VASCULAR PHARMACODYNAMICS OF NG-NITRO-L-ARGININE METHYL-ESTER IN-VITRO AND IN-VIVO

The inhibitory effects of N(G)-nitro-L-arginine methyl ester (L-NAME) on endothelium-dependent vasodilatation were studied in conscious rats and isolated rat aortic rings. In phenylephrine (PE, ED90)-preconstri cted aortae, L-NAME caused prolonged and complete inhibition of acetyl choline (ACh)-induced relaxation with IC50 of 4 x 10(-7) M and Hill co efficient (n) of 1. The inhibition was abolished by L-arginine (L-Arg) , independently of whether it was applied 10 min earlier or 4 hr later than L-NAME. Intravenous bolus injection Of L-NAME caused prolonged i ncreases in mean arterial pressure (MAP), with E(max) of 50 +/- 7 mm H g, ED50 of 5 +/- 1 x 10(-6) mol/kg and n of 2. Intravenous infusion of L-Arg shifted the dose-MAP curve Of L-NAME to the right without chang ing E(max) or n. A modified Schild plot (n = 2) for the action of L-NA ME gave a slope not different from unity, suggesting that L-Arg inhibi ts competitively the MAP response Of L-NAME. Intravenous infusion of A Ch decreased MAP in rats treated with L-NAME (4.8 x 10(-5) mol/kg) or PE. Compared to PE-treated rats, L-NAME inhibited the depressor respon se to ACh by 50%. Thus, a dose of L-NAME 10 times its ED50 in raising MAP only partially blocked the depressor responses to ACh. Our results are consistent with the hypothesis that pressor response to L-NAME re sults from the inhibition of NO synthase only if 1) basal NO synthesis is more effectively blocked by L-NAME than stimulated NO synthesis an d 2) stimulated NO synthesis is inhibited by L-NAME in a one to one an tagonist manner whereas basal NO synthesis is inhibited by L-NAME in a two to one antagonist manner.