Studies on N-omega-nitro-L-arginine and N-omega-nitro-L-arginine methyl ester, putative inhibitors of endothelium-derived relaxing factor synthesis
Description
Endothelium-derived relaxing factor (EDRF) was first described in 1980. The relaxation of isolated large arteries and veins in vitro in response to acetylcholine and certain other agonists is mediated by release of this factor from endothelial cells. EDRF causes relaxation of vascular smooth muscle by activation of soluble guanylate cyclase by a mechanism similar to that of nitroglycerin and nitroprusside. EDRF has been identified as nitric oxide or a closely related nitroso compound which can release nitric oxide. EDRF is synthesized from L-arginine, and structural analogs of L-arginine which act as inhibitors of EDRF synthesis in vitro have been identified. It is possible that endothelial cells release a second, chemically undefined factor, endothelium-derived hyperpolarizing factor, which causes endothelium-dependent hyperpolarization of vascular smooth muscle. Endothelium-dependent hyperpolarization has been reported to be mediated by ATP-sensitive potassium channels in vitro These studies were designed to determine: (1) the effects of N$\sp\omega$-nitro-L-arginine and its methyl ester, arginine analogs which are putative EDRF synthesis inhibitors, on vasodilator responses and vascular tone in vivo; (2) the effects of N$\sp\omega$-nitro-L-arginine on vasorelaxant responses in isolated aortae; (3) if hyperpolarization mediated by ATP-sensitive potassium channels is involved in endothelium-dependent vasodilation in isolated aortae or in vivo; (4) the role of EDRF in the hypotension caused by platelet-activating factor (PAF) The results of these studies demonstrate that EDRF synthesis sensitive to inhibition by N$\sp\omega$-nitro-L-arginine is the predominant or sole mediator of endothelium-dependent vasorelaxation in isolated aortae of the cat and rabbit. The results demonstrate that EDRF synthesized from L-arginine is a major mediator but not the only mediator of responses to endothelium-dependent vasodilator agonists in resistance vessels in the hindquarters vascular bed of the cat, and is also important for maintaining resistance vessels in the hindquarters vascular bed of the cat in a dilated state. These studies suggest that a mechanism sensitive to glybenclamide, an inhibitor of ATP-sensitive potassium channels, may contribute to the N$\sp\omega$-nitro-L-arginine-insensitive vasodilation in response to endothelium-dependent agonists in the resistance vessels of the cat. These results further demonstrate that EDRF release mediates at least in part the vasodilation elicited by PAF in the cat