NG-nitro L-arginine methyl ester and other alkyl esters of arginine are muscarinic receptor antagonists.
Analogues of L-arginine with modifications at the terminal guanidino nitrogen and/or the carboxyl terminus of the molecule have been widely used for their ability to inhibit the production of nitric oxide and are thought to be competitive antagonists of nitric oxide synthase. The present studies were designed to test the possibility that these agents are also muscarinic receptor antagonists. Acetylcholine produced concentration-dependent contraction of endothelium-denuded rabbit coronary artery as well as isolated strips of canine colonic smooth muscle. The arginine analogue NG-nitro L-arginine methyl ester (L-NAME, 100 microM) but not NG-monomethyl L-arginine (L-NMMA, 100 microM) significantly shifted these contractile relations to the right, an effect that was not reversed by addition of 1 mM L-arginine. In radioligand binding studies using the muscarinic radioligand [3H]quinuclidinyl benzilate and tissues known to contain differing contributions of M1, M2, and M3 muscarinic receptors, addition of increasing concentrations of L-NAME resulted in a monophasic competition of binding with affinities (Ki) ranging from 68 microM in endothelium to 317 microM in whole aorta. Addition of the hydrolysis-resistant guanosine 5'-triphosphate analogue GTP gamma S (100 microM) had no effect on L-NAME competition of [3H]quinuclidinyl benzilate binding. Addition of L-NAME in radioligand binding competition studies using the agonist carbachol did not result in an alteration of the receptor's affinity for agonist, confirming the competitive nature of the interaction of L-NAME with the muscarinic receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Buxton
I L
IL
Department of Pharmacology, University of Nevada School of Medicine, Reno 89557-0046.
Cheek
D J
DJ
Eckman
D
D
Westfall
D P
DP
Sanders
K M
KM
Keef
K D
KD
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects; D003106:Colon / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists; D009130:Muscle, Smooth; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D011817:Rabbits; D011869:Radioligand Assay; D013363:Submandibular Gland / Q000187:drug effects; D019323:omega-N-Methylarginine
D018727:Muscarinic Antagonists; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester