We investigated whether captopril is able to potentiate vasodilation and prevent tolerance to a 48-hour infusion of nitroglycerin (NTG). Twenty-six patients were randomly assigned to a 7-day regimen of captopril (50 mg/day) or placebo. The hemodynamic response to a 0.8 mg sublingual NTG dose was assessed by measuring mean arterial pressure (MAP), mean pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), and cardiac output (CO), and calculating systemic (SVR) and pulmonary vascular resistances (PVR). The parameters were obtained serially at baseline and 1 to 10 minutes after the sublingual NTG application (day 1). Then intravenous NTG was started and maintained for 48 hours (1.5 micrograms/kg/min), and the hemodynamic study was repeated (day 3). There was no difference between the captopril and the placebo groups at day 1 (baseline values and response to sublingual NTG). After the 48-hour infusion, there was a complete loss of the NTG effects in the placebo group (day 1 vs day 3: PAP, 20 +/- 5 mm Hg vs 21 +/- 8 mm Hg; MAP, 86 +/- 11 mm Hg vs 90 +/- 9 mm Hg; SVR, 1295 +/- 330 mm Hg vs 1380 +/- 465 dyne.sec.cm-5) whereas there was still evidence of a persistent vasodilation in the captopril group (day 1 vs day 3: PAP, 19 +/- 4 mm Hg vs 13 +/- 4 mm Hg; MAP, 84 +/- 9 mm Hg vs 74 +/- 10 mm Hg; SVR, 1265 +/- 280 mm Hg vs 1140 +/- 425 dyne.sec.cm-5). The response to sublingual NTG on day 3 was markedly attenuated in the placebo group only. We conclude that captopril does not increase the vasodilatory response to nitroglycerin but is able to prevent developing nitrate tolerance in arterial and venous circulation.