Randomized, Double-Blind, Placebo-Controlled Study of Ascorbate on the Preventive Effect of Nitrate Tolerance in Patients With Congestive Heart Failure

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Abstract
Background —Reduced cGMP production caused by increased superoxide has been proposed as a mechanism of nitrate tolerance during continuous nitrate therapy. This study was designed to evaluate the effects of ascorbate, an antioxidant, on the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure. Methods and Results —Twenty patients with congestive heart failure were randomized to receive intravenous infusion of nitroglycerin concomitantly with placebo (placebo group, n=10) or intravenous ascorbate (vitamin C group, n=10). After baseline measurements were obtained, dose titration was started by the infusion of nitroglycerin at a rate of 0.5 μg/kg per minute (titration period). Measurements of hemodynamic parameters and blood sampling were performed serially at 0, 6, 12, 18, and 24 hours after the titration period. At baseline, mean pulmonary artery pressure (MPAP, mm Hg), mean pulmonary capillary wedge pressure (PCWP, mm Hg), plasma vitamin E level (μmol/L), and platelet cGMP level (pmol/10 9 platelets) were comparable in the two groups (placebo group: MPAP, 48±6; PCWP, 24±4; cGMP, 0.76±0.12; vitamin E, 18.2±1.2; vitamin C: MPAP, 49±7; PCWP, 24±4; cGMP, 0.71±0.16; vitamin E, 18.6±1.3). In both groups, at 6 hours after the titration period, MPAP and PCWP were significantly decreased (placebo group: MPAP, 26±5; PCWP, 15±4; vitamin C: MPAP, 26±4; PCWP, 16±4), and platelet cGMP was significantly increased (placebo group: 2.42±0.24; vitamin C: 2.26±0.26). However, at 18 hours after titration, in the placebo group, MPAP (44±5) and PCWP (23±4) were increased, and platelet cGMP (0.85±0.20) and plasma vitamin E levels (12.4±1.4) were significantly decreased. In contrast, in the vitamin C group, MPAP (31±6), PCWP (17±5), platelet cGMP (2.49±0.23), and plasma vitamin E levels (17.6±1.4) were maintained for 18 hours after the titration period. Conclusions —These findings indicate that ascorbate, an antioxidant, may prevent the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.