Endothelin inhibits vasopressin-stimulated water permeability in rat terminal inner medullary collecting duct

Renal tubule solute and water transport is subject to regulation by numerous factors. To characterize direct effects of the re-cently discovered peptide endothelin (ET) on renal tubule trans-port, we determined signaling mechanisms for ET effects on vasopressin (AVP)-stimulated water permeability (PF) in rat terminal inner medullary collecting duct (IMCD) perfused in vitro. ET caused a rapid, dose-dependent, and reversible fall in AVP- but not cyclic AMP-stimulated PFI suggesting that its effect on PF is by inhibition of cyclic AMP accumulation. Indo-methacin did not block ET actions, ruling out a role for prosta-glandins in its effect. The protein kinase C (PKC) inhibitor calphostin, or pretreatment of perfused tubules with pertussis toxin, blocked ET-mediated inhibition of AVP-stimulated PF. ET caused a transient increase in intracellular calcium ([Ca2"J1) in perfused tubules, an effect unchanged in zero cal-cium bath or by PT pretreatment. ET effects on PF and [Ca2+I, desensitized rapidly. Inhibition of PF was transient and largely abolished by 20 min ET preexposure, and repeat exposure to ET did not alter [Ca2J1i. In contrast, PGE2-mediated inhibition of AVP-stimulated PF and increase of ICa2+Ii were sustained and unaltered by prior exposure ofIMCD to ET. Thus desensi-tization to ET is homologous. We conclude that ET is a potent inhibitor of AVP-stimulated water permeability in rat terminal IMCD. Signaling pathways for its effects involve both an inhibi-tory guanine nucleotide-binding protein and phospholipase-mediated activation of PKC. Since ET is synthesized by IMCD cells, this peptide may be an important autocrine modulator of renal epithelial transport. (J. Clin. Invest. 1992. 90:1458