INSULIN EXERTS OPPOSITE EFFECTS ON PLATELET-FUNCTION AT PHYSIOLOGICALAND SUPRAPHYSIOLOGICAL CONCENTRATIONS

In this study, we investigated the effects of a 3-min insulin incubati on both at physiological and at supraphysiological concentrations on p latelet aggregation and intraplatelet cyclic guanosine monophosphate ( cGMP) levels both in the absence and in the presence of phosphodiester ase inhibition. We observed that insulin at concentrations in the rang e 0.25-2 nmol/L decreases platelet response to adenosine 5-diphosphate (ADP), being Effective Dose 50 (ED(50)) for ADP with 2 nmol/L insulin 164+/-15% of the basal value, p=0.005; furthermore, insulin increases intraplatelet content of cGMP (from basal 7.3+/-0.6 pmol/10(9) pits t o 14.6+1.2 pmol/10(9) pits with 2 nmol/L insulin, p=0.0001) and does n ot affect the platelet cGMP increase induced by nitrates. On the contr ary, at very elevated concentrations (25-200 nmol/L) insulin increases platelet aggregation to ADP (ADP ED(50) with 200 nmol/L insulin being 81+4% of the basal value, p=0.01), decreases intraplatelet content of cGMP (from basal 7.2+/-0.1 pmol/10(9) pits to 5.7+/-0.2 pmol/10(9) pi ts with 200 nmol/L insulin, p=0.01) and attenuates the platelet cGMP i ncrease induced by nitrates. When cGMP catabolism is inhibited by theo phylline or the selective cGMP phosphodiesterase inhibitor zaprinast, insulin shows anti-aggregating effects also at highly supraphysiologic al concentrations (25-200 nmol/L). These results indicate that insulin , depending on the concentrations employed, shows opposite effects on platelet function, and they provide information about the mechanisms i nvolved: actually, insulin is able to increase both cGMP synthesis, th rough guanylate cyclase activation, and cGMP catabolism, through phosp hodiesterase activation. At physiological or slightly supraphysiologic al concentrations the first phenomenon is prevailing, so that cGMP int raplatelet values increase and insulin shows antiaggregating propertie s, whereas, at supraphysiological concentrations, insulin reduces cGMP levels through a prevailing phosphodiesterase activation, as supporte d by the fact that, when cGMP catabolism is prevented, insulin shows a nti-aggregating properties also at the highest concentrations used.