DIFFERENTIAL-EFFECTS OF L-ARGININE ON THE INHIBITION BY NG-NITRO-L-ARGININE METHYL-ESTER OF BASAL AND AGONIST-STIMULATED EDRF ACTIVITY

1 An isolated, buffer-perfused rabbit ear preparation was used to investigate the influence of N(G)-nitro-L-arginine methyl ester (L-NAME) on endothelium-dependent vasodilatation 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-mu-M), with an ED50 = 31.1 +/- 7.8 pmol and a maximum dilatation of 69.9 +/- 4.3%. In the presence of 10-mu-M L-NAME the dose-response for vasodilator effects was shifted significantly (P < 0.001) to the right (ED50 = 3.07 +/- 1.18 nmol) and there was a significant (P < 0.01) depression of the maximum response (R(max) = 44.3 +/- 4.0%). The higher concentration of 100-mu-M 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-mu-M, augmented vascular tone induced by 1-mu-M 5-hydroxytryptamine and 1-mu-M 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-mu-M-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 150 s. 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 agonist-induced endothelium-dependent relaxations suggests that there is pharmacological heterogeneity in the mechanisms responsible for the conversion of L-arginine to EDRF.