Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells

Heinrich-Heine-Universität Düsseldorf, Düsseldorf, North Rhine-Westphalia, Germany
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 11/1991; 180(1):286-93. DOI: 10.1016/S0006-291X(05)81290-2
Source: PubMed


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.

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    • "Different types of NO-releasing agents have been developed and are commercially available, such as sodium nitroprusside (SNP), firstly described as a vasodilator, which is used to manage acute hypertensive crisis; or molsidomine, used in the therapy of angina pectoris and heart failure. SIN-1, another NO donor, is known as both NO and ONOO− donor mainly because during NO release from SIN-1 superoxide is also generated [144, 145]. A wide range of NO-releasing drug classes have been developed recently. "
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    • "However, one difficulty with these studies has been an inability to detect NO as a byproduct of GTN metabolism [92]. Moreover, the generation of NO was observed when the concentrations of GTN exceeded therapeutic values [93–98]. A potential solution has been proposed that once GTN is bioactivated within the mitochondria, nitrite or an additional action of mtALDH generates the vasodilatory NO bioactivity [53]. "
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    • "A porphyrinic microsensor working electrode, platinum wire counter electrode and a miniature saturated silver/silver chloride reference electrode were connected to the ISO-NO MARK II potentiostat (WPI, USA). The measurement was practised using distilled water saturated with pure NO gas (according to the WPI manual, [18]). The injection of 1 µl of the NO-saturated water into the glass vial (final concentration of NO in the vial = 595 nM) caused the rapid increase (peak time = 15 ± 5 s) with a subsequent gradual decrease of an NO-induced signal until it reached the background current. "
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