a-192621 and Heart-Failure

To examine the role of endothelin ETA and ETB receptors in congestive heart failure due to cardiomyopathy, the effect of chronic treatment with selective ETA- and ETB-receptor antagonists (atrasentan and A-192621, respectively), alone and in combination, was assessed on functional and biochemical parameters of 52-week-old Bio 14.6 cardiomyopathic hamsters. Compared with control animals, cardiomyopathic hamsters treated for 9 weeks with atrasentan showed no variation in MAP; however, selective ETB- and combined nonselective ETA- and ETB-receptor antagonists increased systemic blood pressure. After selective ETB-receptor blockade, plasma endothelin levels were augmented. Importantly, this increase was highly enhanced (more than 8-fold) by concomitant ETA-receptor antagonism. Furthermore, the left ventricle:body weight ratio of cardiomyopathic hamsters treated with A-192621, alone or in combination with atrasentan, was significantly increased. On the other hand, decreased left ventricular end-diastolic pressure was observed in cardiomyopathic hamsters after selective ETA- or combined nonselective ETA/ETB-receptor antagonism, while only selective ETA-receptor blockade reduced left ventricular endothelin levels. Our results suggest that, in congestive heart failure, ETB receptors are essential to limit circulating endothelin levels, which may argue for improved cardiac benefits after long-term treatment with highly selective ETA-receptor antagonists.

Topics: Animals; Atrasentan; Blood Pressure; Cardiomyopathies; Cricetinae; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Mesocricetus; Nitrates; Nitrites; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Ventricular Function, Left

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal hemodynamic changes and impaired excretory function in congestive heart failure. It has previously been demonstrated that acute administration of ABT-627 (endothelin-A blocker) abolished systemic and renal vasoconstriction in controls and rats with congestive heart failure induced by a surgically created aortocaval fistula (Abassi et al. Clin Sci (Lond) 2002;103:S245-S248). In contrast, acute endothelin-B blockade by A-192621 exaggerated the ET-1 induced systemic and renal vasoconstriction. The present study examined the renal and systemic effects of chronically administered ABT-627 (24 mg/kg per day) or A-192621 (72 mg/kg per day) for 7 days via osmotic minipumps inserted intraperitoneally on the day of operation of sham controls and rats with congestive heart failure. Tailcuff measurements revealed that ABT- 627 significantly decreased mean arterial pressure from 108 +/- 2 mmHg to 87 +/- 2 mmHg (P < 0.05), whereas A-192621 significantly increased mean arterial pressure from 110 +/- 3 mmHg to 122 +/- 3 mmHg (P < 0.05) in controls. Despite the hypotensive effect of ABT-627, daily sodium excretion dramatically increased, but to a lesser extent in A-192621-treated controls. Furthermore, chronic administration of ABT-627 to controls attenuated the systemic and renal vasoconstriction induced by ET-1 (1 nmol/kg intravenous), whereas A-192621 augmented these effects. Similarly, chronic treatment with ABT-627 totally abolished the systemic and renal vasoconstriction caused by injected ET-1 in rats with congestive heart failure, whereas A192621 potentiated these effects. Chronic treatment of animals with congestive heart failure with ABT-627 did not influence daily sodium excretion, whereas treatment with A192621 significantly improved daily sodium excretion. Interestingly, treatment with either ABT-627 or A192621 significantly decreased cardiac hypertrophy in rats with congestive heart failure. In conclusion, in sham controls endothelin-B receptor mediated vasodilation and natriuresis, probably as a result of tubular action, whereas in congestive heart failure the excretory contribution of endothelin-B receptor was attenuated, resulting in Na+ retention.

Topics: Animals; Atrasentan; Blood Pressure; Cardiomegaly; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Infusion Pumps, Implantable; Kidney; Male; Natriuresis; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Vasoconstriction; Vasodilation

The present study examined the effects of two highly selective endothelin-1 (ET-1) receptor antagonists, ABT-627 (ET(A) blocker) and A-192621 (ET(B) blocker), on the systemic and renal haemodynamic effects of ET-1 in normal rats and in rats with experimental congestive heart failure (CHF) produced by aortocaval fistula. Intravenous injection of ET-1 (1.0 nmol x kg(-1) of body weight) to anaesthetized normal rats produced sustained decreases in renal blood flow (RBF) (assessed by ultrasonic flowmetry) and glomerular filtration rate (GFR), and significant increases in renal vascular resistance (RVR) and mean arterial pressure (MAP). Pretreatment with ABT-627 (1 mg x h(-1) x kg(-1) of body weight) abolished the pressor response to ET-1 without affecting the depressor phase, and significantly impaired the renal vasoconstriction. The systemic and renal vasoconstrictive effects of ET-1 in normal rats were significantly augmented by pretreatment with 3.0 mg x h(-1) x kg(-1) of A-192621. Baseline RBF and GFR in rats with CHF were reduced significantly compared with control rats, whereas RVR was elevated. The hypertensive effect of ET-1 was attenuated in rats with CHF. In the presence of ET(A) blockade, the pressor response to ET-1 was completely abolished in CHF rats. Furthermore, pretreatment with ABT-627 enhanced the recovery from ET-1- dependent vasoconstriction and remarkably reversed the ET-1-induced hypofiltration. Blockade of ET(B) receptors in rats with CHF further exposed the exaggerated ET-1-induced renal vasoconstriction. Our data demonstrate that experimental CHF is associated with altered responsiveness to ET(A)- and ET(B)-mediated systemic and renal effects of ET-1. Furthermore, in CHF, as in control rats, the ET(B)-mediated vasodilatory response may serve as an important compensatory counterbalance to the adverse ET(A)-mediated effects.

Topics: Animals; Atrasentan; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Glomerular Filtration Rate; Heart Failure; Kidney; Male; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Renal Circulation; Vascular Resistance

The relative efficacy of endothelin-A (ET(A)) receptor blockade versus combined ET(A)-ET(B) receptor blockade in chronic heart failure (CHF) is still largely unknown.. We compared, in a rat model of CHF (coronary ligation), the hemodynamic and structural effects of 1 month of treatment with the ET(A) antagonist ABT-627 (5 mg x kg(-1) x d(-1)), the ET(B) antagonist A-192621 (30 mg x kg(-1) x d(-1)) or a combination of the 2 drugs. Doses were chosen for their capacity to block the pressor response to ET-1 (for ET(A) blockade) or the depressor responses to sarafotoxin S6c or ET-1 (for ET(B) blockade). ET(A) and combined ET(A)-ET(B) blockade reduced systolic blood pressure to the same extent, whereas ET(B) blockade had no effect. In contrast, only combined ET(A)-ET(B) blockade significantly reduced heart rate. Both ET(A) and combined ET(A)-ET(B) blockade, but not ET(B) 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 ET(B) blockade) decreased LV collagen accumulation.. The chronic blockade of both ET(A) and ET(B) receptors improved systemic hemodynamics, as well as LV function and remodeling, to the same extent as ET(A) receptor blockade alone. However, only combined ET(A)-ET(B) receptor blockade decreased heart rate. Whether this differential effect on heart rate affects the long-term outcome after treatment with ET(A) or mixed ET(A)-ET(B) antagonists in CHF remains to be determined.

Topics: Animals; Atrasentan; Blood Pressure; Collagen; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Myocardial Infarction; Myocardium; Pyrrolidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Ventricular Function, Left