{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:03:07Z","timestamp":1790870587215,"version":"4.1.0"},"reference-count":45,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[1999,4,1]]},"abstract":"<jats:p> Ca<jats:sup>2+<\/jats:sup>-mediated agonists, including UTP, are being developed for therapeutic use in cystic fibrosis (CF) based on their ability to modulate alternative Cl<jats:sup>\u2212<\/jats:sup> conductances. As CF is also characterized by hyperabsorption of Na<jats:sup>+<\/jats:sup>, we determined the effect of mucosal UTP on transepithelial Na<jats:sup>+<\/jats:sup>transport in primary cultures of human bronchial epithelia (HBE). In symmetrical NaCl, UTP induced an initial increase in short-circuit current ( I <jats:sub>sc<\/jats:sub>) followed by a sustained inhibition. To differentiate between effects on Na<jats:sup>+<\/jats:sup> absorption and Cl<jats:sup>\u2212<\/jats:sup> secretion, I <jats:sub>sc<\/jats:sub> was measured in the absence of mucosal and serosal Cl<jats:sup>\u2212<\/jats:sup>( I <jats:sub>Na<\/jats:sub>). Again, mucosal UTP induced an initial increase and then a sustained decrease that reduced amiloride-sensitive I <jats:sub>Na<\/jats:sub> by 73%. The Ca<jats:sup>2+<\/jats:sup>-dependent agonists histamine, bradykinin, serosal UTP, and thapsigargin similarly induced sustained inhibition (62\u201384%) of I <jats:sub>Na<\/jats:sub>. Mucosal UTP induced similar sustained inhibition (half-maximal inhibitory concentration 296 nM) of I <jats:sub>Na<\/jats:sub> in primary cultures of human CF airway homozygous for the \u0394F508 mutation. BAPTA-AM blunted UTP-dependent inhibition of I <jats:sub>Na<\/jats:sub>, but inhibitors of protein kinase C (PKC) and phospholipase A<jats:sub>2<\/jats:sub> had no effect. Indeed, direct activation of PKC by phorbol 12-myristate 13-acetate failed to inhibit Na<jats:sup>+<\/jats:sup> absorption. Apyrase, a tri- and diphosphatase, did not reverse inhibitory effects of UTP on I <jats:sub>Na<\/jats:sub>, suggesting a long-term inhibitory effect of UTP that is independent of receptor occupancy. After establishment of a mucosa-to-serosa K<jats:sup>+<\/jats:sup> concentration gradient and permeabilization of the mucosal membrane with nystatin, mucosal UTP induced an initial increase in K<jats:sup>+<\/jats:sup>current followed by a sustained inhibition. We conclude that increasing cellular Ca<jats:sup>2+<\/jats:sup> induces a long-term inhibition of transepithelial Na<jats:sup>+<\/jats:sup>transport across normal and CF HBE at least partly due to downregulation of a basolateral membrane K<jats:sup>+<\/jats:sup> conductance. Thus UTP may have a dual therapeutic effect in CF airway: 1) stimulation of a Cl<jats:sup>\u2212<\/jats:sup> secretory response and 2) inhibition of Na<jats:sup>+<\/jats:sup> transport. <\/jats:p>","DOI":"10.1152\/ajpcell.1999.276.4.c827","type":"journal-article","created":{"date-parts":[[2017,12,24]],"date-time":"2017-12-24T22:14:51Z","timestamp":1514153691000},"page":"C827-C837","source":"Crossref","is-referenced-by-count":118,"title":["UTP inhibits Na<sup>+<\/sup> absorption in wild-type and \u0394F508  CFTR-expressing human bronchial epithelia"],"prefix":"10.1152","volume":"276","author":[{"given":"Daniel C.","family":"Devor","sequence":"first","affiliation":[{"name":"Departments of Physiology and Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Pilewski","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Cell Biology and"},{"name":"Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.153.6.8665037"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.150.2.8049852"},{"key":"B3","first-page":"648","volume":"40","author":"Brown H. 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