Effect of nitrate tolerance and dipyridamole on the response to SIN1 in the human isolated saphenous vein

Bohyn, Marc; Berkenboom, Guy; Fontaine, Jeanine

doi:10.1007/bf03029770

Cited by 14 publications

(7 citation statements)

References 15 publications

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“…15,16 An impaired biotransformation of GTN and other nitrates, such as isosorbide mononitrate and dinitrate, would also help explain the finding that spontaneous NO donors, such as nitroprusside and other nonorganic NO donors, are subject to relatively lesser degrees of tolerance. [17][18][19][20] Whether reduced biotransformation is a relevant mechanism of tolerance, and, most importantly, which enzymes are involved in the activation of GTN, will require further investigation. The microsomal cytochrome P450, glutathione transferases, NAD(P)H and xanthine oxidases, and, finally, given its cytochrome-like structure, nitric oxide synthase (NOS), [21][22][23][24][25] have all been proposed.…”

Section: Abnormalities In Organic Nitrate Biotransformationmentioning

confidence: 99%

Nitrate Tolerance

2002

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T he first part of this review provided a synopsis of the recent literature about superoxide anion (·O 2 Ϫ ) production, endothelial dysfunction, and the neurohormonal activation that follow long-term administration of organic nitrates. In this issue of Circulation, we will try to integrate these observations with other separate, and, to a certain extent, antagonistic hypotheses that have been proposed for the development of nitrate tolerance. [1][2][3] Hypotheses concerning the pathogenesis of tolerance have traditionally been grouped into 2 different categories. The "dispositional" or "metabolic" theory postulates that the effect of organic nitrates wanes during continuous use as the result of decreased biotransformation or decreased activity of the nitric oxide (NO) adjunct released in this process (end-organ tolerance). The "functional" theory emphasizes the importance of counterregulatory mechanisms that occur in response to nitrate therapy, including neurohormonal activation and plasma volume expansion. These mechanisms could counterbalance and overcome the effects of nitrates, a process that has been termed "pseudotolerance." 3,4 Recent findings described in the first part of this article provide an opportunity to hypothesize explanations for a number of previous observations in the field of nitrate tolerance by applying increased ·O 2 Ϫ production as the underlying mechanism. In the following text, the evidence for this concept is reviewed, and a unifying hypothesis based on a self-promoting mechanism triggered by increased vascular ·O 2 Ϫ generation is proposed. Plasma Volume Expansion During Nitrate TherapySeveral studies reported that nitrate therapy causes plasma volume expansion, as demonstrated by a decreased hematocrit during nitrate therapy both in healthy volunteers 5 and patients with congestive heart failure or ischemic heart disease. 6 This observation led to the hypothesis that increased circulating volume and, subsequently, filling pressures, would counteract the nitroglycerin (GTN)-induced decrease in preload, thus causing nitrate tolerance. Increased water retention and/or fluid shifts from the extravascular to the intravascular compartment have been proposed as mechanisms for these changes. 6,7 The activation of the renin-angiotensin-aldosterone axis and the increased angiotensin II production during tolerance might mediate both processes. Furthermore, the recent demonstration that GTN treatment causes increased levels of isoprostanes, 8 given their direct vasoconstrictor and antinatriuretic effects, 9 provides an additional, redox-mediated explanation. Finally, changes in the redox state in the endothelial cellular milieu, and, in particular, changes in the availability of reduced thiol groups, might induce abnormalities in microvascular permeability. 10 Despite these theories, a number of observations limit the importance of plasma volume expansion as a causal mechanism of tolerance, including: (1) the discrepancy in the time course of the two phenomena 6 ; (2) the demonstration that t...

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Section: Abnormalities In Organic Nitrate Biotransformationmentioning

confidence: 99%

Nitrate Tolerance

2002

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“…Tolerance, first documented in 1867 (15), is a clinical condition associated with a serious impairment of nitrovasodilator function as a result of its continuous administration. Mechanisms proposed to account for the development of nitrate tolerance include the depletion of essential thiols (16), decreased biotransformation of GTN to NO (17), desensitization of sGC (1), enhanced phosphodiesterase activity (18), and production of vascular superoxide (19). Despite extensive research conducted on nitrate tolerance, debate about its origin persists (20,21).…”

