Original ArticlePropofol Causes Sustained Ca2+ Elevation in Endothelial Cells by Stimulating Ryanodine Receptor and Suppressing Plasmalemmal Ca2+ PumpChuang, Chin-Min MD*; Chen, Cing-Yu PhD†; Yen, Pao-Sheng MD‡; Wu, Cheng-Hsun PhD§; Shiao, Lian-Ru MS†; Wong, Kar-Lok MD, PhD¶,‖; Chan, Paul MD, PhD**; Leung, Yuk-Man PhD† Author Information *Department of Emergency Medicine, China Medical University Hospital, Taichung, Taiwan; †Department of Physiology, China Medical University, Taichung, Taiwan; ‡Department of Radiology, Kuang Tien General Hospital, Shalu, Taichung, Taiwan; §Department of Anatomy, China Medical University, Taichung, Taiwan; ¶Department of Anesthesiology, Kuang Tien General Hospital, Shalu, Taichung, Taiwan; ‖Department of Anesthesiology, University of Hong Kong, Hong Kong, China; and **Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Correspondence: Yuk-Man Leung, PhD, Department of Physiology, China Medical University, 91 Hsueh Shi Road, Taichung 40402, Taiwan (e-mail: [email protected]). C.-M. Chuang, Y. -M. Leung, and K. -L. Wong thank China Medical University, Taiwan, for providing fundings (DMR-109-062; DMR-109-093; DMR-110-084; and CMU109-S-21). P. -S. Yen thanks Kuang Tien General Hospital for support (Kuang 109-06). The authors report no conflicts of interest. C. -M. Chuang, C. -Y. Chen, and P. -S. Yen contributed equally as first authors. P. Chan and Y. -M. Leung contributed equally as corresponding authors No humans or animals were used in this study; only cell lines were used in this work, and therefore, ethical approval is not required. Journal of Cardiovascular Pharmacology: May 2022 - Volume 79 - Issue 5 - p 749-757 doi: 10.1097/FJC.0000000000001246 Buy Metrics Abstract Propofol, a general anesthetic administered intravenously, may cause pain at the injection site. The pain is in part due to irritation of vascular endothelial cells. We here investigated the effects of propofol on Ca2+ transport and pain mediator release in human umbilical vein endothelial cells (EA.hy926). Propofol mobilized Ca2+ from cyclopiazonic acid (CPA)-dischargeable pool but did not cause Ca2+ release from the lysosomal Ca2+ stores. Propofol-elicited Ca2+ release was suppressed by 100 μM ryanodine, suggesting the participation of ryanodine receptor channels. Propofol did not affect ATP-triggered Ca2+ release but abolished the Ca2+ influx triggered by ATP; in addition, propofol also suppressed store-operated Ca2+ entry elicited by CPA. Ca2+ clearance during CPA-induced Ca2+ discharge was unaffected by a low Na+ (50 mM) extracellular solution, but strongly suppressed by 5 mM La3+ (an inhibitor of plasmalemmal Ca2+ pump), suggesting Ca2+ extrusion was predominantly through the plasmalemmal Ca2+ pump. Propofol mimicked the effect of La3+ in suppressing Ca2+ clearance. Propofol also stimulated release of pain mediators, namely, reactive oxygen species and bradykinin. Our data suggest propofol elicited Ca2+ release and repressed Ca2+ clearance, causing a sustained cytosolic [Ca2+]i elevation. The latter may cause reactive oxygen species and bradykinin release, resulting in pain. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.