Mechanism of glyceryl trinitrate-induced vasodilation. I. Relationship between drug biotransformation, tissue cyclic GMP elevation and relaxation of rabbit aorta - PubMed (original) (raw)
Affiliations
- PMID: 2826771
Mechanism of glyceryl trinitrate-induced vasodilation. I. Relationship between drug biotransformation, tissue cyclic GMP elevation and relaxation of rabbit aorta
J F Brien et al. J Pharmacol Exp Ther. 1988 Jan.
Abstract
This study was conducted to test the hypothesis that biotransformation of glyceryl trinitrate (GTN) is involved in GTN-induced relaxation of vascular smooth muscle. The temporal relationship between GTN biotransformation, elevation of cyclic GMP content and vasodilation in rabbit aortic strips (RAS) was determined. Isolated RAS were contracted submaximally with phenylephrine, and then were incubated with 0.62 microM [3H]GTN in a 30-sec time course study. GTN-induced relaxation (inhibition of phenylephrine-induced tone) of RAS was monitored; tissue cyclic GMP content was measured by radioimmunoassay; and GTN, glyceryl-1,2-dinitrate (1,2-GDN) and glyceryl-1,3-dinitrate (1,3-GDN) concentrations in RAS were measured by thin-layer chromatography and liquid scintillation spectrometry. There was time-dependent biotransformation of GTN to GDN by the RAS and a time-dependent increase in cyclic GMP content in the RAS. Statistically significant (P less than .05) biotransformation of GTN and elevation of cyclic GMP content in the tissue occurred at 10 sec, whereas the onset of GTN-induced relaxation of RAS occurred at 12 sec. During the tissue biotransformation of GTN, there was preferential formation of 1,2-GDN compared with 1,3-GDN, with 1,2-GDN/1,3-GDN ratio of 3.0/1 at 10 sec, 5.3/1 at 20 sec and 5.8/1 at 30 sec. The results of this study are consistent with the hypothesis that GTN is a prodrug, such that biotransformation to an active metabolite is involved in GTN-induced relaxation of vascular smooth muscle. The data also indicate that the mechanisms of GTN biotransformation and GTN-induced activation of guanylate cyclase may be related intimately.
Similar articles
- The role of nitric oxide formation in organic nitrate-induced vasodilation and organic nitrate tolerance.
Marks GS, Nakatsu K, McLaughlin B, Kawamoto J, Slack C, Brien JF. Marks GS, et al. Z Kardiol. 1989;78 Suppl 2:18-21; discussion 64-7. Z Kardiol. 1989. PMID: 2555978 - Biotransformation of glyceryl trinitrate occurs concurrently with relaxation of rabbit aorta.
Brien JF, McLaughlin BE, Breedon TH, Bennett BM, Nakatsu K, Marks GS. Brien JF, et al. J Pharmacol Exp Ther. 1986 May;237(2):608-14. J Pharmacol Exp Ther. 1986. PMID: 3084761 - Biotransformation of glyceryl trinitrate and elevation of cyclic GMP precede glyceryl trinitrate-induced vasodilation.
Kawamoto JH, McLaughlin BE, Brien JF, Marks GS, Nakatsu K. Kawamoto JH, et al. J Cardiovasc Pharmacol. 1990 May;15(5):714-9. doi: 10.1097/00005344-199005000-00005. J Cardiovasc Pharmacol. 1990. PMID: 1692930 - Clinical pharmacokinetics and pharmacodynamics of glyceryl trinitrate and its metabolites.
Hashimoto S, Kobayashi A. Hashimoto S, et al. Clin Pharmacokinet. 2003;42(3):205-21. doi: 10.2165/00003088-200342030-00001. Clin Pharmacokinet. 2003. PMID: 12603173 Review. - The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles.
Mayer B, Beretta M. Mayer B, et al. Br J Pharmacol. 2008 Sep;155(2):170-84. doi: 10.1038/bjp.2008.263. Epub 2008 Jun 23. Br J Pharmacol. 2008. PMID: 18574453 Free PMC article. Review.
Cited by
- Changes in aldehyde dehydrogenase 2 expression in rat blood vessels during glyceryl trinitrate tolerance development and reversal.
D'Souza Y, Dowlatshahi S, Bennett BM. D'Souza Y, et al. Br J Pharmacol. 2011 Sep;164(2b):632-43. doi: 10.1111/j.1476-5381.2011.01448.x. Br J Pharmacol. 2011. PMID: 21506955 Free PMC article. - Aldehyde dehydrogenase 2 in cardiac protection: a new therapeutic target?
Budas GR, Disatnik MH, Mochly-Rosen D. Budas GR, et al. Trends Cardiovasc Med. 2009 Jul;19(5):158-64. doi: 10.1016/j.tcm.2009.09.003. Trends Cardiovasc Med. 2009. PMID: 20005475 Free PMC article. Review. - Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance.
Sydow K, Daiber A, Oelze M, Chen Z, August M, Wendt M, Ullrich V, Mülsch A, Schulz E, Keaney JF Jr, Stamler JS, Münzel T. Sydow K, et al. J Clin Invest. 2004 Feb;113(3):482-9. doi: 10.1172/JCI19267. J Clin Invest. 2004. PMID: 14755345 Free PMC article. - Identification of the enzymatic mechanism of nitroglycerin bioactivation.
Chen Z, Zhang J, Stamler JS. Chen Z, et al. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8306-11. doi: 10.1073/pnas.122225199. Epub 2002 Jun 4. Proc Natl Acad Sci U S A. 2002. PMID: 12048254 Free PMC article. - Vascular and anti-platelet actions of 1,2- and 1,3-glyceryl dinitrate.
Salvemini D, Pistelli A, Anggard E. Salvemini D, et al. Br J Pharmacol. 1993 Nov;110(3):937-42. doi: 10.1111/j.1476-5381.1993.tb13903.x. Br J Pharmacol. 1993. PMID: 8298817 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources