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The effects of porcine endothelin on renal function were investigated in the isolated perfused rat kidney. After control clearance periods, endothelin (80, 120 or 320 pmol) or vehicle was added to the perfusate, and four 10-min experiments followed. Endothelin markedly reduced renal perfusate flow (RPF) as a result of its potent renal vasoconstrictor effect. At the highest but not low doses of endothelin, glomerular filtration rate (GFR) fell disproportionately to the reduction in RPF. Fractional Na excretion was also increased after kidney exposure to endothelin, suggesting an inhibition of tubular Na reabsorption by the peptide. Perfusion with low [Ca] severely blunted the hemodynamic effects of endothelin. Pharmacological blocking of renal cyclooxygenase by indomethacin or ibuprofen caused a further decline in RPF, GFR and absolute but not fractional Na excretion in kidneys challenged with endothelin. Atrial natriuretic peptide increased GFR and filtration fraction (FF), but not RPF, in kidneys previously exposed to 120 pmol endothelin. This was associated with a dramatic diuretic and natriuretic effect. The results demonstrate that 1) endothelin acts directly on the kidney, eliciting hemodynamic, diuretic and natriuretic responses that are dependent on the dose used and partially on the availability of extracellular Ca, 2) the renal effects of endothelin are exacerbated by cyclooxygenase blocking, suggesting that the vasoconstrictor effect of the peptide may be modulated by vasodilatory prostaglandins, and 3) atrial natriuretic peptide counteracts the renal function deterioration induced by endothelin, raising the possibility of an interplay between these vasoactive hormones in the control of renal function.