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Oral administration of TRPV4 inhibitor improves atrial calcium handling abnormalities in sterile pericarditis rats

LIAO Jie, YANG Shuai-Tao, LU Kai, LU Yang, WU Yu-Wei, DU Yi-Mei^*

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

Abstract

Atrial Ca2+ handling abnormalities, mainly involving the dysfunction of ryanodine receptor (RyR) and sarcoplasmic reticulum Ca2+-ATPase (SERCA), play a role in the pathogenesis of atrial fibrillation (AF). Previously, we found that the expression and function of transient receptor potential vanilloid subtype 4 (TRPV4) are upregulated in a sterile pericarditis (SP) rat model of AF, and oral administration of TRPV4 inhibitor GSK2193874 alleviates AF in this animal model. The aim of this study was to investigate whether oral administration of GSK2193874 could alleviate atrial Ca2+ handling abnormalities in SP rats. A SP rat model of AF was established by daubing sterile talcum powder on both atria of Sprague-Dawley (SD) rats after a pericardiotomy, to simulate the pathogenesis of postoperative atrial fibrillation (POAF). On the 3rd postoperative day, Ca2+ signals of atria were collected in isolated perfused hearts by optical mapping. Ca2+ transient duration (CaD), alternan, and the recovery properties of Ca2+ transient (CaT) were quantified and analyzed. GSK2193874 treatment reversed the abnormal prolongation of time to peak (determined mainly by RyR activity) and CaD (determined mainly by SERCA activity), as well as the regional heterogeneity of CaD in SP rats. Furthermore, GSK2193874 treatment relieved alternan in SP rats, and reduced its incidence of discordant alternan (DIS-ALT). More importantly, GSK2193874 treatment prevented the reduction of the S2/S1 CaT ratio (determined mainly by RyR refractoriness) in SP rats, and decreased its regional heterogeneity. Taken together, oral administration of TRPV4 inhibitor alleviates Ca2+ handling abnormalities in SP rats primarily by blocking the TRPV4-Ca2+-RyR pathway, and thus exerts therapeutic effect on POAF.

Key words: postoperative atrial fibrillation; sterile pericarditis; TRPV4; Ca2+ handling abnormalities; ryanodine receptor

Received: 　　Accepted:

Corresponding author: 杜以梅　　E-mail: yimeidu@mail.hust.edu.cn

DOI: 10.13294/j.aps.2021.0098

Citing This Article：

LIAO Jie, YANG Shuai-Tao, LU Kai, LU Yang, WU Yu-Wei, DU Yi-Mei. Oral administration of TRPV4 inhibitor improves atrial calcium handling abnormalities in sterile pericarditis rats. Acta Physiol Sin 2022; 74 (2): 188-200 (in Chinese with English abstract).