Atrial natriuretic factor (ANF) decreases cardiac filling pressure, suggesting that diminished venous return is an important mechanism for the associated reduction in cardiac output. To determine whether ANF reduces cardiac preload through venodilation in congestive heart failure (CHF), we compared the hemodynamic effects of ANF-(99-126) with those of the venodilator nitroglycerin in conscious rats with CHF induced by coronary artery ligation previously. Depending on the extent of myocardial infarction, rats were subdivided into two groups: 1) mild or 2) severe CHF. Incremental intravenous infusions of ANF (0.1, 0.25, 0.5 micrograms.kg-1.min-1) or nitroglycerin (2, 5, 10 micrograms.kg-1.min-1) were administered for 20 min at each dose. Both agents reduced cardiac filling pressures. There was no change in cardiac output or arterial pressure at any dose of ANF in rats with severe CHF, but cardiac output decreased at higher ANF doses in rats with mild CHF. In contrast, nitroglycerin produced no change in cardiac output at any dose in either CHF group, although it decreased arterial pressure at the higher doses in rats with severe CHF. ANF increased whereas nitroglycerin decreased hematocrit in both CHF groups. The ANF-induced hematocrit increase also occurred in those rats with vesicovenous shunts designed to prevent volume contraction induced by diuresis. These data suggest that ANF and nitroglycerin decreased cardiac filling pressure through different hemodynamic mechanisms. The known venodilator action of nitroglycerin was associated with decreased hematocrit, suggesting enhanced transcapillary fluid migration. However, ANF produced an opposite effect on fluid migration as demonstrated by an increased hematocrit, suggesting a mechanism other than venodilation must be operative in reducing cardiac filling pressure.(ABSTRACT TRUNCATED AT 250 WORDS)