Randomized, double-blind, placebo-controlled study of carvedilol on the prevention of nitrate tolerance in patients with chronic heart failure

Objectives. This study was designed to evaluate the effect of carvedilol on nitrate tolerance in patients with chronic heart failure. Background. The attenuation of cyclic guanosine 5′-monophosphate (cGMP) production due to inactivation of guanylate cyclase by increased superoxide has been reported as mechanism of nitrate tolerance. Carvedilol has been known to combine alpha/beta-blockade with antioxidant properties. Methods. To evaluate the effect of carvedilol on nitrate tolerance, 40 patients with chronic heart failure were randomized to four groups that received either carvedilol (2.5 mg once day [carvedilol group, n = 10]), metoprolol (30 mg once day [metoprolol group, n = 10]), doxazosin (0.5 mg once day [doxazosin group, n = 10]) or placebo (placebo group, n = 10). Vasodilatory response to nitroglycerin (NTG) was assessed with forearm plethysmography by measuring the change in forearm blood flow (FBF) before and 5 min after sublingual administration of 0.3 mg NTG, and at the same time blood samples were taken from veins on the opposite side to measure platelet cGMP. Plethysmography and blood sampling were obtained serially at baseline (day 0); 3 days after carvedilol, metoprolol, doxazosin or placebo administration (day 3); and 3 days after application of 10-mg/24-h NTG tape concomitantly with carvedilol, metoprolol, doxazosin or placebo (day 6). Results. There was no significant difference in the response of FBF (%FBF) and cGMP (%cGMP) to sublingual NTG on day 0 and day 3 among the four groups. On day 6, %FBF and %cGMP were significantly lower in the metoprolol, doxazosin and placebo groups than on day 0 and day 3, but these parameters in the carvedilol group were maintained. Conclusions. These results indicated that carvedilol may prevent nitrate tolerance in patients with chronic heart failure during continuous therapy with NTG.