Nitrate tolerance mechanisms

Wang, E.Q. Lee, W.I. Brazeau, D. Fung, H.L. cDNA microarray analysis of vascular gene expression after nitric oxide donor infusions in rats implications for nitrate tolerance mechanisms. AAPS Pharm. Sci. 2002, 4, ElO. 

B. A., Tarpey, M. M., Harrison, D. G., Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J. Clin. Invest. 95 (1995), p. 187-194... 

The other factor affecting the use of organic nitrates is nitrate tolerance, the mechanism of which is unclear. An early explanation of tolerance was thiol depletion [68] but that now seems unlikely as their is an abundance of thiol in most tissue [69]. A more likely explanation is down regulation of the enzymes involved in the biotransformation but few details are available. An interesting suggestion is that GTN induces increased production of superoxide from the vascular wall and tolerance is caused by reaction of NO, produced enzymatically from GTN, with superoxide to give peroxynitrite and then nitrate [70] (Eq. (16)). 

Tolerance to nitrates is defined as the reduction in hemodynamic effect or the requirement for higher doses to achieve a persistent effect with continuous use in the face of constant plasma concentrations [15]. Nitrate tolerance was first described for nitroglycerin in 1888 [36] it occurs with all organic nitrates, albeit to different extents. For reasons that are not understood, PETN appears to be the least susceptible to the development of tolerance. No, or much less, tolerance is observed with nitrite esters, such as amyl nitrite [37], molsidomine, and sodium nitroprusside. Earlier investigations suggested that a depletion of intracellular thiols is involved in tolerance development [17], but this has not been substantiated in later studies [38, 39]. As with organic nitrate bioactivation, the precise mechanism(s) involved in nitrate tolerance remain(s) unknown, but it is likely to be complex and multifactorial. Two principal... 

Fung HE and Bauer JA. Mechanisms of nitrate tolerance. Cardiovasc Drug Ther 1994 8 489. 

Pathophysiology Hydralazine and isosorbide dinitrate are effective vasodilators which may interfere with the biochemical and molecular mechanisms responsible for the progression of HF Combined use may interfere with the development of nitrate tolerance (62). 

Molsidomine itself is inactive. After oral intake, it is slowly converted into an active metabolite, linsidomine. The differential effectiveness in arterial vs. venous beds is less evident compared to the drugs mentioned above. Moreover, development of nitrate tolerance is of less concern. These differences i n activi ty profi le appear to reflect a different mechanism of NO release. The same applies to the following sodium nitroprusside. 

Elkayam U. Tolerance to organic nitrates evidence, mechanisms, clinical relevance, and strategies for prevention. Ann Intern Med 1991 114(8) 667-77. 

It is well known that chemical compo.sition of rhizosphere solution can affect plant growth. Particularly, uptake of nutrients may be considerably influenced by the ionic concentration of the rhizosphere solution (40). Despite the difficulty of defining the exact concentration of ions in the rhizosphere surrounding each root (or even root portion), it has been unequivocally demonstrated that plants have evolved mechanisms to cope with the uneven distribution of ions in the root surrounding in order to provide adequate supply of each essential nutrient (41). These mechanisms include expression of transporter genes in specific root zones or cells and synthesis of enzymes involved in the uptake and assimilation of nutrients (40,43). Interestingly, it has been shown that specific isoforms of the H -ATPase are expressed in the plasma membrane of cell roots it has been proposed that the expression of specific isoforms in specific tissues is relevant to nutrient (nitrate) acquisition (44) and salt tolerance (45). 

The major limitation of nitrate therapy is the development of tolerance with continuous use. The loss of anti-anginal effects may occur within the first 24 hours of continuous nitrate therapy. While the cause of tolerance is unclear, several mechanisms have been proposed. These include depletion of the sulfhydryl groups necessary for the conversion of nitrates to nitric oxide, activation of neurohormonal systems, increased intravascular volume, and generation of free radicals that degrade nitric oxide. The most effective method to avoid tolerance and maintain the anti-anginal efficacy of nitrates is to allow a daily nitrate-free interval of at least 8 to 12 hours. Nitrates do not provide protection from ischemia during the nitrate-free period. Therefore, the nitrate-free... 

Fung, H-L., Chong, S., Kowaluk, E., Hough, K., Kakemi, M., Mechanisms for the pharmacological interaction of organic nitrates with thiols. Existence of an extracellular pathway for the reversal of nitrate vascular tolerance by N-acetylcytseine. J. Pharmacol. Exp. Ther. 245 (1988), 524-530... 

Over a century ago, empirical observation was made that organic nitrates, including glyceryl trinitrate (GTN), alleviate angina. Since then, GTN has been a mainstay therapy for angina and cardiac failure, even with the possible loss of effectiveness (tolerance) over extended dosing [55] and the risk of platelet hyperactivity in GTN-tolerant patients [54]. Despite this venerable therapeutic history, the mechanism of GTN bioactivation to NO is speculative at best [38]. In 1967, some 15 years before identification of NO as a biological entity, GTN was the first nitrovasodilator shown... 

---