T o determine whether renal prostaglandins participate in the regulation of renal blood flow during acute reduction of cardiac output, cardiac venous return was decreased in 17 anesthetized dogs by inflating a balloon placed in the thoracic inferior vena cava. This maneuver decreased cardiac output from 3.69±0.09 liters/min (mean±SEM) to 2.15±0.19 liters/min (P < 0.01) and the mean arterial blood pressure from 132±4 to 111±5 mm Hg (P < 0.01) and increased total peripheral vascular resistance from 37.6±2.5 to 57.9±4.8 arbitrary resistance units (RU) (P < 0.01). In marked contrast, only slight and insignificant decreases in the renal blood flow from 224±16 to 203±19 ml/min and renal vascular resistance from 0.66±0.06 to 0.61±0.05 arbitrary resistance units (ru) were observed during inflation of the balloon. Concomitant with these hemodynamic changes, plasma renin activity and plasma norepinephrine concentration increased significantly in both the arterial and renal venous bloods. Plasma concentration of prostaglandin E₂ in renal venous blood increased from 34±6 to 129±24 pg/ml (P < 0.01). The subsequent administration of indomethacin or meclofenamate had no significant effect on mean arterial pressure, cardiac output, and total peripheral vascular resistance, but reduced renal blood flow from 203±19 to 156±21 ml/min (P < 0.01) and increased renal vascular resistance from 0.61±0.05 to 1.05±0.21 ru (P < 0.01). Simultaneously, the plasma concentration of prostaglandin E₂ in renal venous blood fell from 129±24 to 19±3 pg/ml (P < 0.01). Administration of indomethacin to five dogs without prior obstruction of the inferior vena cava had no effect upon renal blood flow or renal vascular resistance. The results indicate that acute reduction of cardiac output enhances renal renin secretion and the activity of the renal adrenergic nerves as well as renal prostaglandin synthesis without significantly changing renal blood flow or renal vascular resistance. Inhibition of prostaglandin synthesis during acute reduction of cardiac output results in an increased renal vascular resistance and reduced renal blood flow. Accordingly, that data provide evidence that renal prostaglandins counteract in the kidney the vasoconstrictor mechanisms activated during acute reduction of cardiac output.