Endothelin, a peptide inhibitor of Na(+)-K(+)-ATPase in intact renaltubular epithelial cells.
Endothelin, a potent vasoconstrictor released by vascular endothelial cells, can induce natriuresis in vivo. These studies examined the regulation of Na+ transport by endothelin in suspensions of rabbit proximal tubule (PT) and inner medullary collecting duct (IMCD) cells. Endothelin reduced oxygen consumption (QO2) by 18 +/- 1% in IMCD cells but did not alter QO2 in PT cells. In IMCD cells, endothelin inhibited QO2 half maximally at approximately 5 x 10(-12) M. Several lines of evidence indicate that endothelin reduces QO2 by inhibiting the Na(+)-K(+)-ATPase. 1) Endothelin gave no further inhibition of QO2 after ouabain and blunted the stimulatory effect of amphotericin B on QO2 (+29 +/- 4% in absence of endothelin, 0 +/- 5% in presence of endothelin; n = 6 preparations, P less than 0.001). 2) Endothelin inhibited ouabain-sensitive 86Rb+ uptake by 46.6 +/- 8.6% at 10 s and by 35.4 +/- 5.3% at 30 s without altering uptake at 60 min. 3) Addition of endothelin to IMCD cells induced a net K+ efflux with an initial rate of 32.2 +/- 4.8 nmol.min-1.mg protein-1, consistent with inhibition of the Na(+)-K(+)-ATPase. In contrast to the response observed in intact cells, in permeabilized IMCD cells endothelin did not inhibit ouabain-sensitive ATPase. Several observations indicated that prostaglandin E2 (PGE2) mediates endothelin inhibition of Na(+)-K(+)-ATPase activity. 1) The response to endothelin was blocked by ibuprofen in assays of QO2, net K+ flux, and 86Rb+ uptake. 2) Endothelin and PGE2 gave equivalent, nonadditive inhibition of ouabain-sensitive 86Rb+ uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
Zeidel
M L
ML
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Brady
H R
HR
Kone
B C
BC
Gullans
S R
SR
Brenner
B M
BM
D000818:Animals; D015232:Dinoprostone / Q000494:pharmacology; D016232:Endothelins; D004730:Endothelium, Vascular / Q000502:physiology; D007052:Ibuprofen / Q000494:pharmacology; D066298:In Vitro Techniques; D007679:Kidney Medulla / Q000201:enzymology*; D007684:Kidney Tubules / Q000201:enzymology*; D007685:Kidney Tubules, Collecting / Q000201:enzymology*; D007687:Kidney Tubules, Proximal / Q000201:enzymology*; D007700:Kinetics; D010101:Oxygen Consumption / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011817:Rabbits; D012413:Rubidium / Q000378:metabolism; D012414:Rubidium Radioisotopes; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
D016232:Endothelins; D010455:Peptides; D012414:Rubidium Radioisotopes; D000254:Sodium-Potassium-Exchanging ATPase; D015232:Dinoprostone; D012413:Rubidium; D011188:Potassium; D007052:Ibuprofen