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.