NATRIURETIC PEPTIDE-AUGMENTED INDUCTION OF NITRIC-OXIDE SYNTHASE THROUGH CYCLIC GUANOSINE 3',5'-MONOPHOSPHATE ELEVATION IN VASCULAR SMOOTH-MUSCLE CELLS

To elucidate the role of natriuretic peptides in vascular remodeling, the effects of atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide (CNP) on the induction of inducible nit ric oxide (NO) synthase (iNOS) in rat aortic smooth muscle cells were examined. Although none of the peptides when applied alone induced the production of nitrite, a stable end product of NO, each peptide drama tically enhanced nitrite production induced by a cytokine combination of interleukin-1 alpha and tumor necrosis factor-alpha. Each natriuret ic peptide stimulated intracellular cGMP accumulation in a dose-depend ent manner. Time-dependent nitrite production by the cytokines was inc reased by CNP cotreatment and inhibited by N-G-methyl-L-arginine, indi cating involvement of the L-arginine-NO pathway. Northern blot analysi s showed that the augmented nitrite production was accompanied by an i ncrease in iNOS messenger RNA. A cGMP analog, 8-bromo-cGMP, completely mimicked all of the effects of CNP described above. A cGMP-dependent protein kinase inhibitor, KT5823, paradoxically increased nitrite prod uction and iNOS messenger RNA levels induced by the combination of 8-b romo-cGMP and both cytokines or by the two cytokines only. These data demonstrate the stimulatory effect of cGMP on cytokine-induced iNOS an d imply that natriuretic peptides may play a regulatory role in vascul ar remodeling via the production of large amounts of NO.