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 beta-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 microM) 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 microM. PreproET-1 mRNA expression was also inhibited by carvedilol. Other beta-adrenoceptor antagonists, such as propranolol (10 microM) or celiprolol (10 microM), did not effect ET-1 biosynthesis. Furthermore, the antioxidant probucol (10 microM) 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.