Selective Endothelin-A Versus Combined Endothelin-A/Endothelin-B Receptor Blockade in Rat Chronic Heart Failure
Background—The relative efficacy of endothelin-A (ETA) receptor blockade versus combined ETA-ETB receptor blockade in chronic heart failure (CHF) is still largely unknown.
Methods and Results—We compared, in a rat model of CHF (coronary ligation), the hemodynamic and structural effects of 1 month of treatment with the ETA antagonist ABT-627 (5 mg · kg−1 · d−1), the ETB antagonist A-192621 (30 mg · kg−1 · d−1) or a combination of the 2 drugs. Doses were chosen for their capacity to block the pressor response to ET-1 (for ETA blockade) or the depressor responses to sarafotoxin S6c or ET-1 (for ETB blockade). ETA and combined ETA-ETB blockade reduced systolic blood pressure to the same extent, whereas ETB blockade had no effect. In contrast, only combined ETA-ETB blockade significantly reduced heart rate. Both ETA and combined ETA-ETB blockade, but not ETB blockade alone, increased left ventricular (LV) fractional shortening and wall thickening and reduced LV end-diastolic pressure, as well as LV end-diastolic and end-systolic volumes. However, all treatments (including ETB blockade) decreased LV collagen accumulation.
Conclusions—The chronic blockade of both ETA and ETB receptors improved systemic hemodynamics, as well as LV function and remodeling, to the same extent as ETA receptor blockade alone. However, only combined ETA-ETB receptor blockade decreased heart rate. Whether this differential effect on heart rate affects the long-term outcome after treatment with ETA or mixed ETA-ETB antagonists in CHF remains to be determined.
Mixed endothelin A–endothelin B receptor (ETA-ETB) antagonists exert beneficial effects in experimental chronic heart failure (CHF),1 but selective ETA antagonists have been shown to be either beneficial2 3 4 or deleterious.5 6 However, to date, no study has compared the efficacy of these 2 pharmacological approaches to CHF. Thus, whether simultaneous blockade of ETB receptors will reinforce or reduce the efficacy of ETA antagonists in CHF is still unknown. Moreover, the effects of chronic ETB blockade per se are also unknown. In theory, the blockade of ETB receptors may have deleterious effects by reducing the ETB-mediated endothelium-dependent vasodilatation or by decreasing clearance and, thus, increasing plasma levels of ET. We compared the effect of a selective ETA antagonist, a selective ETB antagonist, or a combination of the 2 antagonists in rat model of CHF.
CHF was induced by myocardial infarction, as described previously.1 Eight days after surgery, the animals were randomized to 1 of the following 5 groups (n=12 per group): sham, CHF untreated, CHF plus ABT-627 (ETA antagonist; 5 mg · kg−1 · d−1), CHF plus A-192621 (ETB antagonist; 30 mg · kg−1 · d−1), and CHF plus a combination of ABT-627 and A-192621. All treatments were administered as a food additive for 4 weeks. The dose of ABT-627 was chosen because it blocked the ETA-mediated sustained vasoconstriction to ET-1 without affecting ETB-mediated transient vasodilatation,7 whereas that of A192621 was the smallest dose that completely blocked ET-1–induced transient vasodilatation without affecting sustained vasoconstriction.8 To verify long-term ET receptor blockade, the effects of intravenous bolus injections of ET-1 (1 nmol/kg) and sarafotoxin S6c (0.3 ng/kg) were assessed after 4 weeks of treatment in randomly selected animals from each group.
Systolic blood pressure and heart rate were determined in conscious rats (plethysmography) just before the start of treatment (7 days after ligation) and after 4 weeks of treatment. Transthoracic Doppler echocardiographic studies were performed in anesthetized rats; arterial pressure and left ventricular (LV) systolic and end-diastolic pressures and dP/dtmax were measured as described previously.1 Before euthanization, a blood sample was taken through the carotid artery to determine plasma ET-1 levels (by ELISA).
All values are given as means±SEM. Differences were compared by t test or by ANOVA followed by a Tukey test for multiple comparisons. They were considered significant at P<0.05.
ETA-ETB Receptor Blockade
After 4 weeks of treatment, the ETA antagonist did not modify the decrease in blood pressure to sarafotoxin S6c or the transient depressor response to ET-1, but it markedly decreased the sustained pressor response to ET-1. The ETB antagonist decreased the response to sarafotoxin S6c and the transient depressor effect of ET-1, but it did not affect the sustained pressor response to ET-1. Combined ETA-ETB treatment reduced the sustained pressor response to ET-1 to the same extent as ETA blockade alone and decreased the response to sarafotoxin S6c and the transient depressor effect of ET-1 to the same extent as ETB blockade alone (Table 1⇓).
After 4 weeks of treatment in CHF rats, ETA blockade and combined ETA-ETB blockade decreased systolic blood pressure significantly and to the same extent, whereas the ETB antagonist treatment had no effect (Figure 1⇓). Both the ETA and the ETB antagonist tended to reduce heart rate. However, a more marked, significant decrease in heart rate was observed after the coadministration of ETA and ETB antagonists (Figure 1⇓)
Cardiac Functional Parameters and Remodeling
Compared with untreated CHF rats, ETA and combined ETA-ETB blockade (but not ETB blockade) reduced LV systolic pressure and LV end-diastolic pressure to the same extent, without affecting LV dP/dtmax (Figure 1⇑).
