{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T23:07:27Z","timestamp":1769209647800,"version":"3.49.0"},"reference-count":55,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2007,4]]},"abstract":"<jats:p> Hypoxic pulmonary vasoconstriction (HPV) occurs with ascent to high altitude and can contribute to development of high altitude pulmonary edema (HAPE). Vascular smooth muscle contains carbonic anhydrase (CA), and acetazolamide (AZ), a CA inhibitor, blunts HPV and might be useful in the prevention of HAPE. The mechanism by which AZ impairs HPV is uncertain. Originally developed as a diuretic, AZ also has direct effects on systemic vascular smooth muscle, including modulation of pH and membrane potential; however, the effect of AZ on pulmonary arterial smooth muscle cells (PASMCs) is unknown. Since HPV requires Ca<jats:sup>2+<\/jats:sup> influx into PASMCs and can be modulated by pH, we hypothesized that AZ alters hypoxia-induced changes in PASMC intracellular pH (pH<jats:sub>i<\/jats:sub>) or Ca<jats:sup>2+<\/jats:sup> concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>). Using fluorescent microscopy, we tested the effect of AZ as well as two other potent CA inhibitors, benzolamide and ethoxzolamide, which exhibit low and high membrane permeability, respectively, on hypoxia-induced responses in PASMCs. Hypoxia caused a significant increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> but no change in pH<jats:sub>i<\/jats:sub>. All three CA inhibitors slightly decreased basal pH<jats:sub>i<\/jats:sub>, but only AZ caused a concentration-dependent decrease in the [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> response to hypoxia. AZ had no effect on the KCl-induced increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> or membrane potential. N-methyl-AZ, a synthesized compound lacking the unsubstituted sulfonamide group required for CA inhibition, had no effect on pH<jats:sub>i<\/jats:sub> but inhibited hypoxia-induced Ca<jats:sup>2+<\/jats:sup> responses. These results suggest that AZ attenuates HPV by selectively inhibiting hypoxia-induced Ca<jats:sup>2+<\/jats:sup> responses via a mechanism independent of CA inhibition, changes in pH<jats:sub>i<\/jats:sub>, or membrane potential. <\/jats:p>","DOI":"10.1152\/ajplung.00161.2006","type":"journal-article","created":{"date-parts":[[2007,1,5]],"date-time":"2007-01-05T20:48:08Z","timestamp":1168030088000},"page":"L1002-L1012","source":"Crossref","is-referenced-by-count":61,"title":["Inhibition of hypoxia-induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition"],"prefix":"10.1152","volume":"292","author":[{"given":"Larissa A.","family":"Shimoda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trevor","family":"Luke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. T.","family":"Sylvester","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui-Wen","family":"Shih","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahamindra","family":"Jain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik R.","family":"Swenson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.1998.sp004117"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01167.2004"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.4A6266.2004"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4835(05)80099-5"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.1834"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1994.266.4.L469"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1016\/S0034-5687(00)00148-1"},{"key":"R8","unstructured":"Emery CJ, Sloan PJ, Mohammed FH, Barer GR. The action of hypercapnia during hypoxia on pulmonary vessels. Bull Eur Physiopath Respir 13: 763\u2013776, 1977."},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1996.80.2.496"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.80.1.21"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1210\/endo.138.10.5460"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1007\/BF00374586"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1995.74.6.2774"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1986.250.2.F203"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01217.2003"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1991.261.4.C565"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02410-0"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1991.260.6.L516"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1997.78.5.2582"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2002.32601.x"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1992.72.5.1787"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.2001.280.2.L264"},{"key":"R23","unstructured":"Maren TH. Carbonic anhydrase inhibition. V. N5-substituted 2-acetylamino-1,3,4-thiadiazole-5-sulfonamides: metabolic conversion and use as control substances. J Pharmacol Exp Ther 117: 385\u2013401, 1956."},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1977.232.4.F291"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.38.2.99"},{"key":"R26","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.FP0040032"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1378\/chest.82.4.404"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.33.4.1043"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703825"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.77.1.131"},{"key":"R31","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1992.262.4.C882"},{"key":"R32","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb\/5.6.586"},{"key":"R33","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1987.63.6.2524"},{"key":"R34","doi-asserted-by":"publisher","DOI":"10.1164\/arrd.1984.129.5.785"},{"key":"R35","doi-asserted-by":"publisher","DOI":"10.1172\/JCI104176"},{"key":"R36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-6576.1986.tb02476.x"},{"key":"R37","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.8.862"},{"key":"R38","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.2000.279.5.L884"},{"key":"R39","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1998.274.5.L842"},{"key":"R40","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198106253042606"},{"key":"R41","unstructured":"Stanbrook HS, Morris KG, McMurtry IF. Prevention and reversal of hypoxic pulmonary hypertension by calcium antagonists. Am Rev Respir Dis 130: 81\u201385, 1984."},{"key":"R42","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.1980.tb00070.x"},{"key":"R43","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2005.10.011"},{"key":"R44","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.98.12061242"},{"key":"R45","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116640"},{"key":"R46","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(200009)48:3<304::AID-ANA4>3.0.CO;2-A"},{"key":"R47","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-0722fje"},{"key":"R48","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-151-39271"},{"key":"R49","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.1997.sp004052"},{"key":"R50","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021668"},{"key":"R51","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00448.2004"},{"key":"R52","doi-asserted-by":"publisher","DOI":"10.1007\/s002329900339"},{"key":"R53","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1993.264.2.L116"},{"key":"R54","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1994.267.1.L52"},{"key":"R55","doi-asserted-by":"crossref","unstructured":"Zhang X, Velumian AA, Jones OT, Carlen PL. Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia 41, Suppl 1: S52\u2013S60, 2000.","DOI":"10.1111\/j.1528-1157.2000.tb02173.x"}],"container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajplung.00161.2006","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,8]],"date-time":"2019-09-08T20:16:27Z","timestamp":1567973787000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajplung.00161.2006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,4]]},"references-count":55,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2007,4]]}},"alternative-id":["10.1152\/ajplung.00161.2006"],"URL":"https:\/\/doi.org\/10.1152\/ajplung.00161.2006","relation":{},"ISSN":["1040-0605","1522-1504"],"issn-type":[{"value":"1040-0605","type":"print"},{"value":"1522-1504","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,4]]}}}