INSULIN INCREASES CYCLIC-NUCLEOTIDE CONTENT IN HUMAN VASCULAR SMOOTH-MUSCLE CELLS - A MECHANISM POTENTIALLY INVOLVED IN INSULIN-INDUCED MODULATION OF VASCULAR TONE

It has been suggested that insulin exerts a vasodilating effect, but t he mechanisms involved are not completely understood. Since cyclic nuc leotides mediate the vasodilation induced by endogenous substances, su ch as prostacyclin and nitric oxide, we aimed to investigate the influ ence of insulin (concentration range 240-960 pmol/l) on both cyclic ad enosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content in human vascular smooth muscle cells, Insulin dose-dependent ly increased both nucleotides (cAMP: from 0.7+/-0.1 to 2.6+/-0.4 pmol/ 10(6) cells, p = 0.0001; cGMP: from 1.3+/-0.2 to 3.4+/-0.7 pmol/10(6) cells, p = 0.033). This increase is receptor-mediated, since it was bl unted when cells were preincubated with the tyrosine kinase inhibitor genistein. The effect of insulin remained significant (p = 0.0001) whe n preincubation with the phosphodiesterase inhibitor theophylline prev ented cyclic nucleotide catabolism. The increase of cGMP was blunted w hen the cells were preincubated with the guanylate cyclase inhibitor m ethylene blue, and with the nitric oxide-synthase inhibitor N-G-monome thyl-L-arginine. At all the concentrations tested, insulin potentiated the increase of cAMP induced by the stable prostacyclin analogue Ilop rost (p = 0.0001), whereas only at 1920 pmol/l did it potentiate the c GMP increase induced by glyceryltrinitrate (p = 0.05), This study demo nstrates that the vasodilating effects exerted by insulin may at least in part be attributable to an increase of both cGMP and cAMP via a re ceptor-mediated activation of adenylate and guanylate cyclases in huma n vascular smooth muscle cells and that the insulin effect on cGMP is mediated by nitric oxide.