Journal ArticleDOI
Mechanisms of nitrate action and vascular tolerance
H.-L. Fung,S. Chong,E. Kowaluk +2 more
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TLDR
The various potential mechanisms contributing to nitrate tolerance are discussed and it is still uncertain whether reduction in intracellular sulfhydryl availability is the operative mechanism.Abstract:
The various potential mechanisms contributing to nitrate tolerance are discussed. Pharmacokinetic alterations of the organic nitrate in the systemic circulation do not readily reflect pharmacologic tolerance. Neurohormonal changes do accompany continuous nitrate therapy, but the causative factor of tolerance, if it exists, has not been identified. Vascular metabolism of organic nitrates is impaired during in vitro nitrate tolerance, but it is still uncertain whether reduction in intracellular sulfhydryl availability is the operative mechanism. Vascular cyclic GMP production may be reduced during tolerance, but this change may not parallel that observed in vascular relaxation.read more
Citations
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Journal ArticleDOI
Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure
Harinder Gogia,Anilkumar Mehra,Sunita Parikh,Murli Raman,Jasvir Ajit-Uppal,Janet V. Johnson,Uri Elkayam +6 more
TL;DR: In patients with chronic heart failure due to left ventricular systolic dysfunction, the concomitant use of oral hydralazine prevents early development of nitrate tolerance and results in a persistent nitrate-mediated hemodynamic effect on systemic and pulmonary artery andleft ventricular filling pressures.
Journal ArticleDOI
Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention.
TL;DR: Evidence indicates that prolonged in-vitro exposure to organic nitrates, continuous intravenous or topical administration of nitrate, and frequent in- vivo oral dosing result in the rapid development of tolerance to the peripheral as well as to the coronary vasodilatory effects of the drugs.
Journal ArticleDOI
Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure.
John Anthony Bauer,Ho-Leung Fung +1 more
TL;DR: The beneficial interaction of hydralazine on the preload effects of nitroglycerin may explain the long-term clinical efficacy ofhydralazine/nitrate combination in CHF and suggest that the mechanism of in vivo nitrate tolerance inCHF may be systemic rather than vascular in origin.
Journal ArticleDOI
Biochemical mechanism of organic nitrate action.
TL;DR: Although sulfhydryl donors can partially reverse nitroglycerin-induced tolerance in patients, this phenomenon is not sufficient to implicate intracellular sulfHydryl depletion as an operating mechanism of clinical nitrate tolerance.
Journal ArticleDOI
Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure
TL;DR: Tolerance towards the beneficial effects of nitrates on hemodynamics and on exercise performance also develops rapidly during continuous or long-term nitrate therapy, and for these reasons nitrates are not used as first-line therapy to treat chronic heart failure.
References
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Journal Article
Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates.
Louis J. Ignarro,Howard Lippton,J C Edwards,William H. Baricos,Albert L. Hyman,P. J. Kadowitz,Carl A. Gruetter +6 more
Journal Article
Mechanism of tolerance development to organic nitrates
TL;DR: It is proposed that organic nitrate tolerance involves the oxidation of a critical sulfhydryl in the glyceryl trinitrate "receptor" and this hypothesis is supported by the reversal of both in vitro - and in vivo -induced glycery ltrinitrate tolerance by the disulfide reducing agent, dithiothreitol.
Journal Article
Sulfhydryl requirement for relaxation of vascular smooth muscle
TL;DR: There appears to be two distinct vasodilation responses, one activated by direct interaction with a specific receptor site and not necessarily requiring SH oxidation as a primary event, and a second group of nonspecific vasodilators in which vasodillation is correlated with ability to react with SH groups.
Journal ArticleDOI
Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine.
TL;DR: It is concluded that NAC potentiates the vasodilator effects of NTG in man and suggests that sulfhydryl availability and/or redox state may be determinants of in vivo responsiveness to NTG.
Journal ArticleDOI
In vivo induction and reversal of nitroglycerin tolerance in human coronary arteries.
D. C. May,Jeffrey J. Popma,W. H. Black,Saul Schaefer,H. R. Lee,Benjamin D. Levine,L. D. Hillis +6 more
TL;DR: The coronary vasodilator effect of nitroglycerin is attenuated by an intravenous infusion of nitreglycerin and that tolerance to the agent can be reversed by administration of the sulfhydryl-group donor N-acetylcysteine, indicating the development of partial tolerance.