More answers to the still unresolved question of nitrate tolerance

Abstract

Organic nitrates are traditionally felt to be a safe adjuvant in the chronic therapy of patients with coronary artery disease. Despite their long use, progress in the understanding of the pharmacology and mechanism of action of these drugs has been achieved only in the last two decades, with the identification of the role of oxidative stress in the pathophysiology of nitrate tolerance, with, the discovery of the ancillary effects of nitrates, and with the demonstration that nitrate therapy has important chronic side effects that might modify patients' prognosis. These advances are however mostly confined to the molecular level or to studies in healthy volunteers, and the true impact of organic nitrates on clinical outcome remains unknown. Complicating this issue, evidence supports the existence of important differences among the different drugs belonging to the group, and there are reasons to believe that the nitrates should not be treated as a homogeneous class. As well, the understanding of the effects of alternative nitric oxide (NO) donors is currently being developed, and future studies will need to test whether the properties of these new medications may compensate and prevent the abnormalities imposed by chronic nitrate therapy. Intermittent therapy with nitroglycerin and isosorbide mononitrate is now established in clinical practice, but they should neither be considered a definitive solution to the problem of nitrate tolerance. Both these strategies are not deprived of complications, and should currently be seen as a compromise rather than a way fully to exploit the benefits of NO donor therapy.--

Disruption of Physiological Balance Between Nitric Oxide and Endothelium-Dependent Hyperpolarization Impairs Cardiovascular Homeostasis in Mice

“…42 However, in Cav-1-KO and eNOS-Tg mice, the coronary flow responses to sodium nitroprusside were significantly reduced, whereas those to adenosine were preserved, suggesting that NO tolerance was developed after TAC in those mice. 43 These results are consistent with the widely accepted notion that EDH works as a compensatory vasodilator system when NO-mediated relaxations are hampered. Thus, EDH dominance in microcirculation is a vital mechanism to maintain sufficient tissue perfusion in the setting of cardiac pressure overload where NO-mediated responses are compromised.…”

In vitro and in vivo Characterization of a New Organic Nitrate Hybrid Drug Covalently Bound to Pioglitazone

“…By adding the nitrate linker to pioglitazone, it is hoped that normal NO levels and activity will be restored. The benefits of an organic nitrate that is devoid of induction of oxidative stress, nitrate tolerance, endothelial dysfunction and other clinical side effects have been explored in full detail in animal studies [8,13] as well as in human subjects [38,39,40,41] and was also reviewed [42,43,44]. In summary, the results of these studies clearly demonstrate that CLC-3000 contains a vasodilation activity which is not evident with pioglitazone alone, and that 7 days of exposure in vivo showed little evidence of inducing oxidative stress or other safety concerns in Wistar rats.…”

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

“…[7][8][9]. The reasons for these discordant findings are variously attributed to an uncoupling of NOS for L-arginine (10), tolerance and induction per se of vascular dysfunction with the organic nitrates (11), and oxidation of tetrahydrobiopterin (9). These issues suggest that the failure of translation may lie in the failure of effective delivery of NO rather than a lack of efficacy of NO.…”