L-arginine-dependent vascular smooth muscle relaxation and cGMP formation.
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.
Gold
M E
ME
Department of Pharmacology, University of California School of Medicine, Los Angeles 90024.
Wood
K S
KS
Byrns
R E
RE
Buga
G M
GM
Ignarro
L J
LJ
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D002417:Cattle; D006152:Cyclic GMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology; D008855:Microscopy, Electron, Scanning; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D009569:Nitric Oxide; D001120:Arginine; D006152:Cyclic GMP