An intracardiac production of aldosterone has been recently reported in rat. This production is increased both acutely and chronically by angiotensin II, observations suggesting that the heart contains a steroidogenic system that is regulated similarly to the adrenal one. Cardiac production of aldosterone is small compared with that of the adrenal, raising the question of its function in normal conditions. Moreover, the regulation of this synthesis in pathophysiologic states remains unknown. In an analysis of the effects of a one-month myocardial infarction (MI) on the cardiac steroidogenic system, it was observed that aldosterone-synthase mRNA and the aldosterone concentration were increased by 2- and 3.5-fold, respectively, in the noninfarcted part of the rat left ventricle. MI also induced a 1. 9-fold increase in the cardiac angiotensin II level. Losartan prevented these changes, and the MI-induced collagen deposition in noninfarcted area of the left ventricle was reduced by 1.6- and 2. 5-fold by both spironolactone and losartan treatments, respectively. Thus, these observations indicate that MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This activation is mediated by cardiac angiotensin II via the angiotensin II type 1 (AT1) receptor, and the resultant increase of intracardiac aldosterone level may be involved in post-MI ventricular remodeling.

In patients with cirrhosis, the plasma level of endothelin, a potent vasoconstrictor peptide, is elevated, and endothelin plays a role in increased intrahepatic vascular resistance. Thus, the aim of this study was to evaluate the hemodynamic effects of bosentan, a mixed ET A and ET B endothelin receptor antagonist in three models of portal hypertension. In all groups of rats, endothelin (2 g/kg intravenously) administration significantly increased intrahepatic vascular resistance. In rats with secondary biliary cirrhosis, bosentan (30 mg/kg) significantly reduced portal pressure from 14.6 ؎ 1.2 to 12.1 ؎ 0.6 mm Hg, while portal blood flow and cardiac output increased by 45% and 57%, respectively. Thus, hepatocollateral vascular resistance decreased significantly from 177 ؎ 19 to 101 ؎ 9 dyn · s · cm ؊5 ؋ 10 ؊3 . Similar results were observed in rats with CCl 4 -induced cirrhosis. In isolated perfused cirrhotic rat livers, bosentan (1 to 100 mol/L) had no significant effect on hepatic vascular resistance. In portal vein-stenosed rats, bosentan administration significantly decreased portal pressure from 13.1 ؎ 0.6 to 11.4 ؎ 0.5 mm Hg by reducing portosystemic vascular resistance, because bosentan had no effect on vascular resistance of normal rat liver. In conclusion, bosentan administration decreased portal pressure in vivo by reducing hepatocollateral vascular resistance in rats with cirrhosis. Thus, mixed endothelin receptor antagonists might be a new approach in the pharmacological treatment of portal hypertension. (HEPATOLOGY 1998;28:655-659.)Numerous studies have found that plasma concentrations of endothelin-1 (ET-1) and endothelin-3 (ET-3) are increased in patients with cirrhosis and are related to the severity of the liver disease. 1-8 Despite this, these patients have low arterial pressure and systemic vascular resistance. This discrepant finding may be caused, at least in part, by a vascular hyporesponsiveness to endothelins that has been identified in cirrhotic rats. 9,10 Moreover, it has been shown that endothelins induce sinusoidal vasoconstriction through both ET A and ET B receptors and increase intrahepatic vascular resistance in the normal and perfused cirrhotic liver. [11][12][13][14][15] These results suggest that endothelins play a role in the mechanism of intrahepatic portal hypertension. Thus, administration of the mixed ET A and ET B receptor antagonist, 16,17 bosentan, may decrease intrahepatic vascular resistance and decrease portal hypertension. The aim of this study was to evaluate the acute hemodynamic effect of both bosentan and endothelin in two animal models of cirrhosis and in one model with extrahepatic portal hypertension. MATERIALS AND METHODSAnimals. Sixty-four male Sprague-Dawley rats (Charles River Laboratories, Saint-Aubin-lès-Elbeuf, France) were divided into four groups. The first group contained 16 normal rats. The second group contained 16 rats with portal hypertension induced by the partial ligation of the portal vein, as previously described. 18 The hemodynamic study w...