Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.

The cumulative hypotensive effect of bosentan suggests that, besides angiotensin II, endothelin-1 is independently involved in the pathophysiology of hypertension, which presents new therapeutic perspectives.

Beta3-AR stimulation exerts hypotensive effects, increases cardiac contractility and stimulates lipolysis in hypertensive dogs.

Abstract-Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%; PϽ0.01). These changes were accompanied by increased myocardial expression of preproendothelin-1 (2.5 times; PϽ0.05) and skeletal ␣-actin (3.6 times; PϽ0.05), but the expression of cardiac ␣-actin was not modified. Oral administration of carvedilol at a dose of 30 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 to rats with aortic banding normalized carotid pressure and left ventricular weight as well as preproendothelin-1 and skeletal ␣-actin gene expression. Carvedilol at a lower dose (7.5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1) and lacidipine 1 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy (PϽ0.01) and preproendothelin-1 overexpression (PϽ0.05). Labetalol (60 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) tended to exert similar effects but insignificantly. These results show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be related to their ability to blunt myocardial preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 did not prevent myocardial overexpression of skeletal ␣-actin, which suggests that, in this model, reexpression of a fetal gene can be activated by pressure overload independently of cardiac hypertrophy. ndothelin-1 (ET-1), a potent vasoconstrictor peptide produced by endothelial cells, 1 is endowed with remarkable growth-promoting properties. In cultured neonatal cardiac myocytes, ET-1 induces hypertrophy, 2,3 whereas other stimuli, such as mechanical stretch or angiotensin II (Ang II), may evoke hypertrophic growth by increasing ET-1 biosynthesis. 4,5 ET-1 has also been shown to play an important role in some in vivo models of cardiac hypertrophy. ET-1 receptor antagonists prevent, at least transiently, left ventricular (LV) hypertrophy evoked by suprarenal aortic banding. 6 ET-1 receptor blockade has been reported to attenuate cardiac hypertrophy in strokeprone spontaneously hypertensive rats (SHRSP) fed a high-salt diet, 7,8 in uninephrectomized rats receiving deoxycorticosterone acetate and a high-salt diet, 9,10 in renovascular hypertensive rats, 11 and in rats infused with Ang II 12 or norepinephrine. 13 Carvedilol is a nonselective, vasodilating ␤-blocker with potent antioxidant and free radical-scavenging properties 14 that is used in the treatment of hypertension, angina, and congestive heart failure. 15 Unlike other ␤-blockers, carvedilol reduces ET-1 biosynthesis in cultured endothelial cells. 16,17 Recently, carvedilol, at doses that do not reduce systemic blood pressure, has been re...