It is still unclear, however, which primary stimulus specifically activates ET-dependent signaling pathways. We therefore examined in adult rats (n ϭ 51) the effects of a selective ET A receptor antagonist in experimental models of cardiac hypertrophy, in which myocardial growth is predominantly initiated by a single primary stimulus. Rats were exposed to mechanical overload (ascending aortic stenosis), increased levels of circulating ANG II (ANG II infusion combined with hydralazine), or adrenergic stimulation (infusion of norepinephrine in a subpressor dose) for 7 days. All experimental treatments significantly increased left ventricular weight/body weight ratios compared with untreated rats, whereas systolic left ventricular peak pressure was increased only after ascending aortic stenosis. ET A receptor blockade exclusively reduced norepinephrine-induced cardiac hypertrophy and atrial natriuretic peptide gene expression. Blood pressure levels and heart rates remained unaffected during ET A receptor blockade in all experimental groups. These data indicate that in rat left ventricle, the ET-dependent signaling pathway leading to early development of cardiac hypertrophy and fetal gene expression is primarily activated by norepinephrine. angiotensin II; endothelin-A receptor; gene expression; norepinephrine; remodeling ENDOTHELIN (ET) is a potent vasoconstrictor that was first described by Yanagisawa and co-workers in 1988 (35). During the past years, it has become clear that in addition to its hemodynamic effects, ET-1 can also act as a growth-promoting hormone in the myocardium. Initial observations made on isolated cardiomyocytes revealed an increase of protein biosynthesis and cellular volume after the addition of ET-1 to the culture medium (11). Consecutive studies in intact animals demonstrated a stimulation of the cardiac ET system in several forms of extrinsic cardiac hypertrophy (2,10,12,15,20,21), particularly during its early development (12,15,21). Correspondingly, either selective ET A subtype receptor blockade or unselective ET A/B subtype receptor blockade significantly attenuated early myocardial hypertrophy and fetal gene expression associated with renal artery stenosis (7, 9), suprarenal abdominal aortic banding (12), ANG II infusion (8), and high-dose infusion of norepinephrine (NE) (15). In all of these pathophysiologically relevant models, however, several primary stimuli, which can individually induce myocardial hypertrophy, are activated concurrently, i.e., mechanical load, the renin-angiotensin system, and/or the sympathetic nervous system. Accordingly, it remains unclear whether the cardiac ET system is specifically activated either by one or by a combined action of several primary stimuli or whether it constitutes a more general downstream signaling pathway of myocardial growth.In the present study, we therefore sought to design experimental paradigms of extrinsically induced cardiac hypertrophy, in which myocardial growth is predominantly initiated by a single primary stimulus. To incr...
