The renal and neurohumoral effects of prolonged cardiopulmonary baroreflex unloading and the relationship of these changes to urinary sodium excretion have not been well documented in humans. In this study, 12 normal males underwent lower body negative pressure at -15 mmHg for 90 min, a maneuver that deactivates cardiopulmonary baroreceptors. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and filtration fraction (FF) were measured in eight of these subjects using inulin and p-aminohippuric acid clearance techniques. During reduction of central venous pressure, arterial blood pressure and heart rate did not change. Plasma concentrations of atrial natriuretic factor (ANF) decreased markedly (22 +/- 2 to 12 +/- 1 pg/ml, P = 0.0001) as did the second messenger of ANF's biological action, guanosine 3',5'-cyclic monophosphate, whereas renin and vasopressin were not significantly altered. There was a significant rise in plasma norepinephrine (1.6 +/- 0.2 to 2.4 +/- 0.4 nmol/l, P = 0.03). GFR (104 +/- 9 to 68 +/- 6 ml/min, P = 0.007) and FF (0.18 +/- 0.01 to 0.14 +/- 0.01, P = 0.007) decreased significantly, with maintenance of ERPF. There was a significant antinatriuresis without an antikaliuresis and a significant reduction in free water clearance. These changes in renal hemodynamics are unlike the known effects of renal vasoconstrictors, and the alterations in solute and free water clearance are consistent with the removal of the known actions of ANF from tubular target sites. Taken together, our findings suggest that a mechanism other than activation of vasoconstrictors, possibly the diminution of the influence of ANF on the kidney, may be operative in the renal adjustments to cardiopulmonary baroreflex deactivation in humans.