INSULIN-INDUCED ATTENUATION OF NORADRENALINE-MEDIATED VASOCONSTRICTION IN RESISTANCE ARTERIES FROM WISTAR RATS IS NITRIC-OXIDE DEPENDENT

1. We studied the mechanism of insulin-mediated attenuation of noradre naline-induced vasoconstriction in mesenteric resistance arteries (app roximately 210 mu m diameter) from 10-week-old male Wistar rats (n = 1 0; weight 321 +/- 11 g). Exposure to physiological concentrations of i nsulin (50 m-units/l) significantly blunted the contractile response t o noradrenaline over the concentration range 3 x 10(-6) to 3 x 10(-5) mol/l (16 vessels; 13.1 +/- 4.3% reduction in maximum tension at 3 x 1 0(-5) mol/l noradrenaline; P < 0.01 versus no insulin). 2. This effect of insulin was prevented by the nitric oxide synthase inhibitor NG-ni tro-L-arginine methyl ester (10(-4) mol/l; 16 vessels; 3.3 +/- 9.1% re duction in maximum tension; P = 0.8 versus no insulin). There was no e vidence of fatigue in four noradrenaline dose-response curves for 16 c ontrol vessels in the absence of insulin and NG-nitro-L-arginine methy l ester (P = 0.8; first versus second dose-response curve). With L-arg inine present in the incubation medium, insulin again attenuated the n oradrenaline-induced vasoconstriction (10.7 +/- 3.2% reduction in tens ion; P = 0.02 versus L-arginine and no insulin; P = not significant ve rsus insulin and no L-arginine). 3. Endothelium-dependent relaxation w as initially confirmed in all vessels by demonstrating normal acetylch oline- (5.4 x 10(-7) to 1.1 x 10(-4) mol/l) induced vasodilatation in vessels preconstricted with noradrenaline (6 x 10(-6) mol/l) in the ab sence of NG-nitro-L-arginine methyl ester, L-arginine and insulin (P = not significant between the different groups of vessels). 4. We concl ude that insulin attenuates noradrenaline-induced vasoconstriction in resistance arteries by stimulation of nitric oxide release. Abnormal i nsulin-stimulated nitric oxide release could be of relevance in the pa thogenesis of hypertension and diabetic microvascular disease.