NITRIC-OXIDE INHIBITS ANGIOTENSIN-II-INDUCED MIGRATION OF RAT AORTIC SMOOTH-MUSCLE CELL - ROLE OF CYCLIC-NUCLEOTIDES AND ANGIOTENSIN(1) RECEPTORS

Nitric oxide (NO) and angiotensin II (AII) can effect vascular smooth muscle cell (SMC) proliferation. However, the effects of such agents o n SMC migration, an equally important phenomenon with regard to vascul ar pathophysiology, have received little attention. The objectives of the present study were: (a) to determine whether NO inhibits AII-induc ed migration of vascular SMCs; (b) to investigate the mechanism of the interaction of NO and An on SMC migration; and (c) to evaluate the AI I receptor subtype that mediates AII-induced SMC migration. Migration of rat SMCs was evaluated using a modified Boydens Chamber (transwell inserts with gelatin-coated polycarbonate membranes, 8 mu m pore size) . AII stimulated SMC migration in a concentration-dependent manner, an d this effect was inhibited by sodium nitroprusside (SNP) and S-nitros o-N-acetylpenicillamine (SNAP). In the presence of L-arginine, but not D-arginine, IL-1 beta, an inducer of inducible NO synthase, also inhi bited AII-induced SMC migration, and this effect was prevented by the NO-synthase inhibitor, N-nitro-L-arginine methyl ester. The effects of NO donors on AII-induced SMC migration were mimicked by 8-bromo-cGMP. Also, the antimigratory effects of SNAP were partially inhibited by L Y83583 (an inhibitor of Soluble guanylyl cyclase) and by KT5823 (an in hibitor of cGMP-dependent protein kinase). Although 8-bromo-cAMP (cAMP ) also mimicked the antimigratory effects of NO donors, the antimigrat ory effects of SNAP were not altered by 2',5' -dideoxyadenosine (an in hibitor of adenyl cyclase) or by (R)-p-adenosine-3',5'-cyclic phosphor othioate (an inhibitor of the cAMP-dependent protein kinase). Low conc entrations of the subtype AT(1)-receptor antagonist CGP 48933, but not the subtype AT(2)-receptor antagonist CGP 42112, blocked AII-induced SMC migration. These findings indicate that (a) NO inhibits AII-induce d migration of vascular SMCs; (6) the antimigratory effect of NO is me diated in part via a cGMP-dependent mechanism; and (c) AII stimulates SMC migration via an AT(1) receptor.