Echocardiographic studies (Figure 2⇓) show that ETA blockade increased LV fractional shortening and LV posterior wall thickening, whereas the ETB antagonist did not affect these parameters. Coadministration of the selective ETA and the selective ETB antagonist increased both LV fractional shortening and LV posterior wall thickening to the same extent as treatment with the ETA antagonist alone.
The ETA antagonist limited the progressive increase of LV end-diastolic diameter, but the ETB antagonist did not affect this parameter. Coadministration of the ETA and the ETB antagonist decreased LV end-diastolic diameter to the same extent as treatment with the ETA antagonist alone (Figure 2⇑).
Plasma ET-1 Levels
Compared with sham animals, plasma levels of ET-1 were increased in CHF animals (7±1 and 13±3 fmol/mL, respectively; P<0.05). ETA, ETB, or combined ETA-ETB blockade did not affect the levels of ET-1 (13±3, 15±2, and 18±5 fmol/mL, respectively).
Infarct size was not significantly different between the groups (Table 2⇓). Neither treatment affected heart weight or the heart weight to body weight ratio. In contrast, all treatments (ETA, ETB, or combined ETA-ETB blockade) decreased LV collagen density significantly and to the same extent (Table 2⇓).
The main results of our study, which was performed using a rat model of CHF, are as follows. (1) Chronic, simultaneous blockade of both ETA and ETB receptors improved systemic and cardiac hemodynamics, as well as LV function and remodeling, to the same extent as ETA receptor blockade alone. However, these effects were associated with a significant reduction of heart rate only with simultaneous ETA-ETB receptor blockade. (2) Chronic, selective ETB receptor blockade per se did not affect systemic and cardiac hemodynamics, nor the LV dilation of CHF animals, but it did reduce LV collagen density.
Effect of ETB Receptor Blockade
After 1 month of treatment, the ETB antagonist did not alter blood pressure, suggesting the absence of ETB-mediated vasomotor tone under these conditions. In contrast, short-term administration of ETB receptor blockers has been shown to induce vasoconstriction in humans9 and animals.10 It is possible that ETB-mediated endothelium vasodilatation might be reduced in CHF secondary to endothelial dysfunction or that the vasodilatory effects of ETB receptor stimulation differ in acute and chronic situations. Alternatively, CHF might be associated with a downregulation of endothelial ETB receptors.11 Although we observed no changes in the systemic response to sarafotoxin S6c, this does not exclude a heterogeneous adaptation of the ET system at the level of different organs.
Despite the lack of hemodynamic effects and functional improvement, chronic ETB receptor blockade reduced cardiac collagen accumulation. Thus, in contrast to selective ETA or mixed ETA-ETB administration, which provoke a major reduction of cardiac load, other mechanisms, independent of cardiac hemodynamic changes, are involved in ETB blockade. Indeed, ET activates cardiac fibroblasts though ETB receptors.12 Moreover, by reducing the ETB-mediated release of aldosterone,13 which is implicated in collagen accumulation in CHF, ETB receptor blockade might indirectly reduce collagen accumulation.
Selective ETA Versus Combined ETA-ETB Receptor Blockade
We observed that the effects of chronic, selective ETA blockade on systemic and cardiac hemodynamics, as well as on LV dilatation and cardiac collagen accumulation, were quantitatively similar to those induced by combined ETA-ETB blockade. These results demonstrate that simultaneous blockade of ETB receptors does not adversely affect the outcome of treatment with an ETA antagonist in experimental CHF.
In the present study, the effects of ETA or combined ETA-ETB blockade were quantitatively similar to those of an angiotensin-converting enzyme (ACE) inhibitor. However, this does not exclude possible synergistic effects of ACE inhibitors and ET antagonists in CHF. Whether ET antagonists can induce beneficial effects after ACE inhibition is still largely unknown and requires further investigation.
Importantly, whereas heart rate was only slightly and nonsignificantly reduced by treatment with the ETA or the ETB antagonist, a more marked, significant decrease in heart rate was observed after simultaneous ETA-ETB blockade. The more marked reduction in heart rate might have important consequences. Indeed, because of the nonlinearity of the relationship between heart rate and the diastolic part of the cardiac cycle, a small decrease in heart rate results in a dramatic increase in diastolic coronary perfusion time and improves LV filling. This, together with the reduced oxygen requirements, will improve the oxygen supply-demand ratio. However, whether these differences in terms of heart rate reduction affect the long-term outcome of the treatments for CHF cannot be answered from the present study.
The authors thank Eliane Abdelhouab for her excellent assistance and Abbott Laboratories for providing the ET antagonists.
- Received April 7, 2000.
- Revision received May 24, 2000.
- Accepted June 8, 2000.
- Copyright © 2000 by American Heart Association
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