Endothelial dysfunction associated with impaired production and/or stability of NO occurs in both type 1 and type 2 diabetics (79,80), and in obese insulin-resistant subjects (119). Multiple mechanisms contribute to the impairment in endothelium-dependent vasorelaxation in diabetes, including the oxidative inactivation of NO, reduced eNOS expression, reduced eNOS activity, vascular insulin resistance, elevation of circulating levels of asymmetric dimethylarginine (an endogenous NOS inhibitor), and a deficiency in tetrahydrobiopterin, a cofactor for eNOS (120-126).
Both ACE inhibition and ATI receptor antagonism improves acetylcholine-induced vasorelaxation in NIDDM subjects (127,128). Treatment of normotensive type 1 diabetics with an ACE inhibitor has also been shown to increase acetylcholine-induced vasorelaxation in (129,130). In these studies, no difference in vasodilatation induced by NO donors (sodium nitroprusside) was observed in diabetic vs control subjects, suggesting that the endothelium dysfunction was related to impairment in the generation of NO rather than an impaired response potential. ACE inhibition may improve endothelium-dependent relaxation by suppressing Ang II effects on vascular NADH/NADPH oxidase production of superoxide anions and/or vascular insulin signaling (131-133). Although ACE inhibition improves endothelium-dependent vasorelaxation induced by acute aceylcholine infusion (127,130) it did not improve endothelial function in response to flow-mediated dilation (134,135). Therefore, ACE inhibition appears to selectively affect endothelium response acetylcholine infusion in diabetes. Additional studies are needed to determine whether ACE inhibition affects endothelial functions in diabetes apart from its hemodynamic effects.
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