Carvedilol inhibits endothelin-1 biosynthesis in cultured human coronary artery endothelial cells

Carvedilol, a multiple action neurohumoral antagonist, has been reported recently to significantly reduce mortality in congestive heart failure (CHF) patients, In addition to being a P-adrenoceptor antagonist, one of the unique aspects of the biological effects of carvedilol is that it is also a potent antioxidant with antimitogenic properties, As there is a significant correlation between plasma immunoreactive endothelin-1 (ET-1) levels and the severity of CHF, the present study was designed to determine the effects of carvedilol on ET-1 biosynthesis in cultured human coronary artery endothelial cells (HCAECs). HCAECs were treated with carvedilol 15 min prior to the addition of serum and ET-1 levels were measured in the cell culture conditioned medium 24 h later. Carvedilol (10 mu M) significantly inhibited basal ET-1 production in HCAECs by 62 +/- 8%. Carvedilol produced a concentration-dependent inhibition of serum-mediated stimulation of ET-1 biosynthesis with an IC50 = 1.2 mu M. PreproET-1 mRNA expression was also inhibited by carvedilol. Other P-adrenoceptor antagonists, such as propranolol (10 mu M) or celiprolol (10 mu M), did not effect ET-1 biosynthesis. Furthermore, the antioxidant probucol (10 mu M) did not effect ET-1 production. Immunohistochemical analysis of HCAECs demonstrated that resting HCAECs have expression of ET-1 and can be inhibited by carvedilol, The results of the present study demonstrate that serum stimulation of HCAECs produced an increase in ET-1 expression, and carvedilol treatment caused a marked decrease in stimulated ET-1 expression as compared to serum-treated HCAECs. These data indicate that carvedilol directly inhibits the biosynthesis of ET-1 in HCAECs, and this effect may contribute to its vasodilating and antiproliferative actions. Furthermore, these effects may contribute to the ability of carvedilol to improve clinical outcome in CHF patients. (C) 1998 Academic Press Limited.