PREVENTION OF NITRATE TOLERANCE WITH CONCOMITANT ADMINISTRATION OF HYDRALAZINE

Organic: nitrates have frequently been used for the treatment of patie nts with congestive heart failure (CHI;). Nitrate tolerance has been i dentified as a major limitation of this therapy preventing a continuou s effect. In the past several years, an effort has been made to develo p strategies to prevent nitrate tolerance. Recent animal experimentati on has demonstrated the prevention of nitrate tolerance with a concomi tant administration of hydralazine. A later study demonstrated similar results in a patient with chronic CHF. The use of oral hydralazine (7 5 mg qid) resulted in prevention of early development of nitrate toler ance and attenuation of nitrate mediated hemodynamic effects which occ urred within the first several hours after initiation of nitroglycerin therapy in the control group not receiving hydralazine. Recent data o btained in in vitro studies have demonstrated enhancement of vascular su peroxide production secondary to exposure to nitrates which may be an important mechanism leading to nitrate tolerance. These same studie s demonstrated a strong antioxidant effect of hydralazine reducing sup eroxide formation and preventing nitrate tolerance. Both animal and hu man experiments have demonstrated prevention of nitrate tolerance with a concomitant use of hydralazine. In vitro studies suggest that hydra lazine, by virtue of its antioxidant effects, prevents the nitrate med iated formation of vascular superoxide, and thus prevents nitrate tole rance. These data provide an explanation for the benefit demonstrated in the V-HeFT studies with the combination of isosorbide dinitrate and hydralazine in the treatment of patients with chronic CHF, and provid e a support for the use of this therapeutic regimen in the treatment p atients with chronic heart failure.