Previous studies suggest that adenosine A₁ receptor antagonists may promote natriuresis without deleterious effects on renal function. This study evaluated renal and hemodynamic effects as well as safety, pharmacokinetics, and tolerability of BG9928, a selective adenosine A₁-receptor antagonist, in patients with heart failure. In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation study, 33 patients received a single dose of BG9928 (0.03, 0.3, 1.0, or 3.0 mg/kg) or placebo intravenously. Change from baseline in urinary sodium excretion for the 8-hour postdose interval was greater for all dosing groups versus placebo. The 0.03-mg/kg and 0.3-mg/kg groups had significant reductions in body weight versus placebo (-0.8 kg, -1.1 kg, 0.3 kg, respectively; P < 005). No changes in creatinine clearance or hemodynamic parameters were observed among any of the BG9928 groups versus placebo. However, pulmonary capillary wedge pressure tended to decrease and correlated with weight loss. Across the range of doses studied, pharmacokinetic parameters were linear and predictable. One patient who received the highest dose (3.0 mg/kg) developed seizures, and no further patients received that dose. Single intravenous BG9928 doses of up to 1.0 mg/kg were well tolerated and increased sodium excretion without worsening renal function. Further studies are needed to determine the clinical benefit of adenosine A₁ receptor antagonism.