Nitrate tolerance

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. 

Finally, in this context, it should be noted that Laursen et al. [121] dispute the whole concept that nitrate tolerance is associated with reduced bioconversion of GTN to NO. 

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... 

M. E., Meister, A., Nitrate tolerance in vivo is not associated with depletion of arteria. or venous thiol levels. Circ. 

Kurz, S., Hink, U., Nickenig, G., Borthayre, A. B., Harrison, D. G., Munzel, T., Evidence for a causal role for the renin-angiotensin system in nitrate tolerance. Circulation 99 (1999), p. 3181-3187... 

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... 

Mulsch, A., Busse, R., Bassenge. E., Desensitization of guanylate cyclase in nitrate tolerance does not impair endothelium-dependent responses. Eur. J.Pharmacol. 158 (1988),... 

Hinz, B., Schroeder, H., Nitrate tolerance is specific for nitric acid esters and its recovery requires an intact protein synthesis. Biochem. Biophys.Res. Commun. 252 (1998), p. 232-235... 

Bohyn, M., Berkenboom, G., Fontaine, J., Effect of nitrate tolerance and dipyridamole on the response to SINj in human isolated saphenous vein. Cardiovasc. Drugs. Then 5 (1991), p. 457-462... 

Laursen, J. B., Mulsch, S., Boesgaard, S., Mordvintcev, P., Trautner S., Gruhn, N., Nielsen-Kudsk, J. E., Busse, R., Alsershvile, J., In vivo nitrate tolerance is not associated with reduced bioconversion of nitroglycerin to nitric oxide. Circulation 94 (1996), p.2241-2247... 

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... 

Gori, T., Parker, J.D., The puzzle of nitrate tolerance pieces smaller than we thought Circulation 106(18) (2002) p.2404-2408... 

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. 

Molsidomine itself is inactive. After oral intake, it is slowly converted into an active metabolite. Apparently, there is little likelihood of "nitrate tolerance . 

For sustained daytime angina prophylaxis, nitrates are of limited value because "nitrate pauses of about 12 h are appropriate if nitrate tolerance is to be avoided. If attacks occur during the day, ISDN, or its metabolite isosorbide mononitrate, may be given in the morning and at noon (e.g ISDN 40 mg in extended-release capsules). Because of hepatic presystemic elimination, NTG is not suitable for oral administratioa Continuous delivery via a transdermal patch would also not seem advisable because of the potential development of tolerance. With molsidomine, there is less risk of a nitrate tolerance however, due to its potential carcinogenicity, its clinical use is restricted. 

Abrams J. 1980. Nitrate tolerance and dependence. American Heart Journal 99 113-123. 

To help avoid nitrate tolerance, clinicians should employ the smallest effective dose and administer the compound infrequently. A daily nitrate-free period is also recommended, particularly with use of the transdermal patches or ointment. A better understanding of the pharmacokinetic profile achieved with these sustained-release formulations should result in more effective dosing regimens. 

Since depletion of tissue stores of sulfhydryl groups has been proposed to play an important role in nitrate tolerance, some investigators have administered sulfhydryl-containing compounds in an attempt to reverse or prevent the development of tolerance. The most commonly used agent is A-acetylcysteine (NAC), which is hydrolyzed in vivo to cysteine. Although some... 

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

Kurz S et al. Evidence for a causal role of the renin-angiotensin system in nitrate tolerance. Circulation 1999 99 3181-3187. 

Csont T, Ferdinandy P. Cardioprotective effects of glyceryl trinitrate beyond vascular nitrate tolerance. Pharmacol Ther. 2005 105 57-68. 

Munzel T, Daiber A, Mulsch A. Explaining the phenomenon of nitrate tolerance. Circ Res. 2005 97 618-628. 

L. Cloarec-Blanchard, C. Funck-Brentano, A. Carayon, and P. Jaillon. Rapid development of nitrate tolerance in healthy volunteers assessment using spectral analysis of short-term blood pressure and heart rate variability. J. Cardiovasc. Pharmacol. 24 266-273, 1994. 

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