Endothelin-Converting Enzyme Inhibition in the Rat Model of Acute Heart Failure: Heart Function and Neurohormonal Activation

Abstract

Endothelin-1 (ET-1) has been implicated in many cardiovascular diseases, including acute heart failure (AHF) due to myocardial ischemia. Previously we described the oral endothelin-converting enzyme (ECE) inhibitor, PP36, and in this study, we investigated its cardioprotective effect in more detail, and examined the role of PP36 in the neurohormonal activation in rats that had been subjected to acute myocardial ischemia due to the microsphere embolization of coronary microcirculation. PP36 treatment (3.5 x 10(-5) M/kg/day) led to a significant fourfold decrease in hypertensive response when big-ET-1 was administered to healthy, conscious rats. ECE inhibition did not affect mortality during the first 48 hours after ischemia initiation. Systemic hemodynamic, heart function, and neurohormonal activation were analyzed in the healthy control group, the AHF group, and the AHF+PP36 group two days after AHF induction. In conscious rats in the AHF+PP36 group, mean arterial pressure (MAP) was restored and became similar to that of the MAP of the control group. In anesthetized rats, in the AHF+PP36 group, MAP was not restored and was 22% lower than the MAP of the control group. Myocardial contractility was partially restored and cardiac relaxation significantly improved after PP36 application. Further analysis of cardiac output and peripheral resistance in anesthetized rats revealed no differences between the AHF group and the AHF+PP36 group. There were no differences in plasma ET-1 concentration, serum angiotensin converting enzyme activity, and in the adrenal glands' catecholamine content between the AHF group and the AHF+PP36 group. However, rats in the AHF+PP36 group demonstrated a 60% decrease in cardiac endothelial nitric oxide synthase (eNOS) protein expression, and a 56% reduction of myocardial norepinephrine release, when compared with the AHF group's animals. These results suggest that PP36 can preserve heart function during the recovery from acute ischemic injury, and may modulate the cardiac norepinephrine release and eNOS protein level.

Endothelin-1 and Norepinephrine Overflow from Cardiac Sympathetic Nerve Endings in Myocardial Ischemia

“…However, previous in vivo studies of myocardial ischemia in animal models have provided clinically relevant information [25–29, 53]. In accordance with ex vivo data, each of the selective ET A R antagonists [26, 28], the nonselective ET A R/ET B R antagonist [25, 27, 28] and the ECE inhibitor [29] have been reported to suppress increases in NE levels resulting from myocardial ischemia. For example, Fraccarollo et al [26] demonstrated that long-term treatment with the selective ET A R antagonist LU135252 decreased plasma NE concentrations 12 weeks after proximal left coronary artery ligation in rats.…”

“…Likewise, Kolettis et al [27] reported that bosentan markedly decreased serum NE levels 24 h postligation of the left coronary artery as well as the total duration of ventricular tachyarrhythmias during the delayed phase (1–24 h) postligation in rats. In addition, an orally active ECE inhibitor PP36 has been indicated to suppress cardiac tissue NE release 48 h after acute myocardial ischemia due to microsphere embolization of coronary microcirculation in rats [29]. Left ventricular contractility was partially restored and distention significantly improved by PP36 treatment in this research.…”

“…It has been reported that an ischemic event results in increases in ET-1 levels [15–18] and its binding sites [19, 20]. Additionally, blockade of its effects has been shown to act protectively against postischemic cardiac and/or coronary dysfunction both in animal studies [18, 21–29] and human clinical trials [30, 31]. These findings suggest that ET-1 plays an important role in the pathophysiology of myocardial ischemia.…”