Nitrate Tolerance

Abstract

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...

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

“…This was demonstrated by significant reductions in percentage shortening and maximal rates of shortening and relaxation of the rabbit cardiac myocytes. Similar effects on the heart have been demonstrated previously [10,13,14]. Inhibition of the cyclic GMP protein kinase with KT5823 partially reversed these effects.…”

“…Long-term administration of nitrates causes nitrate tolerance or tachyphylaxis in many species including man [4,5,7,8,10,11]. Recently, there has been a strong focus on a proposed free radical hypothesis.…”

“…Nitrate tolerance or tachyphylaxis is characterized by a reduction in the nitrate-induced cyclic GMP-mediated pathway [4]. Proposed mechanisms of tolerance include: (1) depletion of critical sulfhydryl groups [5], (2) desensitization of guanylyl cyclase [6], (3) impaired bioconversion of nitrates leading to diminished NO-release [7], (4) reduced generation of NO from nitrates [8], (5) increased activity of the cyclic GMP phosphodiesterase, which decreases cyclic GMP levels [9] and (6) a free radical hypothesis proposing increased oxidant stress [10,11]. Nitroglycerininduced reactive oxygen species also inhibit the activation of nitroglycerin by thiol oxidation of mitochondrial aldehyde dehydrogenase which might explain why nitroglycerin elicits mitochondrial superoxide formation and nitrate tolerance [12].…”

Aldehyde dehydrogenase 2 protects human umbilical vein endothelial cells against oxidative damage and increases endothelial nitric oxide production to reverse nitroglycerin tolerance

“…In addition, GTN tolerance (Fadel et al, 2012) and corresponding biological and chemical changes (Gori and Parker, 2002;Daiber et al, 2009) have been attributed to ROS-induced oxidative stress. In this study, we observed that more ROS were produced under GTN tolerance conditions.…”

Modulated nitric oxide delivery in three-dimensional biomaterials for vascular functionality

“…[33,35] Despite of the extensive usage the past, the effectiveness of organic nitrates and nitrites are limited for prolonged continuous treatment due to the development of pharmacologic tolerance and endothelial dysfunction. [36] This is because the NO donors rely on enzymatic activation to release NO, particularly for inflammatory conditions. In addition, in vivo studies have shown that endothelial dysfunction and oxidative stress probably aggravate the tolerance, and increase the risk in cardiovascular events.…”