Comparison of the inhibitory potencies of N(G)-methyl-, N(G)-nitro- and N(G)-amino-L-arginine on EDRF function in the rat: evidence for continuous basal EDRF release.
The relative potencies of the argininolytic agents NG-methyl-L-arginine (L-NMA), NG-nitro-L-arginine (L-NNA) and NG-amino-L-arginine (L-NAA) were assayed by their inhibitory effect on both basal and stimulated release of endothelium-derived NO in vitro and in vivo. Basal NO release was indirectly assessed by the ability of the analogs to contract phenylephrine-preconstricted rat aortic rings and their ability to produce a hypertensive response in awake, unanesthetized normotensive rats. In aortic rings, the three analogs induced vasocontraction and inhibited the vasorelaxation mediated by ACh-stimulated endothelial NO release. In this latter assay, L-NNA was 30 times more potent than either L-NMA or L-NAA. In free-moving rats, the agents caused dose-dependent increases in arterial pressure due to the blockade of endogenous NO formation. Dose-response analysis indicated that L-NNA was 87 and 230 times more potent than L-NMA and L-NAA, respectively. Pretreatment with L-NNA was also found to selectively inhibit, but not abolish, the depressor effects of acetylcholine in unanesthetized and phenylephrine- or vasopressin-infused normotensive-pithed rats. These studies indicate that L-NNA is a potent antagonist of endothelium-derived relaxing factor formation in vitro and in vivo. The contractile and hypertensive effects of the argininolytic agents clearly demonstrates that a continuous basal release of endothelium-derived relaxing factor/NO occurs in both isolated vascular rings and whole animals.
Vargas
H M
HM
Department of Pharmacology, University of California School of Medicine, Los Angeles.
Cuevas
J M
JM
Ignarro
L J
LJ
Chaudhuri
G
G
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009566:Nitrates / Q000378:metabolism; D017942:Nitric Acid; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019335:Nitroarginine; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D026423:S-Nitroso-N-Acetylpenicillamine; D013564:Sympathetic Nervous System / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects; D014667:Vasopressins / Q000494:pharmacology; D019323:omega-N-Methylarginine
D009566:Nitrates; D014667:Vasopressins; D010656:Phenylephrine; D019335:Nitroarginine; D006830:Hydralazine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D017942:Nitric Acid; C063904:N(G)-aminoarginine; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D010396:Penicillamine; D000109:Acetylcholine