Inotropic agents differentially inhibit the induction of nitric oxide synthase by endotoxin in cultured macrophages

We investigated the effects of inotropic agents with phosphodiesterase III inhibitory properties, amrinone, pimobendan and vesnarinone, and cell permeable cyclic nucleotide analogue, 8-bromo adenosine 3'5'-cyclic monophosphate (8 Br-cAMP) on the induction of nitric oxide synthase (NOS) by lipopolysaccharide in J774A.1 macrophages in vitro. Although all three inotropic agents inhibited nitrite accumulation, the degree of inhibition was different, with pimobendan being the most potent inhibitor and amrinone the least. Vesnarinone inhibited nitrite formation biphasically. 8 Br-cAMP increased nitrite production at high concentrations, suggesting that the inhibitory effects of inotropic agents could not be explained by an increase in cAMP. Although differential inhibition of inducible NOS by inotropic agents may explain the different effects of these drugs in patients with heart failure, further study is necessary to reach this conclusion.