In Vivo Nitrate Tolerance Is Not Associated With Reduced Bioconversion of Nitroglycerin to Nitric Oxide
- 1 November 1996
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 94 (9), 2241-2247
- https://doi.org/10.1161/01.cir.94.9.2241
Abstract
Background In vitro data suggest that reduced bioconversion of nitroglycerin (NTG) to nitric oxide (NO) contributes to the development of vascular and hemodynamic tolerance to NTG. We examined the in vivo validity of this hypothesis by measuring NTG-derived NO formation by in vivo spin-trapping of NO in vascular tissues from nitrate-tolerant and -nontolerant rats. Methods and Results Five groups (n=6 to 8 each) of conscious chronically catheterized rats received NTG (0.2 or 1 mg/h IV) for 72 hours (nitrate-tolerant groups). Four other groups received either NTG vehicle (placebo, for 72 hours) or were left untreated (control). Nitrate tolerance was substantiated by a reduced (55% to 85%) hypotensive response to NTG in vivo and a reduced relaxation to NTG in isolated aortic rings. NTG-derived NO formation in aorta, vena cava, heart, and liver was measured as NOFe(DETC) 2 and NO-heme complexes formed in vivo during 35 minutes combined with ex vivo cryogenic electron spin resonance spectroscopy. NO formation was significantly ( P <.05) increased in all tissues in nitrate-tolerant rats in an NTG dose–dependent manner. Furthermore, the amount of NO formed from a bolus dose of NTG (6.5 mg/kg over 20 minutes) was similar in nitrate-tolerant and -nontolerant rats. Conclusions The results suggest that vascular and hemodynamic NTG tolerance occurs despite high and similar rates of NO formation by NTG in tolerant and nontolerant target tissues. This finding is compatible with the assumption that reduced biological activity of NO, rather than reduced bioconversion of NTG to NO, contributes to in vivo development of nitrate tolerance.Keywords
This publication has 11 references indexed in Scilit:
- Specificity of different organic nitrates to elicit NO formation in rabbit vascular tissues and organs in vivoBritish Journal of Pharmacology, 1995
- Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance.JCI Insight, 1995
- Relationship between nitroglycerin-induced vascular relaxation and nitric oxide production: Probes with inhibitors and tolerance developmentBiochemical Pharmacology, 1993
- Conversion of glyceryl trinitrate to nitric oxide in tolerant and non‐tolerant smooth muscle and endothelial cellsBritish Journal of Pharmacology, 1993
- Quantification of nitric oxide in biological samples by electron spin resonance spectroscopyNeuroprotocols, 1992
- Endothelium- and sydnonimine-induced responses of native and cultured aortic smooth muscle cells are not impaired by nitroglycerin toleranceNaunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie, 1989
- Nitric oxide-induced vasodilation of organic nitrate-tolerant rabbit aortaCanadian Journal of Physiology and Pharmacology, 1988
- Prevention and Reversal of Nitrate Tolerance in Patients with Congestive Heart FailureNew England Journal of Medicine, 1987
- A strain-gauge myograph for isometric measurements of tension in isolated small blood vessels and other muscle preparationsJournal of Pharmacological Methods, 1986
- Oral Isosorbide dinitrate in angina pectoris: Comparison of duration of action and dose-response relation during acute and sustained therapyThe American Journal of Cardiology, 1982