CHARACTERIZATION OF AN INHIBITOR OF NITRIC-OXIDE SYNTHASE IN HUMAN-HAND VEINS

The enzyme nitric oxide synthase mediates synthesis of nitric oxide (N O) from 1-arginine in endothelial cells. NO, also known as endothelium -dependent relaxing factor (EDRF), diffuses to smooth muscle cells whe re it leads to cGMP production and dilation. We characterized the pote ncy, efficacy and time course of N-G-monomethyl-1-arginine (1-NMMA) as an inhibitor of bradykinin-mediated, endothelium-dependent dilation u sing the human hand-vein compliance technique. We also compared the ef ficacy of 1-NMMA with methylene blue, an inhibitor of guanylate cyclas e, in blocking bradykinin-mediated vasodilation. 1-NMMA potently inhib ited bradykinin-induced venodilation with a log ED(50) of 3.74+/-0.52 (geometric mean of 5.5 mu g/ min). Responses to bradykinin (0.27-555 n g/min) were tested in veins pre-constricted with the alpha-adrenergic agonist phenylephrine. 1-NMMA (25 mu g/min) decreased bradykinin's max imal venodilatory response from 90+/-22% to 39 +/-15% (p <0.05). Compl ete recovery of bradykinin venodilation was obtained within 155 minute s after stopping 1-NMMA infusion, indicating that its effects were rev ersible. In another set of experiments we compared the efficacy of met hylene blue to 1-NMMA; methylene blue decreased bradykinin-mediated ve nodilatory response to 53+/-17%; when 1-NMMA was added, the response w as 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 like ly functionally reversible.