the marked influence of the antagonist on reduction of peripheral vascular resistance.

In the present study, a modest but statistically insignificant increase in heart rate was seen after administration of bosentan in dogs with heart failure, with little or no change in mean arterial pressure. Bosentan also increased peak LV +dP/dt and reduced LV end-diastolic pressure. These observations raise the possibility that bosentan may have a direct effect on the myocardium that is independent of vasodilation. One possible explanation is that bosentan may trigger increased sympathetic discharge. Observations in the present study in three dogs with heart failure, however, did not show increased plasma norepinephrine concentration after the administration of bosentan. Also, we are not aware of any data that would suggest that bosentan has partial agonist activity that would explain the improvement in LV systolic function. In dogs with heart failure, a pure vasodilator such as nitroprusside also has been shown⁴² to significantly increase peak LV +dP/dt and decrease LV end-diastolic pressure despite significant afterload reduction. In patients with severe heart failure, nitroprusside also was shown⁴³ to increase cardiac index despite a significant decline in preload and afterload. Given these observations, one cannot exclude the likelihood that bosentan also elicits improvements in indexes of LV systolic function through vasodilation. In the present study, we also observed significant improvement in indexes of LV relaxation in dogs with heart failure, namely, an increase in peak LV -dP/dt and a decrease in after administration of bosentan. Additional studies are needed to determine the mechanism through which ET-1 receptor blockers in general or bosentan in particular improves LV relaxation.

The canine model of heart failure used in the present study manifests many of the sequelae of heart failure seen in humans. In addition to severe LV dysfunction, increased systemic vascular resistance, reduced cardiac output, and activation of neuroendocrine systems,²⁰ the model manifests many other features of heart failure seen in humans, including ventricular remodeling,^{21 44} development of chronic ventricular arrhythmias⁴⁵ and functional mitral regurgitation,⁴⁶ downregulation of cardiac ß-adrenergic receptors,⁴⁷ and progressive deterioration of LV function long after cessation of coronary microembolizations.²¹ The model also has been characterized in terms of its hemodynamic response to prototypical drugs used in the treatment of heart failure in humans. The hemodynamic response of the model to intravenous drugs including dobutamine, nitroprusside, ACE inhibitors, and digoxin⁴² as well as to long-term treatment with ß-blockers, ACE inhibitors, and digoxin²¹ is comparable to that seen in patients with heart failure. These data confirm the usefulness of this model as a tool for preclinical testing of new pharmacological compounds targeted for the treatment of heart failure and suggest that bosentan may have a role in the treatment of heart failure in humans.

In conclusion, the results of the present study indicate that intravenous bosentan, a competitive ET-1 receptor antagonist, improves overall cardiac performance in dogs with chronic heart failure. The exact mechanisms responsible for this improvement remain to be elucidated. The observations made suggest that ET-1 receptor antagonists may be useful therapeutic agents in the treatment of heart failure. Additional preclinical, long-term studies are needed to establish further the potential usefulness of this class of drugs as adjuncts to the long-term treatment of heart failure.

	Acknowledgment

Top Abstract Introduction Methods Results Discussion Acknowledgment References

 
This study was supported in part by a grant from the National Heart, Lung, and Blood Institute (No. HL-49090).

	Selected Abbreviations and Acronyms

 

dP/dt = peak rate of change of left ventricular pressure during isovolumic contraction (+) and relaxation (-) ET = endothelin LV = left ventricle, left ventricular RIA = radioimmunoassay = relaxation time constant TFA = trifluoroacetic acid

Received July 17, 1995; revision received January 31, 1996; accepted February 1, 1996.

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