Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells.
The vasodilator action of organic nitrates is thought to be mediated by an increase in the level of cGMP following stimulation of the cytosolic enzyme guanylate cyclase in the vascular smooth muscle cell. However, direct evidence for the formation of the putative active metabolite, nitric oxide (NO) within the different compartments of the vascular wall is still missing. We here demonstrate for the first time that cultured vascular smooth muscle cells as well as endothelial cells from different species actively metabolize organic nitrates to NO. We furthermore present evidence for an outward transport of cGMP from both cell types following stimulation of soluble guanylate cyclase. The rate of NO release closely correlated with the rate of cGMP egression. Biotransformation of organic nitrates to NO appeared to comprise at least two different components, a heat-sensitive enzymatic pathway which is short-lived and prone to rapid desensitization and a second non-enzymatic component which is apparently unsaturable and longer lasting. The marked decrease in the release of NO and cGMP upon the repeated administration of organic nitrates suggests that the phenomenon of "nitrate tolerance" is mainly due to an impaired biotransformation. We propose that the metabolism of nitrates to NO may have important implications for the prevention of atherosclerosis and the therapeutic modulation of blood cell function.
Feelisch
M
M
Department of Pharmacology, Schwarz Pharma, Monheim, Germany.
Kelm
M
M
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001711:Biotransformation; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D006358:Hot Temperature; D007548:Isosorbide Dinitrate / Q000493:pharmacokinetics*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000493:pharmacokinetics*; D011863:Radioimmunoassay; D013552:Swine; D013696:Temperature
D009569:Nitric Oxide; D005996:Nitroglycerin; D006152:Cyclic GMP; D007548:Isosorbide Dinitrate