Adrenomedullin Increases Inducible Nitric Oxide Synthase in Rat Vascular Smooth Muscle Cells Stimulated With Interleukin-1

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Abstract
We investigated the effects of adrenomedullin on nitric oxide synthesis by measuring the production of nitrite, a stable metabolite of nitric oxide, in cultured rat vascular smooth muscle cells. Incubation of cultures with interleukin-1β (10 ng/mL) for 24 hours caused a significant increase in nitrite generation. The interleukin-1β–induced nitrite production by vascular smooth muscle cells was significantly increased by adrenomedullin in a dose-dependent manner (10 −10 to 10 −6 mol/L). This effect of adrenomedullin was significantly inhibited in the presence of N G -monomethyl- l -arginine. The adrenomedullin-induced nitrite production by interleukin-1β–stimulated cells was accompanied by increased inducible nitric oxide synthase mRNA accumulation. In the presence of the phosphodiesterase inhibitor isobutylmethylxanthine, interleukin-1β–induced nitrite accumulation was further increased, but the effect of adrenomedullin was not additive or synergistic. Adrenomedullin dose dependently increased intracellular cAMP levels of vascular smooth muscle cells. These results indicate that adrenomedullin augments nitric oxide synthesis in interleukin-1β–stimulated vascular smooth muscle cells, at least partially through a cAMP-dependent pathway.