AJP - Heart and Circulatory Physiology, Vol 259, Issue 6 1813-H1821, Copyright © 1990 by American Physiological Society

ARTICLES

L-arginine-dependent vascular smooth muscle relaxation and cGMP formation

M. E. Gold, K. S. Wood, R. E. Byrns, G. M. Buga and L. J. Ignarro
Department of Pharmacology, University of California School of Medicine, Los Angeles 90024.

The objective of this study was to ascertain whether endothelium-dependent relaxation and guanosine 3',5'-cyclic monophosphate (cGMP) formation in bovine pulmonary artery are dependent on L-arginine. Arterial rings responded to acetylcholine and A23187 with increased cGMP accumulation and relaxation and showed resting L-arginine levels of approximately 300 microM. Addition of L-arginine failed to cause relaxation or cGMP accumulation. Arterial rings incubated under tension at 37 degree C for 24 h showed a three- to fourfold decline in L-arginine levels, and this decline was accompanied by a similar decline in resting cGMP levels as well as complete refractoriness to endothelium-dependent relaxation and cGMP formation in response to acetylcholine and A23187, without alteration of responsiveness to nitric oxide, s-nitrosothiols, or nitroglycerin. The endothelium in 24-h incubated arterial rings was normal morphologically, as assessed by scanning electron microscopy. L-Arginine caused endothelial-dependent relaxation and cGMP formation in L-arginine-depleted rings, which was antagonized by oxyhemoglobin and methylene blue. Bovine aortic endothelial cells grown in L-arginine-deficient medium supplemented with D-arginine during the final 24 h of growth failed to generate endothelium-derived nitric oxide, as assessed by bioassay cascade. L-Canavanine, but not L-lysine or L-ornithine, protected against the decline in L-arginine and cGMP levels and loss of endothelium-dependent relaxation that was characteristic of 24-h incubated arterial rings. The pharmacological properties of L-arginine were shared by L-arginine ethyl ester, L-arginine methyl ester, and L-homoarginine but not N-alpha-benzoyl-L-arginine ethyl ester or L-canavanine. These observations indicate that L-arginine or a structural analogue may be obligatory for endothelium-dependent relaxation and cGMP formation.

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