HYDRALAZINE-INDUCED PREVENTION OF NITRATE TOLERANCE - EXPERIMENTAL AND CLINICAL-EVIDENCE AND POTENTIAL MECHANISMS

The clinical use of hydralazine in combination with organic nitrates h as resulted in a beneficial effect on survival, cardiac function, and exercise tolerance, More recently, hydralazine has been shown to preve nt development of nitrate tolerance and early attenuation of nitrate-m ediated hemodynamic effects in both experimental animals as well as pa tients with severe heart failure due to depression of left ventricular systolic Function, Recent in vitro animal results have shown that pro longed nitroglycerin treatment results in increased production of endo genous vascular superoxide (c) overdot O-2 production due to a specifi c NADH-dependent membrane-associated oxidase and that this is at least in part responsible for the development of nitrate tolerance, Further studies demonstrated that concomitant administration of hydralazine n ormalized endogenous rates of vascular (c) overdot O-2 production and prevented the development of nitrate tolerance, The ability of hydrala zine to inhibit vascular (c) overdot O-2 anion production and to preve nt the development of nitrate tolerance may provide further explanatio ns for the benefits demonstrated in the V-HeFT studies with the hydral azine-isosorbide dinitrate combination in the treatment of patients wi th chronic CHF. (C) 1998 by Excerpta Medica, Inc.