1 Nitric oxide (NO)-mediated, endothelium-dependent vasodilator function in rat aortic smooth muscle was investigated in an in vitro model of endogenous vascular superoxide anion stress, generated by pretreatment with the Cu/Zn superoxide dismutase (SOD, EC 1.15.1.1) inhibitor, diethyldithiocarbamate (DETCA). 2 Contraction to noradrenaline (NA, 1 nM ± 1 mM) in endothelium-intact vessels was augmented after a 30 min pretreatment with DETCA (10 mM) followed by 30 min washout. This eect was abolished by N G -nitro-L-arginine methyl ester (L-NAME, 0.3 mM) and removal of the endothelium and partially reversed by exogenous Cu/Zn SOD (200 u ml 71 ). 3 Endothelium-and basal NO-dependent vasorelaxation to the phosphodiesterase (PDE) type V inhibitor ONO-1505 (4-[2-(2-hydroxyethoxy)ethylamino]-2-(1H-imidazol-1-yl)-6-methoxyquinazoline methanesulphonate) (0.1 ± 10 mM) was inhibited after DETCA (10 mM) pretreatment. In addition, the ability of L-NAME (0.3 mM) to enhance established contractile tone was eectively absent. 4 In contrast, DETCA pretreatment did not signi®cantly aect vasorelaxation to acetylcholine (ACh, 1 nM ± 3 mM) or S-nitroso-N-acetyl penicillamine (SNAP, 0.03 ± 30 mM). However, L-NAME (0.3 mM) unmasked an inhibitory eect of DETCA pretreatment on vasorelaxation to SNAP in endotheliumintact vessels while markedly potentiating vasorelaxation to SNAP in control tissue. 5 L-NAME (0.3 mM)-and exogenous catalase (200 u ml 71 )-sensitive vasorelaxation to exogenous Cu/ Zn SOD (200 u ml 71 ) was greater after DETCA (10 mM) pretreatment in endothelium-intact aortic rings. This dierence was abolished by catalase (200 u ml 71 ). 6 In conclusion, tissue Cu/Zn SOD inhibition elicited a selective lesion in basal endothelial function in rat isolated aortic smooth muscle, consistent with the inactivation of basal NO by superoxide anion. The resulting leftward shift in nitrovasodilator reactivity, due to the loss of the tonic depression by basal NO, is likely to mask the inhibitory eect of superoxide anion on agonist-stimulated endothelial function and nitrovasodilator-derived NO, thereby accounting for the dierential pattern of endothelial dysfunction after DETCA pretreatment.
Nitric oxide (NO)-mediated vasodilation induced by hyperinsulinaemia might involve an indirect action which promotes agonist-stimulated endothelial function. Our aim was to attempt to demonstrate such modulation of endothelium-dependent vasodilation by insulin in the rat isolated aorta. We found that vasodilation in response to acetylcholine, but not to adenosine diphosphate (ADP), histamine or the calcium ionophore A23187, was modestly enhanced after 20-min pretreatment with human insulin (100 nM) whereas endothelium-independent responses to the NO donor sodium nitroprusside were not significantly affected. Human insulin thus has the acute pharmacological action of selectively enhancing muscarinic receptor-mediated endothelial function in rat aortic vascular smooth muscle in-vitro.
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