EFFECTS OF VESNARINONE ON NITRIC-OXIDE SYNTHESIS IN RAT CARDIAC MYOCYTES

Objective: The purpose of this study was to investigate the effects of vesnarinone on nitric oxide (NO) synthesis in cardiac myocytes. Metho ds: We measured the accumulation of nitrite, a stable oxidation produc t of NO, and the expression of inducible NO synthase (iNOS) protein in cultured neonatal rat cardiac myocytes. Results: Incubation of the cu ltures with interleukin-1 beta (IL-1 beta; 10 ng/ml) and tumor necrosi s factor alpha (TNF alpha; 10 ng/ml) caused a marked increase in nitri te production. Although vesnarinone by itself showed no effect on nitr ite accumulation, it enhanced cytokine-induced nitrite production by c ardiac myocytes in a dose-dependent manner. The effect of vesnarinone was completely abolished in the presence of N-G-monomethyl-L-arginine or actinomycin D. The vesnarinone-induced nitrite production was accom panied by increased iNOS protein expression. In the presence of dibuty ryl-cAMP, cytokine-induced nitrite accumulation was further increased. but the stimulatory effect of vesnarinone on nitrite accumulation was diminished. The effect of vesnarinone was also inhibited by Rp-8-Br-c AMPS, a competitive inhibitor of protein kinase A, in a dose-dependent manner. Conclusions: These findings indicate that vesnarinone increas es NO synthesis in cytokine-stimulated cardiac myocytes, at least part ially through a cAMP-dependent pathway. (C) 1998 Elsevier Science B.V.