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confidence: 99%

Effects of Nitroglycerin on Soluble Guanylate Cyclase

Artz¹,

Schmidt²,

McCracken³

et al. 2002

Journal of Biological Chemistry

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Soluble guanylate cyclase (sGC) is a heterodimeric hemoprotein that catalyzes the conversion of GTP to cGMP. Upon binding NO to its heme cofactor, purified sGC was activated 300-fold. sGC was only activated 67-fold by nitroglycerin (GTN) and Cys; and in the absence of Cys, GTN did not activate sGC. Electronic absorption spectroscopy studies showed that upon NO binding, the Soret of ferrous sGC shifted from 431 to 399 nm. The data also revealed that activation of sGC by GTN/Cys was not via the expected ferrous heme-NO species as indicated by the absence of the 399 nm heme Soret. Furthermore, EPR studies of the reaction of GTN/Cys with sGC confirmed that no ferrous heme-NO species was formed but that there was heme oxidation. Potassium ferricyanide is known to oxidize ferrous sGC to the ferric oxidation state. Spectroscopic and activity data for the reactions of sGC with GTN alone or with K 3 Fe(CN) 6 were indistinguishable. These data suggest the following: 1) GTN/Cys do not activate sGC via GTN biotransformation to NO in vitro, and 2) in the absence of added thiol, GTN oxidizes sGC.

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“…GTN tolerance has been associated with decrease in systemic and pulmonary arterial pressure and decreased cardiac preload and afterload (Abrams 1987). Several mechanisms have been proposed to account for the development of tolerance to GTN, including depletion of essential thiols (Needleman et al 1972), decreased biotransformation of GTN to NO (Chung & Fung 1993), desensitization of soluble guanylate cyclase (Waldman et al 1986), enhanced phosphodiesterase activity (Bohyn et al 1991) and production of vascular superoxide (Munzel et al 1995a).…”

Section: Discussionmentioning

confidence: 99%

Endothelin ETA receptor antagonist did not affect development of tolerance to glyceryl trinitrate in rat

Rai

Bhalla

Gulati

2004

Journal of Pharmacy and Pharmacology

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Glyceryl trinitrate (GTN), extensively used for the treatment of cardiovascular disorders, is associated with rapid development of tolerance. The exact mechanism responsible for tolerance development to GTN is still not known. Recently, it has been demonstrated that GTN tolerance is associated with increased expression of endothelin (ET). This study was carried out to determine the effect of ET(A) receptor antagonist, BMS182874, on the development of tolerance to GTN in urethane-anaesthetized rats. Diastolic blood pressure (DBP), systolic blood pressure (SBP) and heart rate (HR) were continuously recorded in vehicle- and BMS182874 (3 mg kg(-1), i.v.)-treated rats. GTN was infused at the rate of 10 microg min(-1), intravenously for 4 h. Tolerance to GTN was determined using challenge doses of GTN (10, 30 and 90 microg, i.v.). GTN produced a fall in DBP, SBP and an increase in HR. In vehicle-treated rats, the fall in SBP before induction of GTN tolerance was 28 +/- 2, 43 +/- 4 and 52 +/- 4 mmHg with 10, 30 and 90 microg GTN, respectively. However, following GTN infusion (10 microg min(-1), i.v. for 4 h) a rapid development of tolerance was observed and the fall in SBP was 1 +/- 1, 9 +/- 4 and 15 +/- 4 mmHg with 10, 30 and 90 microg GTN, respectively. Similarly, in BMS182874-treated rats the fall in SBP in non-tolerant rats was 28 +/- 4, 42 +/- 4 and 48 +/- 5 mmHg with 10, 30 and 90 microg GTN, respectively. In BMS182874-treated rats following GTN infusion (10 microg min(-1), i.v. for 4 h) a rapid development of tolerance was observed and the fall in SBP was 4 +/- 3, 10 +/- 2 and 13 +/- 4 mmHg with 10, 30 and 90 microg GTN, respectively. The decrease in DBP and SBP in vehicle- and BMS182874-treated GTN-tolerant rats was statistically similar. These results suggest that ET(A) receptor antagonist BMS182874 did not affect development of tolerance to GTN in rats.

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Effect of nitrate tolerance and dipyridamole on the response to SIN1 in the human isolated saphenous vein

Cited by 14 publications

References 15 publications

Nitrate Tolerance

Nitrate Tolerance

Effects of Nitroglycerin on Soluble Guanylate Cyclase

Endothelin ETA receptor antagonist did not affect development of tolerance to glyceryl trinitrate in rat

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