Characterization of an inhibitor of nitric oxide synthase in human-hand veins.
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-l-arginine (l-NMMA) as an inhibitor of bradykinin-mediated, endothelium-dependent dilation using the human hand-vein compliance technique. We also compared the efficacy of l-NMMA with methylene blue, an inhibitor of guanylate cyclase, in blocking bradykinin-mediated vasodilation. l-NMMA potently inhibited bradykinin-induced venodilation with a log ED50 of 3.74 +/- 0.52 (geometric mean of 5.5 micrograms/min). Responses to bradykinin (0.27-555 ng/min) were tested in veins pre-constricted with the alpha-adrenergic agonist phenylephrine. l-NMMA (25 micrograms/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 l-NMMA infusion, indicating that its effects were reversible. In another set of experiments we compared the efficacy of methylene blue to l-NMMA; methylene blue decreased bradykinin-mediated venodilatory response to 53 +/- 17%; when l-NMMA was added, the response was further decreased to 32 +/- 9% (p < 0.002). We conclude that l-NMMA is a very efficacious NO synthase inhibitor in human veins and it is likely functionally reversible.
Bedarida
G V
GV
Division of Clinical Pharmacology, Stanford University Medical Center, California.
Kim
D
D
Blaschke
T F
TF
Hoffman
B B
BB
D000328:Adult; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006225:Hand / Q000098:blood supply; D006801:Humans; D008297:Male; D008751:Methylene Blue; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019001:Nitric Oxide Synthase; D010656:Phenylephrine / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014680:Veins / Q000201:enzymology; D019323:omega-N-Methylarginine
D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D001920:Bradykinin; D008751:Methylene Blue