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The electrophysiological effects of parathyroid hormone (PTH) were studied in a primary cell culture model of the chick (Gallus domesticus) proximal tubule. In this model, confluent monolayers are grown on permeable filters and exhibit vectorial transport, including glucose-stimulated current. Under short-circuit conditions, PTH, at 10(-9) M, induced a positive current [short-circuit current (I(sc))] response, with an average 2-min peak response of 14.30 +/- 1.58 microA/cm(2) over the baseline I(sc,) followed by a slow decay. The PTH response was dose dependent, with a half-maximal response at 5 x 10(-9) M and maximal response at 5 x 10(-8) M. Forskolin and dibutyryl-cAMP also stimulated I(sc), as did the phosphodiesterase inhibitor IBMX. In contrast, the phorbol ester PMA inhibited baseline I(sc). The PTH response was nearly abolished by apical addition of 100 microM EIPA, an inhibitor of Na(+)/H(+) exchangers, and partially blocked by the Cl(-) channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB; 100 microM) and glibenclamide (300 microM). Higher doses of EIPA or NPPB alone (500 microM) were almost fully effective, with no or slight additional effects of NPPB or EIPA, respectively. The anion exchange inhibitor DIDS (100 microM) and the Na(+) channel blocker amiloride (10 microM) had no effect. Bilateral reduction of Cl(-) in the buffer, from 137 to 2.6 mM, abolished the PTH response; increasing Cl(-) concentration restored the I(sc) response, with a half-maximal effect at 50 mM. These data suggest that, in the chick proximal tubule, PTH activates both an Na(+)/H(+) exchanger and a Cl(-) channel that may be functionally linked.