It has been reported that nitroglycerin (GTN) tolerance can be prevented by the concurrent administration of hydralazine. Although the mechanism of this effect remains unknown, it is possible that hydralazine modifies counter-regulatory responses to nitrate administration. To address this question, we examined the impact of hydralazine therapy on the development of tolerance during sustained therapy with GTN. Twenty normal volunteers and 18 patients with chronic heart failure (mean ejection fraction 30 +/- 2%) were treated for 1 week with hydralazine or placebo in a randomized double-blind fashion. Hydralazine therapy (or placebo) was continued, and subjects then received continuous transdermal GTN for 5 to 7 days. On the first and last day of transdermal GTN therapy, standing HR, systolic blood pressure and hematocrit responses were assessed. HR and blood pressure responses to sublingual GTN (0.6 mg) were also evaluated before and during sustained transdermal GTN therapy. Significant loss of the hemodynamic effects of transdermal GTN occurred during sustained therapy in both the normal volunteer and heart failure groups. Hydralazine had no effect on the development of tolerance to the hemodynamic effect of GTN in either group. In both, transdermal GTN therapy was associated with a significant fall in hematocrit that persisted for the entire treatment period. Hydralazine had no effect on this response. These data suggest that hydralazine therapy does not prevent loss of systemic arterial effects or prevent plasma volume expansion during sustained transdermal GTN therapy.