{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:57:59Z","timestamp":1791482279661,"version":"4.3.4"},"reference-count":58,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2013,2,15]]},"abstract":"\n \n Rationale:<\/jats:underline>\n <\/jats:title>\n \n An increase in cytosolic free Ca\n 2+<\/jats:sup>\n concentration ([Ca\n 2+<\/jats:sup>\n ]\n cyt<\/jats:sub>\n ) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation and pulmonary vascular remodeling. The dihydropyridine Ca\n 2+<\/jats:sup>\n channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH).\n <\/jats:p>\n <\/jats:sec>\n \n \n Objective:<\/jats:underline>\n <\/jats:title>\n \n Our previous study demonstrated that the Ca\n 2+<\/jats:sup>\n -sensing receptor (CaSR) was upregulated and the extracellular Ca\n 2+<\/jats:sup>\n -induced increase in [Ca\n 2+<\/jats:sup>\n ]\n cyt<\/jats:sub>\n was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (eg, nifedipine) increase [Ca\n 2+<\/jats:sup>\n ]\n cyt<\/jats:sub>\n by activating CaSR in PASMC from IPAH patients (in which CaSR is upregulated), but not in normal PASMC.\n <\/jats:p>\n <\/jats:sec>\n \n \n Methods and Results:<\/jats:underline>\n <\/jats:title>\n \n The nifedipine-mediated increase in [Ca\n 2+<\/jats:sup>\n ]\n cyt<\/jats:sub>\n in IPAH-PASMC was concentration dependent with a half maximal effective concentration of 0.20 \u00b5mol\/L. Knockdown of CaSR with siRNA in IPAH-PASMC significantly inhibited the nifedipine-induced increase in [Ca\n 2+<\/jats:sup>\n ]\n cyt<\/jats:sub>\n , whereas overexpression of CaSR in normal PASMC conferred the nifedipine-induced rise in [Ca\n 2+<\/jats:sup>\n ]\n cyt<\/jats:sub>\n . Other dihydropyridines, nicardipine and Bay K8644, had similar augmenting effects on the CaSR-mediated increase in [Ca\n 2+<\/jats:sup>\n ]\n cyt<\/jats:sub>\n in IPAH-PASMC; however, the nondihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca\n 2+<\/jats:sup>\n ]\n cyt<\/jats:sub>\n .\n <\/jats:p>\n <\/jats:sec>\n \n \n Conclusions:<\/jats:underline>\n <\/jats:title>\n \n The dihydropyridine derivatives increase [Ca\n 2+<\/jats:sup>\n ]\n cyt<\/jats:sub>\n by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca\n 2+<\/jats:sup>\n channels; therefore, it is possible that the use of dihydropyridine Ca\n 2+<\/jats:sup>\n channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circresaha.113.300897","type":"journal-article","created":{"date-parts":[[2013,1,9]],"date-time":"2013-01-09T13:40:46Z","timestamp":1357738846000},"page":"640-650","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":52,"title":["Dihydropyridine Ca\n 2+<\/sup>\n Channel Blockers Increase Cytosolic [Ca\n 2+<\/sup>\n ] by Activating Ca\n 2+<\/sup>\n -sensing Receptors in Pulmonary Arterial Smooth Muscle Cells"],"prefix":"10.1161","volume":"112","author":[{"given":"Aya","family":"Yamamura","sequence":"first","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisao","family":"Yamamura","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Guo","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana M.","family":"Zimnicka","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wan","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun A.","family":"Ko","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly A.","family":"Smith","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M.","family":"Pohl","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Song","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Zeifman","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Makino","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason X.-J.","family":"Yuan","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine and Department of Pharmacology, Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL (Q.G., A.M.Z., J.W., E.A.K., K.A.S., N.M.P., S.S., A.Z., A.M., J.X.-J.Y.); Kinjo Gakuin University School of Pharmacy, Nagoya, Japan (A.Y.); and Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.123901"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01317.x"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.76.1.135"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199207093270203"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.119.1.128"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2005.05.004"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr282"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.488486"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.98.12020265"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo-128-6-3047"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.9.4814"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9038"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M413403200"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.112.266361"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.4168"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.1.239"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1154"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0043"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.98.14.1400"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0405908101"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.90548.2008"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.4103\/2045-8932.83447"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00028.2005"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.2001.280.4.L801"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00391.2006"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.05040.x"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1984.56.2.375"},{"key":"e_1_3_4_29_2","first-page":"21","article-title":"Studies of the mechanism of hypoxic pulmonary vasoconstriction.","volume":"8","author":"McMurtry IF","year":"1982","unstructured":"McMurtry IF, Rounds S, Stanbrook HS. 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