Carvedilol stimulates nitric oxide synthesis in rat cardiac myocytes

The purpose of this study was to investigate the effects of the beta-adrenergic blocker carvedilol on nitric oxide (NO) synthesis in cardiac myocytes. We measured the accumulation of nitrite, a stable oxidation product of NO, and the expression of inducible NO synthase (iNOS) protein in cultured neonatal rat cardiac myocytes. Incubation of the cultures with interleukin 1 beta (IL-1 beta; 10 ng/ml) caused a marked increase in nitrite production. Although carvedilol alone showed no effect on nitrite accumulation, it significantly enhanced IL-1 beta-induced nitrite production by cardiac myocytes. The effect of carvedilol was completely abolished in the presence of aminoguanidine or actinomycin D. The nitrite production enhanced by carvedilol was accompanied by increased iNOS protein expression. Unlike carvedilol, other beta-blockers, namely propranolol, atenolol and arotinolol, did not enhance IL-1 beta-induced nitrite production. Addition of isoproterenol significantly increased nitrite production by IL-1 beta-stimulated cardiac myocytes. Atenolol suppressed this isoproterenol-induced nitrite accumulation, while carvedilol further increased the nitrite accumulation. These findings indicate that carvedilol increases NO synthesis in IL-1 beta-stimulated rat cardiac myocytes by a beta-adrenoceptor-independent mechanism.