PREVENTION OF TOLERANCE TO HEMODYNAMIC-EFFECTS OF NITRATES WITH CONCOMITANT USE OF HYDRALAZINE IN PATIENTS WITH CHRONIC HEART-FAILURE

Objectives. This study was designed to determine the effect of oral hy dralazine on the development of nitrate tolerance in patients with chr onic congestive heart failure. Background. Early development of nitrat e tolerance with either continuous administration of intravenous or to pical nitrate preparations or frequent dosing of oral nitrates leads t o significant attenuation of nitrate-mediated hemodynamic and anti-isc hemic effects. In recent animal experiments, prevention of nitroglycer in induced hemodynamic tolerance with a concomitant use of hydralazine was demonstrated. This finding may have important clinical relevance. Methods. Twenty-eight patients with chronic heart failure due to left ventricular systolic dysfunction were randomized to receive either a continuous infusion (24 h) of nitroglycerin alone (group I, 14 patient s) or concomitantly with oral hydralazine (75 mg four times a day [gro up II, 14 patients]). The effect of nitroglycerin in each group was ev aluated by analysis of variance for repeated measures. The power of th e analysis to detect a 5.4 mm Hg (20%) change in mean pulmonary artery wedge pressure was 90%. Results. Baseline hemodynamic variables as we ll as the initial hemodynamic response to nitroglycerin were comparabl e in both groups. Compared with the initial response to nitroglycerin, a significant attenuation of effect was found in group I at 24 h in m ean (+/-SE) pulmonary artery pressure (27 +/- 4% vs, 10 +/- 3%, p < 0. 05) and mean pulmonary artery wedge pressure (40 +/- 4% vs. 16 +/- 4%, p < 0.05). In group II, conversely, oral hydralazine prevented nitrog lycerin-induced hemodynamic tolerance and resulted in a persistent eff ect on mean pulmonary artery and wedge pressures throughout the study period (31 +/- 3% vs. 27 +/- 4%, p = 0.13 and 37 +/- 4% vs. 34 +/- 6%, p = 0.40, respectively), In addition, the initial effect on blood pre ssure was attenuated at 24 h in group I (5 +/- 2% vs, 12 +/- 3%, p < 0 .05) but not in group II (15 +/- 3% vs. 17 +/- 2%, p = 0.46). Conclusi ons. In patients with chronic heart failure due to left ventricular sy stolic dysfunction, the concomitant use of oral hydralazine prevents e arly development of nitrate tolerance and results in a persistent nitr ate-mediated hemodynamic effect on systemic and pulmonary artery and l eft ventricular filling pressures. These data may support the concurre nt use of hydralazine in patients with heart failure treated with orga nic nitrates. (J Am Coll Cardiol 1995;26:1575-80)