• Qin Yang, Jun-Hao Huang, Xiao-Qiang Yao, Malcolm John Underwood, and Cheuk-Man Yu.
• Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China; TEDA International Cardiovascular Hospital, Medical College, Nankai University, Tianjin, China. Electronic address: yangqs@cuhk.edu.hk.
• J. Thorac. Cardiovasc. Surg.. 2014 Oct 1;148(4):1665-1673.e1.

ObjectivesAlthough membrane depolarization by hyperkalemia is known to reduce Ca2+ influx in endothelial cells, the mechanism by which endothelial Ca2+ channel is affected by hyperkalemia remains poorly studied. We studied the effect of hyperkalemia on canonical transient receptor potential channels, in particular canonical transient receptor potential channel 3, in modulation of endothelial intracellular Ca2+ concentration. Endothelium-derived hyperpolarizing factor-mediated function is Ca2+ dependent, and hyperkalemic cardioplegia/organ preservation solutions impair endothelium-derived hyperpolarizing factor-mediated function. We explored the role of canonical transient receptor potential channel 3 in endothelium-derived hyperpolarizing factor-mediated function and investigated whether modulation of these channels preserves endothelial Ca2+ influx and endothelium-derived hyperpolarizing factor-mediated function under the condition of hyperkalemic/cardioplegic exposure.MethodsIntracellular Ca2+ concentration was measured with fluorescent dye in primary cultured porcine coronary endothelial cells exposed to hyperkalemic/cardioplegic solutions containing mild to extreme high K+ concentration. Endothelium-derived hyperpolarizing factor-mediated relaxation under hyperkalemic/cardioplegic exposure was studied in small porcine coronary arteries in a myograph in the presence of cyclooxygenase and nitric oxide synthase inhibitors and nitric oxide scavenger.ResultsCanonical transient receptor potential channel 3 blocker inhibited bradykinin-induced Ca2+ influx and attenuated endothelium-derived hyperpolarizing factor-mediated response. Hyperkalemic exposure inhibited canonical transient receptor potential channel 3-mediated Ca2+ influx in a K+ concentration-dependent manner (120>20>10 mmol/L). Ca2+ influx decreased in porcine coronary endothelial cells exposed to histidine-tryptophan-ketoglutarate, St Thomas' Hospital, and University of Wisconsin solutions that contained mild (10 mmol/L), moderate (20 mmol/L), and extreme high (125 mmol/L) K+ concentration, respectively. Canonical transient receptor potential channel activator prevented the reduction of Ca2+ influx in porcine coronary endothelial cells exposed to solutions containing mild to moderate high [K+]o and restored endothelium-derived hyperpolarizing factor-mediated response that was impaired by hyperkalemic exposure.ConclusionsCanonical transient receptor potential channel 3 is involved in endothelium-derived hyperpolarizing factor-mediated function in coronary arteries. Hyperkalemia inhibited canonical transient receptor potential channel 3-mediated Ca2+ influx in endothelial cells. Canonical transient receptor potential channel activation restores Ca2+ influx suppressed by hyperkalemia and prevents dysfunction of endothelium-derived hyperpolarizing factor.Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

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