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The 8-pCPT-cGMP antiaggregatory effects, however, were greater in controls for each concentration of the cyclic nucleotide analog at all investigated times (P <0.
In fact, in the present study we used highly lipophilic, permeable cyclic nucleotide analogs (i.
50], values of both cyclic nucleotide analogs were correlated with HONIA IR and with other variables such as HDL cholesterol, triglycerides, and systolic and diastolic blood pressure, whose alterations are considered for the diagnosis of metabolic syndrome (27).
50], values of both cyclic nucleotide analogs remained significantly correlated with HONIA IR, thus suggesting that the molecular defect involved in the resistance to cyclic nucleotides is directly related to insulin resistance.
Mechanistically, the present study clearly showed impaired activation of the cyclic nucleotide /specific kinase/ VASP pathways in individuals with central obesity.
Because the molecular defects observed in obese individuals are involved in crucial steps of the control of platelet function (12-16), the present results may be relevant in explaining resistance not only to the antiaggregatory effects of the cyclic nucleotide analogs but also to other antiaggregatory mediators, which we investigated in previous studies (6, 9,11).
The phosphorylation state of VASP in intact cells is regulated to a major extent by serine/ threonine protein phosphatases (37); therefore further studies are needed to evaluate whether increased activity of these phosphatases may play a role in the reduced content of phosphorylated VASP in platelets from obese individuals in response to cyclic nucleotide analogs.
Our previous studies showed resistance to antiaggregatory action of agents due to impaired ability to increase cyclic nucleotide synthesis (6-11).
Simple and multiple regression analysis concerning the relation between cyclic nucleotide IC50 values and different variables measured in controls and obese individuals.
Platelet response to cyclic nucleotides is complex and depends on nucleotide concentrations and the timecourse of platelet exposure.