INVITRO AND EXVIVO INHIBITORY EFFECTS OF L-ENANTIOMERS AND D-ENANTIOMERS OF NG-NITRO-ARGININE ON ENDOTHELIUM-DEPENDENT RELAXATION OF RAT AORTA

The in vitro and ex vivo inhibitory effects of N(G)-nitro-L-arginine ( L-NNA) and N(G)-nitro-D-arginine (D-NNA) on endothelium-dependent rela xations were studied in rat aortic rings. L-NNA (3 x 10(-7) to 3 x 10( -5) M) but not D-NNA (3 x 10(-6) to 3 x 10(-4) M) induced contraction of resting aortic rings and potentiated phenylephrine-induced contract ion in a concentration-dependent manner. In phenylephrine-preconstrict ed aortic rings, L-NNA (3 x 10(-7) to 3 x 10(-5) M) and D-NNA (3 x 10( -6) to 3 x 10(-4) M) concentration-dependently inhibited the rellaxati on response to acetylcholine (ACh) with similar efficacies and IC50 va lues of 10(-6) and 3.9 x 10(-5) M, respectively. In addition, both L-N NA (3 X 10(-5) M) and D-NNA (3 x 10(-4) M) almost totally inhibited th e relaxation of preconstricted rings by the calcium ionophore A 23187. The inhibitory effects Of L- and D-NNA remained for at least 4 hr aft er the preparations were washed out. Neither the inhibitory effects Of L- and D-NNA on ACh-induced relaxation nor the ACh-induced relaxation itself were affected by Pretreatment with indomlethacin. However, pre treatment (1 0 min) or post-treatment (1 hr later) with L-Arg (10(-3) M) completely prevented or markedly reversed the inhibitory effects Of L- and D-NNA. Intravenous bolus injections Of L-NNA (1.6 x 10(-4) mmo l/kg) and D-NNA (1.6 x 10(-4) mmol/kg) caused sustained increases in b lood pressure in conscious, unrestrained rats in vivo and inhibited AC h-induced relaxation of aortic rings ex vivo. These findings suggest t hat both Land D-NNA cause efficacious, long-lasting and reversible inh ibition of endothelium-dependent relaxation, for which the L-enantiome ric form is the preferred but not essential configuration required to inhibit endothelium-dependent relaxation.