Our goal was to determine whether hyperinsulinaemic and diabetic state can affect vasodepressor effects of insulin and pioglitazone (PIO), an insulin-sensitizing thiazolidinedione drug. For this purpose, we established an experimental type 2 diabetic model (streptozotocin-nicotinamide model) in adult male rats (DIA group) and some of them were treated with chronically high-dose insulin for 14 weeks (INS-T DIA group). Blood pressure, glucose, HbA(1C), triglyceride, cholesterol, plasma insulin levels and body weight were measured. Endothelium-denuded aortic rings were suspended in tissue baths for reactivity studies. Cumulative concentration-response curves of serotonin (5-hydroxytryptamine; 5-HT) were evaluated before and after 1 h incubations with insulin (10(-7) or 10(-4) U/l), or PIO (10 mu mol/l) or insulin plus PIO. PIO or higher concentration of insulin (10(-4) U/l), each alone, attenuated 5-HT induced contractions in both groups of aortae. Vasodepressor effect of insulin was diminished by 12% 4% in aortae from INS-T DIA group. The presence of PIO in the bath did not affect impaired vasodepressor response of insulin. Contractions induced by KCl, or Bay K 8644 were partly inhibited after PIO incubations, with similar E-max and pD(2) values in both groups of aortae. The results indicate that PIO does not modulate directly vasodepressor effect of insulin in hyperinsulinaemic/diabetic state. But, the direct vasodepressor effect of PIO, partly by Ca2+ channel inhibition, may be beneficial by improving insulin utilization due to increasing blood flow to the insulin-sensitive tissues in hyperinsulinaemic/diabetic state.