title: Differential effects of L-arginine on the inhibition by NG-nitro-L-arginine methyl ester of basal and agonist-stimulated EDRF activity.
abstract: 1. An isolated, buffer-perfused rabbit ear preparation was used to investigate the influence of NG-nitro-L-arginine methyl ester (L-NAME) on endothelium-dependent vasodiltation and modulation of vasoconstrictor responses and vascular conductance. 2. Acetylcholine (0.55 pmol-1.6 nmol) caused dose-related vasodilatation of preparations constricted by the combination of 5-hydroxytryptamine and histamine (both 1 microM), with an ED50 = 31.1 +/- 7.8 pmol and a maximum dilatation of 69.9 +/- 4.3%. In the presence of 10 microM L-NAME the dose-response for vasodilator effects was shifted significantly (P less than 0.001) to the right (ED50 = 3.07 +/- 1.18 nmol) and there was a significant (P less than 0.01) depression of the maximum response (Rmax = 44.3 +/- 4.0%). The higher concentration of 100 microM L-NAME completely abolished vasodilatation to acetylcholine. L-Arginine (10 mM) did not reverse the inhibitory actions of L-NAME at either concentration. 3. L-NAME 100 microM, augmented vascular tone induced by 1 microM 5-hydroxytryptamine and 1 microM histamine, thus altering the characteristics of both pressure/flow and conductance/flow relationships such that conductance was reduced at all flow rates. The augmentation of constrictor tone was reversed in a concentration-dependent manner by L-arginine (10 microM-10 mM) and the effect of L-NAME on the conductance/flow relationships was similarly reversed by 10 mM L-arginine. The augmentation of tone was endothelium-dependent as it did not occur following functional destruction of the endothelium by perfusion of the vascular bed with the detergent CHAPS (0.3%) for 150s. 4. In conclusion, L-NAME is a potent inhibitor of agonist-induced endothelium-dependent vasodilatation. L-NAME reduces vascular conductance in pharmacologically constricted preparations and this emphasizes the important role of EDRF in vascular regulation. The ability of L-arginine to reverse L-NAME-induced inhibition of basal EDRF activity but not L-NAME-induced inhibition of agonistinduced endothelium-dependent relaxations suggests that there is pharmacological heterogeneity in the mechanisms responsible for the conversion of L-arginine to EDRF.
authors.affiliation: Department of Diagnostic Radiology, University of Wales College of Medicine, Heath Park, Cardiff.
authors.forename: M D
authors.initials: MD
authors.lastname: Randall
authors.forename: T M
authors.initials: TM
authors.lastname: Griffith
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology*; D002793:Cholic Acids / Q000494:pharmacology; D004431:Ear, External / Q000098:blood supply; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D002793:Cholic Acids; D009569:Nitric Oxide; D012701:Serotonin; D006632:Histamine; D001120:Arginine; D000109:Acetylcholine; C028213:3-((3-cholamidopropyl)dimethylammonium)-1-propanesulfonate; D019331:NG-Nitroarginine Methyl Ester