{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:38:50Z","timestamp":1791113930721,"version":"4.1.0"},"reference-count":70,"publisher":"American Physiological Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2012,12,15]]},"abstract":"<jats:p>Pulmonary artery smooth muscle cells (PASMCs) are more depolarized and display higher Ca<jats:sup>2+<\/jats:sup>levels in pulmonary hypertension (PH). Whether the functional properties and expression of Ca<jats:sup>2+<\/jats:sup>-activated Cl\u2212 channels (Cl<jats:sub>Ca<\/jats:sub>), an important excitatory mechanism in PASMCs, are altered in PH is unknown. The potential role of Cl<jats:sub>Ca<\/jats:sub>channels in PH was investigated using the monocrotaline (MCT)-induced PH model in the rat. Three weeks postinjection with a single dose of MCT (50 mg\/kg ip), the animals developed right ventricular hypertrophy (heart weight measurements) and changes in pulmonary arterial flow (pulse-waved Doppler imaging) that were consistent with increased pulmonary arterial pressure and PH. Whole cell patch experiments revealed an increase in niflumic acid (NFA)-sensitive Ca<jats:sup>2+<\/jats:sup>-activated Cl<jats:sup>\u2212<\/jats:sup>current [ I<jats:sub>Cl(Ca)<\/jats:sub>] density in PASMCs from large conduit and small intralobar pulmonary arteries of MCT-treated rats vs. aged-matched saline-injected controls. Quantitative RT-PCR and Western blot analysis revealed that the alterations in I<jats:sub>Cl(Ca)<\/jats:sub>were accompanied by parallel changes in the expression of TMEM16A, a gene recently shown to encode for Cl<jats:sub>Ca<\/jats:sub>channels. The contraction to serotonin of conduit and intralobar pulmonary arteries from MCT-treated rats exhibited greater sensitivity to nifedipine (1 \u03bcM), an l-type Ca<jats:sup>2+<\/jats:sup>channel blocker, and NFA (30 or 100 \u03bcM, with or without 10 \u03bcM indomethacin to inhibit cyclooxygenases) or T16A<jats:sub>Inh<\/jats:sub>-A01 (10 \u03bcM), TMEM16A\/Cl<jats:sub>Ca<\/jats:sub>channel inhibitors, than that of control animals. In conclusion, augmented Cl<jats:sub>Ca<\/jats:sub>\/TMEM16A channel activity is a major contributor to the changes in electromechanical coupling of PA in this model of PH. TMEM16A-encoded channels may therefore represent a novel therapeutic target in this disease.<\/jats:p>","DOI":"10.1152\/ajpcell.00044.2012","type":"journal-article","created":{"date-parts":[[2012,10,4]],"date-time":"2012-10-04T06:18:52Z","timestamp":1349331532000},"page":"C1229-C1243","source":"Crossref","is-referenced-by-count":112,"title":["Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension"],"prefix":"10.1152","volume":"303","author":[{"given":"Abigail S.","family":"Forrest","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia C.","family":"Joyce","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa 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