Differential effects of l ‐arginine on the inhibition by N G ‐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 μ m ), with an ED 50 = 31.1 ± 7.8 pmol and a maximum dilatation of 69.9 ± 4.3%. In the presence of 10 μ m l ‐NAME the dose‐response for vasodilator effects was shifted significantly ( P < 0.001) to the right (ED 50 = 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 μ m l ‐NAME completely abolished vasodilatation to acetylcholine. l ‐Arginine (10 m m ) did not reverse the inhibitory actions of l ‐NAME at either concentration. 3 l ‐NAME 100 μ m , augmented vascular tone induced by 1 μ m 5‐hydroxytryptamine and 1 μ 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 μ m –10 m m ) and the effect of l ‐NAME on the conductance/flow relationships was similarly reversed by 10 m m 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.