Chemical Pathways Proposed for the In Vitro Metabolism of Nitrovasodilators and Their Conversion into Vasoactive Species
Despite the extensive therapeutic use of nitrovasodilators and a fairly good knowledge of the hemodynamic alterations which lead to an improvement in myocardial performance, until recently surprisingly poor data were available concerning their mode of action at the molecular level. It now seems well documented that the pharmacodynamic action of these compounds is mediated by an activation of the soluble isoenzyme of guanylate cyclase (sGC, EC, 22.214.171.124). Relaxation studies with isolated vessel preparations revealed that there are at least two independent ways of sGC stimulation: an indirect endothelium-related process and a second one which results in sGC stimulation on bypassing the endothelium-dependent process. Substances like acetylcholine, ATP, or bradykinin on the one hand only behave in a vasodilatory manner in the presence of an intact endothelial layer while nitrovasodilators like nitrite (NO2 −), glyceryl trinitrate (GTN), and sodium nitroprusside (SNP) on the other hand are relaxant agents in either case. That is why the existence of a humoral “endothelium-derived relaxing factor” (EDRF) was postulated, which after penetration into the smooth muscle cell is responsible for sGC activation by endothelium-dependent vasodilators. The consecutive raise in cytosolic cyclic guanosine monophosphate (cGMP) concentration induces a complex cascade of protein phosphorylations, finally resulting in smooth muscle relaxation [12, 34].
KeywordsGlutathione Cysteine Homocysteine Bradykinin Hydroxylamine
Unable to display preview. Download preview PDF.
- 1.Ahlner J, Axelsson KL, Ljusegren M, Grundstrom N, Andersson RG (1987) Demonstration of a high-affinity component of glyceryl trinitrate-induced vasodilatation in the bovine mesenteric artery. J Cyclic Nuleotide Protein Phosphor Res 11: 445–456Google Scholar
- 5.Cantoni C, Bianchi MA, Beretta G (1975) Stabilita di nitrosoderivati (nitrosotioli, nitrosofenoli e nitrosoemoglobina) a pH alkalino (in Italian). Ind Aliment 14 (7): 79–81Google Scholar
- 9.Feelisch M, Noack E (1989) Thiol-induced generation of nitric oxide (NO) accounts for the vasodilatory action of furoxans (abstract). Naunyn Schmiedebergs Arch Pharmacol 339 [Suppl]: 67Google Scholar
- 10.Feelisch M, Noack E, Schroder H (1988) Explanation of the discrepancy between the degree of organic nitrate decomposition, nitrite formation and guanylate cyclase stimulation. Eur Heart J 9 [Suppl A]: 57–62Google Scholar
- 12.Fiscus RR, Rapoport RM, Murad F (1984) Endothelium-dependent and nitrovasodilator-induced activation of cyclic GMP-dependent protein kinase in rat aorta. J Cyclic Nucleotide Protein Phospor Res 9 (6): 415–425Google Scholar
- 16.Haussmann HJ, Werringloer J (1987) Mechanism and control of the denitrosation of N-nitrosodimethylamine. In: Bartsch H, O’Neill IK, Schulte-Herman R (eds) Relevance of N-nitroso compounds to human cancer: exposure and mechanisms. IARC Sci Publ 84: 109–112Google Scholar
- 17.Hay M (1983) The chemical nature and physiological action of nitroglycerin. Practitioner 30: 422–433Google Scholar
- 18.Heppel LA, Hilmoe RJ (1950) Metabolism of inorganic nitrite and nitrate esters: II. The enzymatic reduction of nitroglycerin and erythritol tetranitrate by glutathione. J Biol Chem 183: 129–138Google Scholar
- 23.Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL, Kadowitz PJ, Gruetter CA (1981) Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Thcr 218: 739–749Google Scholar
- 31.Mirna A, Hofmann K (1969) Über den Verbleib von Nitrit in Fleischwaren. I. Umsetzung von Nitrit mit Sulfhydrylverbindungen (in German). Fleischwirtschaft 10: 1361–1366Google Scholar
- 35.Needleman P, Johnson EM (1975) The pharmacological and biochemical interaction of organic nitrates with sulfhydryls: possible correlations with the mechanism of tolerance development, vasodilation and mitochondrial and enzyme reactions. In: Needlemann P (ed) Organic nitrates. Springer, Berlin Heidelberg New York, pp 97–114 (Handbook of experimental pharmacology, vol 40)Google Scholar
- 39.Steurer G, Schiitz W (1984) Guanylate cyclase stimulation by nitro-compounds is dependent on free Ca2+ Experientia 40: 970–971Google Scholar