NG-methyl-L-arginine causes endothelium-dependent contraction and inhibition of cyclic GMP formation in artery and vein.
The objective of this study was to determine whether the vascular smooth muscle contractile effect of NG-methyl-L-arginine (NMA) is endothelium dependent and attributed to a decline in smooth muscle levels of cyclic GMP. Vascular smooth muscle levels of cyclic GMP are severalfold greater in endothelium-intact than in endothelium-denuded preparations because of the continuous formation and release of a lipophilic endothelium-derived chemical factor that diffuses into the underlying smooth muscle and activates cytosolic guanylate cyclase. This chemical substance, believed to be nitric oxide (NO) or a labile nitroso precursor, appears to account for the biological actions of endothelium-derived relaxing factor. NMA inhibits the formation of NO from endogenous L-arginine in endothelial cells. In the present study, NMA caused marked endothelium-dependent contraction of isolated rings of bovine pulmonary artery and vein, and this was similar to the contraction elicited by hemoglobin, an inhibitor of the relaxant action of NO. Both NMA and hemoglobin caused endothelium-dependent potentiation of contractile responses to phenylephrine in artery and vein. NMA caused endothelium-dependent decreases in the resting or basal levels of cyclic GMP in artery and vein to levels that were characteristic of those in endothelium-denuded vessels. Finally, NMA inhibited endothelium-dependent relaxant responses and cyclic GMP formation stimulated by acetylcholine and bradykinin. These observations reveal that interference with the continuous or basal generation of endothelium-derived NO in artery and vein can cause marked increases in vascular smooth muscle tone as a result of inhibition of cyclic GMP formation.
Gold
M E
ME
Department of Pharmacology, University of California, School of Medicine, Los Angeles 90024.
Wood
K S
KS
Byrns
R E
RE
Fukuto
J
J
Ignarro
L J
LJ
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D002417:Cattle; D006152:Cyclic GMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology*; D066298:In Vitro Techniques; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D010108:Oxyhemoglobins / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D011667:Pulmonary Veins / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*; D019323:omega-N-Methylarginine
D010108:Oxyhemoglobins; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D001120:Arginine; D006152:Cyclic GMP; D000109:Acetylcholine; D001920:Bradykinin