PEPTIDE YY INHIBITS VASOPRESSIN-STIMULATED CHLORIDE SECRETION IN INNER MEDULLARY COLLECTING DUCT CELLS

mIMCD-k2 cells are derived from the inner medullary collecting duct of a mouse and exhibit electrogenic sodium absorption and cAMP- and vaso pressin (AVP)-stimulated electrogenic chloride secretion [N. L. Kizer; B. Lewis, and B. A. Stanton. Am. J. Physiol. 268 (Renal Fluid Electro lyte Physiol. 37): F347-F355, 1995; and N. L. Kiter, D. Vandorpe, B. L ewis, B. Bunting, J. Russell, and B. A. Stanton. Am. J. Physiol. 268 ( Renal Fluid Electrolyte Physiol. 37): F854-F861, 1995]. The purpose of the present. study was to determine how peptide YY (PYY) affects elec trogenic Na+ and Cl- current in mIMCD-k2 cells. Short-circuit currents (I-sc) were measured across monolayers of mIMCD-k2 cells mounted in U ssing-type chambers. PYY did not alter baseline I-sc, nor did it alter I-sc in chloride-free conditions, indicating no effect on electrogeni c sodium transport. Baseline chloride current in these cells is low, t herefore, chloride short-circuit current (I-sc(Cl)) was stimulated wit h AVP (10 nM) added to the basolateral surface and 10 mu M amiloride a dded to the apical surface. Although apical applications of PYY had no effect, basolateral application of PYY caused attenuation of I-sc(Cl) , with the maximal inhibitory dose (100 nM) causing 52 +/- 1.3% inhibi tion (IC50 = 0.11 nM). Inhibition by PYY of I-sc(Cl) is mediated throu gh the Y-2 receptor subtype, as PYY-(3-36) was the only PYY analog tes ted that caused inhibition and was equipotent to PYY. Inhibition by PY Y of I-sc(Cl) was abolished following incubation with pertussis toxin. We also show that PYY inhibits AVP-stimulated cAMP accumulation, with a maximal inhibitory dose (100 nM) causing a 38% +/- 6% inhibition (I C50 = 0.16 nM), comparable to inhibition by PYY of I-sc(Cl). We conclu de that PYY acts through either G(i) or G(o) to inhibit adenylate cycl ase activity, leading to a decrease in AVP-stimulated chloride current .