Cyclic AMP Augments Cytokine-stimulated Nitric Oxide Synthesis in Rat Cardiac Myocytes

We investigated the effect of adenosine 3′,5′-cyclic monophosphate (cAMP) on inducible nitric oxide synthase (iNOS) expression in cultured neonatal rat cardiac myocytes. Incubation of cardiac myocytes for 24 h with interleukin-1β(IL-1β) caused a significant increase in the production of nitrite, a stable metabolite of nitric oxide. Dibutyl cAMP (db-cAMP) significantly augmented nitrite production by IL-1β-stimulated, but not by unstimulated cells, in a dose-dependent manner. db-cAMP also dose dependently increased nitrite production by tumor necrosis factor-α(TNF-α)-stimulated cells. Simultaneous incubation with NG-mono?methyl- -arginine completely inhibited the effect of db-cAMP on nitrite production. cAMP-induced nitrite production by cytokine-stimulated cells was accompanied by increased iNOS mRNA accumulation. The synergistic effect of cAMP on IL-1β-induced nitrite accumulation was mimicked by cAMP-generating agonists forskolin and isoproterenol. These results indicate that cAMP upregulates cytokine-induced iNOS expression in cardiac myocytes.