The hypothesis was tested that acute hypoxemia may be a physiological stimulus for atrial natriuretic factor (ANF) secretion in anesthetized, spontaneously breathing rabbits. Base-line plasma ANF (range from 29.8 to 219 pg/ml; mean +/- SE = 87.0 +/- 14.1 pg/ml; n = 16 rabbits) was negatively correlated with base-line arterial PO2 (r = -0.759; P less than 0.01) but not with PCO2, pH, mean arterial blood pressure, central venous pressure (CVP), minute ventilation, heart rate, or type of anesthetics used. Acute hypoxemia (arterial PO2 22.3-44.3 mmHg) lasting 10 min increased plasma ANF levels over base line by 69.2 +/- 47.7 (SE) pg/ml at 6 min and 87.5 +/- 46.8 (SE) pg/ml at 9 min (P less than 0.01; n = 9). The increase in arterial pH and minute ventilation and the decrease of arterial PCO2 paralleled the changes in plasma ANF. Mean arterial blood pressure, CVP, and heart rate did not change significantly. ANF responses to hypoxemia (range from 4.4 to 423 pg/ml) correlated with base-line CVP (r = 0.761; P less than 0.01) and base-line ANF (r = 0.523; P less than 0.05) but with no other measured variable. Although the mediators of hypoxemia-induced release of ANF need to be explored further, this study raises the possibility that ANF might be involved in the adaptation to hypoxemia.