In the present study the response to acute saline loading was investigated. During a 24-day study period six male subjects followed a standardized diet including a daily intake of 40 ml water and 125 mg NaCl per kg body weight. Before, during, and after a ten-day period of 6 degrees head down tilt (HDT) each volunteer received an intravenous 0.9% saline infusion of 22 ml/kg body weight over 20 minutes. HDT produced significant losses in body weight and in blood volume, but the responses to saline loading were similar during all phases of the study. Plasma levels of atrial natriuretic peptide (ANP) did not increase, while plasma levels of cyclic GMP increased by about 40% 90 minutes after each infusion. Urine flow nearly doubled during second hour post-infusion. Sodium excretion showed a 3-fold increase and remained elevated during the third hour, while potassium excretion was significantly reduced. Urinary excretion of cyclic GMP reached a peak during the second hour post-infusion. At the end of these short-term periods the cumulative water- and sodium-balance data disclosed that only about 20% of the infused water and less than 15% of the infused sodium was excreted during each experiment. In addition to the short-term renal response, urine flow and sodium excretion remained significantly elevated for more than 48 hours after each saline load. The long-term renal response was paralleled by an increased excretion of urinary cyclic GMP. HDT produced significant changes in body fluid distribution, but only minor changes in the regulatory responses to an acute saline load. We conclude from these data that the excretion of an acute isotonic saline load requires several days and that the renal response appears to be independent of the secretion of ANP from the heart.