Nitrates, organic tolerance

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... 

In their studies of the flavoprotein inhibitor, DPI, Bennett and colleagues [91, 120] found that DPI inhibited GTN-induced accumulation of cGMP to the same extent in aortae from naive and from GTN-tolerant animals. They argued that, if inactivation of flavoproteins is a major cause of tolerance, then there should be less scope for further, DPI-induced inactivation in tolerant animals, compared with naive ones. Their conclusion, accordingly, was that, while flavoproteins may participate in biotransformation of organic nitrates and associated vasodilation, their alteration cannot be the basis for nitrate tolerance. 

Effects of the flavoprotein inhibitor, diphenylene iodonium sulfate, on ex vivo organic nitrate tolerance in the rat. J. Pharmacol. Exp. Ther. 293 (2000), p. 569-577... 

Because of the high pH required for this process and the poor vasodilator properties of nitrite, this process cannot explain the biological action of organic nitrates. There are two problems in the use of organic nitrates as vasodilators 1. the conditions necessary for the biotransformation that converts an organic nitrate into NO, and 2. the phenomenon of tolerance. The two may be linked. 

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)). 

Some new organic nitrates are of interest. Sininitrodil [76] (Fig. 8.7), SPM-4744 and SM P-5185 [77] selectively dilate large microvessels and SPM-5185 is resistant to cross-tolerance with GTN in human blood vessels in vitro. 

GTN is a very convenient organic nitrate to use, although during handling its explosive nature should be remembered. If the experimental results are suspect in any way it might be wise to try one of the organic nitrates, which do not display tolerance. In research, as in other areas of human life, it is wise to be nimble. 

They are more potent than nitrates and there is no development of tolerance [78]. Their drawbacks are that they are very volatile (and therefore difficult to deliver quantitatively) and photochemically and thermally unstable. Organic nitrites are excellent nitrosating agents, particularly for thiols (Eq. (17)). 

In other work, C87-3754has been compared with SIN-1, the equivalent metabolite from molsidomine, and from the organic nitrate class, isosorbide-5-mononitrate (IS-5-MN) [146]. In this latter study, which involved long term oral administration in a dog model, IS-5-MN showed tolerance whilst the sydnonimines showed no self- or cross-tolerance. Elsewhere, tolerance studies in dogs by oral or continuous infusion of C87-3754 have shown benefits in the treatment of a failing heart, without tolerance [147] and with better results than those observed by nitroglycerin [148]. 

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... 

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... 

Uses. Organic nitrates are used chiefly in angina pectoris (p. 308, 310), less frequently in severe forms of chronic and acute congestive heart failure. Continuous intake of higher doses with maintenance of steady plasma levels leads to loss of efficacy, inasmuch as the organism becomes refractory (tachy-phylactic). This nitrate tolerance can be avoided if a daily nitrate-free interval is maintained, e.g., overnight. 

Vascular headache, postural hypotension, and reflex tachycardia are common side effects of organic nitrate therapy. Fortunately, tolerance to nitrate-induced headache develops after a few days of therapy. Postural hypotension and tachycardia can be minimized by proper dosage adjustment and by instructing the patient to sit... 

Organic nitrites, such as the volatile antianginal amyl nitrite, also require metabolic activation to elicit vasorelaxation, although the responsible enzyme has not been identified. Nitrites are arterial vasodilators and do not exhibit the rapid tolerance seen with nitrates. 

The primary adverse effects associated with organic nitrates are headache, dizziness, and orthostatic hypotension.47 These effects are related to the drugs ability to dilate peripheral blood vessels and decrease peripheral resistance. Nausea may also be a problem in some patients. As indicated earlier, tolerance to the beneficial effects of nitrates can occur during continuous administration, but providing daily nitrate-free intervals should prevent this problem. 

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