Endothelium-derived nitric oxide: pharmacology and relationship to the actions of organic nitrate esters.
Vascular smooth muscle relaxation elicited by various endogenous substances results from their interaction with vascular endothelial cells to triger the formation of endothelium-derived relaxing factor (EDRF). EDRF from pulmonary and peripheral arteries and veins and from cultured and freshly harvested aortic endothelial cells has been identified pharmacologically and chemically as nitric oxide (NO) or a labile nitroso compound. Endothelium-derived NO (EDNO) and authentic NO activate the cytoplasmic form of guanylate cyclase by heme-dependent mechanism and thereby stimulate intracellular cyclic GMP accumulation in cells including vascular smooth muscle and platelets. Cyclic GMP functions as a second messenger to cause vascular muscle relaxation and inhibition of platelet aggregation and adhesion to vascular endothelial surfaces. EDNO is synthesized from L-arginine and perhaps arginine-containing peptides by an unidentified calcium-requiring process coupled to the occupation of extracellular endothelial receptors. The biological actions of EDNO are terminated by spontaneous oxidation to NO2- and NO3-. The biological half-life of the very lipophilic EDNO is only 3-5 sec and this allows EDNO to function locally as an autacoid. Nitroglycerin and other organic nitrate esters elicit endothelium-independent relaxation after entering vascular smooth muscle cells and undergoing denitration and formation of NO. The pharmacological actions of nitroglycerin are therefore essentially the same as those of EDNO, and the endogenous NO receptor is the heme group bound to soluble guanylate cyclase. EDNO may serve a biological role to modulate local blood flow and platelet function.
Ignarro
L J
LJ
Department of Pharmacology, University of California, Los Angeles 90024.
D000818:Animals; D006801:Humans; D009566:Nitrates / Q000378:metabolism / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
D009566:Nitrates; D014665:Vasodilator Agents; D009569:Nitric Oxide; D005996:Nitroglycerin