Characterization of an Inhibitor of Nitric Oxide Synthase in Human-Hand Veins

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Abstract
The enzyme nitric oxide synthase mediates synthesis of nitric oxide (NO) from 1-arginine in endothelial cells. NO, also known as endothelium-dependent relaxing factor (EDRF), diffuses to smooth muscle cells where it leads to cGMP production and dilation. We characterized the potency, efficacy and time course of NG-monomethyl-1-arginine (1-NMMA) as an inhibitor of bradykinin-mediated, endothelium-dependent dilation using the human hand-vein compliance technique. We also compared the efficacy of 1-NMMA with methylene blue, an inhibitor of guanylate cyclase, in blocking bradykinin-mediated vasodilation. 1-NMMA potently inhibited bradykinin-induced venodilation with a log ED50 of 3.74 ± 0.52 (geometric mean of 5.5 μg/ min). Responses to bradykinin (0.27-555 ng/min) were tested in veins pre-constricted with the α-adrenergic agonist phenylephrine. 1-NMMA (25 μg/min) decreased bradykinin's maximal venodilatory response from 90 ± 22 % to 39 ± 15% (p<0.05). Complete recovery of bradykinin venodilation was obtained within 155 minutes after stopping 1-NMMA infusion, indicating that its effects were reversible. In another set of experiments we compared the efficacy of methylene blue to 1-NMMA; methylene blue decreased bradykinin-mediated venodilatory response to 53 ± 17%; when 1-NMMA was added, the response was further decreased to 32±9% (p<0.002). We conclude that 1-NMMA is a very efficacious NO synthase inhibitor in human veins and it is likely functionally reversible.

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