Hydralazine-Induced Prevention of Nitrate Tolerance: Experimental and Clinical Evidence and Potential Mechanisms

Abstract The clinical use of hydralazine in combination with organic nitrates has resulted in a beneficial effect on survival, cardiac function, and exercise tolerance. More recently, hydralazine has been shown to prevent development of nitrate tolerance and early attenuation of nitrate-mediated hemodynamic effects in both experimental animals as well as patients with severe heart failure due to depression of left ventricular systolic function. Recent in vitro animal results have shown that prolonged nitroglycerin treatment results in increased production of endogenous vascular superoxide (ċO 2 ) production due to a specific 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 normalized endogenous rates of vascular ċO 2 production and prevented the development of nitrate tolerance. The ability of hydralazine to inhibit vascular ċO 2 anion production and to prevent the development of nitrate tolerance may provide further explanations for the benefits demonstrated in the V-HeFT studies with the hydralazine–isosorbide dinitrate combination in the treatment of patients with chronic CHF.