The hemodynamic, renal, neurohormonal effects and pharmacokinetics of synthetic atrial natriuretic factor (ANF) were studied in six conscious dogs with severe heart failure induced by right ventricular pacing at 250 beats/min for 5.0 +/- 0.6 weeks. Severe heart failure was characterized by a low cardiac output (2.1 +/- 0.1 L/min, elevated pulmonary capillary wedge pressure (26.8 +/- 2.8 mmHg) and right atrial pressure (14.5 +/- 2.2 mmHg). Synthetic ANF (human 99ser-126tyr ANF) was administered intravenously as 2 consecutive 30 min infusions (0.02 and 0.10 microgram/kg.min respectively); and each infusion was preceded by a priming dose of 1 microgram/kg. In contrast to the potent vasorelaxant, natriuretic and renin-lowering effects previously reported in normal dogs, these effects were not observed in the dogs with heart failure with either dose of ANF. The plasma half-life was 10.0 +/- 2.6 min, significantly longer than that reported previously in normal dogs. These data suggest that in this model of heart failure, the pharmacokinetics of ANF are altered and there is generalized target organ resistance to the actions of ANF.