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 hydralazine on the development of nitrate tolerance in patients with chronic congestive heart failure. Background. Early development of nitrate tolerance with either continuous administration of intravenous or topical nitrate preparations or frequent dosing of oral nitrates leads to significant attenuation of nitrate-mediated hemodynamic and anti-ischemic effects. In recent animal experiments, prevention of nitroglycerin-induced hemodynamic tolerance with 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 continuous infusion (24 h) of nitroglycerin alone (group I, 14 patients) or concomitantly with oral hydralazine (75 mg four times day [group II, 14 patients]). The effect of nitroglycerin in each group was evaluated by analysis of variance for repeated measures. The power of the analysis to detect 5.4-mm Hg (20%) change in mean pulmonary artery wedge pressure was 90%. Results. Baseline hemodynamic variables as well as the initial hemodynamic response to nitroglycerin were comparable in both groups. Compared with the initial response to nitroglycerin, significant attenuation of effect was found in group I at 24 h in mean (±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 nitroglycerin-induced hemodynamic tolerance and resulted in persistent effect 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 pressure 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). Conclusions. In patients with chronic heart failure due to left ventricular systolic dysfunction, the concomitant use of oral hydralazine prevents early development of nitrate tolerance and results in persistent nitrate-mediated hemodynamic effect on systemic and pulmonary artery and left ventricular filling pressures. These dat may support the concurrent use of hydralazine in patients with heart failure treated with organic nitrates.