Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells.
ABSTRACT 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.
Full-textDOI: · Available from: Martin Feelisch, Mar 31, 2015
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ABSTRACT: The cause of toxicity of Solanum nigrum extract (Sn) and its possible remedy are reported. The -N-NO derivative formed from –NH group of the glycoalkaloids of Sn, by interaction with systemic NO, would cause toxicity in animals ingesting the plant. In the present study, -N-NO derivative of glycoalkaloids was produced by using HNO 2 and the toxicity of the products were measured by swelling of mitochondria. The protective role of magnesium ion, when in conjugation with the glycoalkaloids, against N-nitrosation and resultant decrease in toxicity of the products were assessed. This finding indicated the preventive nature of magnesium conjugation in the formation of -N-NO bonding, which was replicated by similar sequence of reaction in L-proline. The results indicated that, Mg 2+ ion complexation of the glycoalkaloids was responsible for the reduction of toxicity of Sn extract. Additionally, the occurrence and beneficent role of conjugation of other metal ions with the Sn-glycoalkaloids are reported.
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ABSTRACT: Objective: To determine whether the considerable interindividual variability in nitroglycerin-induced venodilation in humans is related to the polymorphic expression of the μ class of glutathione S-transferase (GSTμ). Recently vascular glutathione S-transferase (EC 184.108.40.206) of the μ-class (GSTμ, a polymorphic group of enzymes present in only about 60% of the population, have been identified and shown in vitro to possess high metabolic activity toward nitroglycerin. Their clinical relevance is unknown.Design: Dose-response relationships to nitroglycerin were constructed in vivo measuring changes in compliance of dorsal hand veins in 26 healthy volunteers during local infusion of small amounts of nitroglycerin. Polymerase chain reaction was applied to detect the deoxyribonudeic acid sequence that codes GST μ in whole blood samples.Results: The GSTμ isozyme was present in 15 subjects (58%) and deficient in 11 subjects. Values for mean maximum venodilation (Emax) and dose rates producing 50% of Emax (ED50) were not significantly different between the groups with or without GSTμ. The respective values were 98% and 103% dilation for Emax and 9 and 16 ng/min for ED50. There was no gender difference in the venodilatory response to nitroglycerin.Conclusions: Subjects lacking GSTμ can clearly respond normally to nitroglycerin, and the large interindividual variability in nitroglycerin potency is not related to the expression of this polymorphic enzyme. Intersubject variability is therefore more likely to be the result of differences in the presence or activity of other vascular enzymes or in steps further distal in the venodilatory cascade.Clinical Pharmacology & Therapeutics 04/1993; 53(4):463-468. DOI:10.1038/clpt.1993.52 · 7.39 Impact Factor