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Role of free Radicals

Drug Action (Nitrate Tolerance)

Organic nitrates are used for the therapy of a large variety of cardiovascular diseases in which enhanced vasodilator responses of certain vascular sections are beneficial, e.g. in myocardial ischemia. Yet, most nitrovasodilators have one common disadvantage: the generation of nitrate tolerance, especially during non-intermittent administration. Tolerance is a multifactorial phenomenon including neuro-hormonal counter-regulation and enhanced responses to vasoconstrictor agonists opposing the NO-induced cGMP-mediated vasodilation. Despite many hypotheses and investigations on nitrate tolerance its precise mechanisms have yet to be clearly defined. However, recently it was observed that during tolerance, the metabolism of glyceryltrinitrate (GTN) was associated with an enhanced superoxide production probably evolving from an enhanced activity of NAD(P)H oxido-reductase during continuous exposure to GTN. To suppress superoxide-mediated inactivation of NO, which is an activator of soluble guanylyl cyclase (sGC) and of cGMP-mediated vasodilation, we tested various antioxidants for their efficacy to prevent GTN tolerance and to decrease the enhanced levels of superoxide associated with a chronic exposure to GTN. Among a-tocopherol (Vit-E), N -acetyl-cysteine, dimethyl sulfoxide and ascorbate (Vit-C), the latter proved to be the most efficient.

References
  1. Fink B, Schwemmer M, Bassenge E. Prevention of Nitrate Tolerance : New Concepts. Cardiovasc Drug Ther. 2002; In Print.

  2. Fink B, Bassenge E. PETN in contrast to GTN does not induce tolerance associated with enhanced oxidant stress in human beings. Journal of Cardiovascular Pharmacology. 2002.

  3. Müllenheim J, Müller S, Laber U et al. The effect of high-dose pentaerythritol tetranitrate on the development of nitrate toerance in rabbits. Naunyn-Schmiedeberg's Arch Pharmacol. 2001;364:269-275.

  4. Fink B, Dikalov S, Bassenge E. A new approach for extracellular spin trapping of nitroglycerin-induced formation of superoxide radicals both in vitro and in vivo. Free Rad Biol Med. 2000;28:121-128.

  5. Dikalov S, Fink B, Skatchkov M et al. Comparison of Glyceryl Trinitrate-induced with Pentaerythrityl Tetranitrate-induced in vivo Formation of Suproxide Radicals: Effect of Vitamin C. Free Rad Biol Med. 1999;27:170-176.

  6. Fink B, Schwemmer M, Fink N et al. Tolerance to nitrates with enhanced radical formation suppressed by carvedilol. J Cardiovasc Pharmacol. 1999;34:800-805.

  7. Bassenge E, Fink N, Skatchkov M et al. Dietary Supplement with Vitamin C Prevents Nitrate Tolerance. J Clin Invest. 1998;102:67-71.

  8. Fink B, Bassenge E. Unexpected, tolerance-devoid vasomotor and platelet actions of pentaerytrityl tetranitrate. J Cardiovasc Pharmacol. 1997;30:831-836.

  9. Münzel T, Kurz S, Rajagopalan S et al. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug. J Clin Invest. 1996;98:1465-1470.

  10. Münzel T, Sayegh H, Freeman BA et al. Evidence for enhanced vascular superoxide anion production in nitrate tolerance. J Clin Invest. 1995;95:187-194.

  11. Münzel T, Holtz J, Mülsch A et al. Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance- independent interactions exist. Circulation. 1989;79:188-197.

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