STUDIES ON THE INFLUENCE OF INSULIN ON CYCLIC ADENOSINE-MONOPHOSPHATEINHUMAN VASCULAR SMOOTH-MUSCLE CELLS - DEPENDENCE ON CYCLIC GUANOSINE-MONOPHOSPHATE AND MODULATION OF CATECHOLAMINE EFFECTS

Insulin increases both cyclic guanosine monophosphate (cGMP) and cycli c adenosine monophosphate (cAMP) in human vascular smooth muscle cells (hVSMC) and attenuates noraderenaline-induced vasoconstriction. In th e present study, we aimed at investigating in hVSMC: 1) the interrelat ionships between insulin-induced increases of cGMP and cAMP; 2) the in sulin effect on the catecholamine modulation of cAMP. Catecholamines c ause both vasoconstriction and vasodilation. Vaso-constriction is attr ibutable to the reduced synthesis of cAMP in hVSMC through alpha(2)-ad renoceptors and to direct effects on calcium fluxes through alpha(1)-a drenoceptors; vasodilation is attributable to the increased synthesis of cAMP through beta-adrenoceptors. In the present study, we determine d the influence of insulin on cAMP in hVSMC incubated with or without: a) the inhibitor of guanylate cyclase methylene blue or the inhibitor of nitric oxide synthase N-G-monomethyl-L-arginine (L-NMMA); b) the b eta-adrenergic agonists isoproterenol and salbutamol; c) the physiolog ical catecholamines noradrenaline and adrenaline, d) noradrenaline + t he beta-adrenergic antagonist propranolol or the alpha(2)-adrenergic a ntagonist yohimbine; e) noradrenaline + methylene blue or L-NMMA. We d emonstrated that: 1) the Inhibition of the insulin-induced cGMP synthe sis blunts the insulin-induced increase of cAMP; 2) insulin induces a significant increase of cAMP also in the presence of isoproterenol, sa lbutamol, noradrenaline and adrenaline: the combined effects of insuli n and catecholamines were additive in some, but not in all the experim ents; 3) insulin enhances the cAMP concentrations induced by noradrena line also in the presence of alpha(2)- or beta-adrenergic antagonists: 4) in the presence of methylene blue or L-NMMA insulin does not modif y the noradrenaline effects on cAMP.