Browsing by Author "Lin, Yung-Kuo"

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Ablation of androgen receptor gene triggers right ventricular outflow tract ventricular tachycardia
(2015-06-15)
Tsai, Wen-Chin
;
Lu, Yen-Yu
;
Chen, Yao-Chang
;
Chang, Chien-Jung
;
Kao, Yu-Hsun
Background: Sex hormones and calcium (Ca2+) regulation play roles in the pathophysiology of ventricular tachycardia from right ventricular outflow tract (RVOT). The purpose of this study was to evaluate whether androgen receptor knockout (ARKO) can increase RVOT arrhythmogenesis through modulating RVOT electrophysiology and Ca2+ homeostasis. Methods: Conventional microelectrodes were used to study the action potential (AP) in RVOT tissues prepared from wild type (WT) and ARKO mice (aged 6-10 months) before and after caffeine (1 mM), isoproterenol (1 mu M), adenosine (10 mu M) and flecainide (5 mu M) administration. The Fluo-3 fluorescence Ca2+ imaging with confocal microscopy and western blots were used to investigate intracellular Ca2+ (Ca-i(2+)) transients, Ca2+ sparks, and the expressions of ionic channel proteins in ARKO and WT RVOT myocytes. Results: We found that ARKO RVOTs (n = 13) had longer AP duration, faster burst firing (5.4 +/- 0.7 vs. 3.4 +/- 0.7 Hz, P < 0.05), and higher incidence of early afterdepolarizations (82% vs. 8%, P < 0.001) than WT RVOTs (n = 11). Adenosine and flecainide can suppress caffeine-or isoproterenol-induced spontaneous rates and burst firing in WT RVOTs, but not in ARKO RVOTs. ARKO RVOT myocytes had a higher frequency (7.7 +/- 2.8 vs. 1.3 +/- 0.4 spark/mm/s, P < 0.05) and incidence (89% vs. 47%, P < 0.05) of Ca2+ sparks, and greater expressions of Cav1.2, NCX, phosphorylated RyR (s2814), phosphorylated phospholamban (Thr17), CAMKII and GRK2 than WT RVOT myocytes. However, ARKO andWT RVOT myocytes exhibit similar Ca-i(2+) transients and SR Ca2+ content, and less expression of calsequestrin. Conclusions: ARKO changes RVOT electrophysiology and Ca2+ homeostasis with increased ventricular arrhythmogenesis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
Selective and non-selective non-steroidal anti-inflammatory drugs differentially regulate pulmonary vein and atrial arrhythmogenesis
(2015-04-01)
Chang, Chien-Jung
;
Cheng, Chen-Chuan
;
Yang, Ten-Fang
;
Chen, Yao-Chang
;
Lin, Yung-Kuo
Background: Non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of atrial fibrillation (AF). This study investigated whether selective and non-selective NSAIDs differentially regulate the arrhythmogenesis of pulmonary veins and atria. Methods: Conventional microelectrodes were used to record action potentials (APs) in isolated rabbit PVs, sinoatrial node (SAN), left atrium (LA), and right atrium (RA) preparations before and after celecoxib or indomethacin administration. A whole-cell patch clamp was used to record the sodium-calcium exchanger (NCX) current, L-type calcium current (ICa-L), and late sodium current (INa-late) before and after celecoxib administration in isolated PV cardiomyocytes. Results: Celecoxib (0.3, 1, and 3 mu M) reduced PV spontaneous beating rates, and induced delayed afterdepolarizations and burst firings in four of eight PV preparations (50%, p < 0.05). Celecoxib also reduced SAN beating rates and decreased AP durations (APDs) in RA and LA, but did not change the resting membrane potential. Indomethacin (0.3, 1, 3, and 10 mu M) changed neither the PV or SAN beating rates nor RA APDs, but it reduced LA APDs. Celecoxib (3 mu M) significantly increased the NCX current and decreased the ICa-L, but did not change the INa-late. Ranolazine (10 mu M) suppressed celecoxib (3 mu M)-induced PV burst firings in 6 (86%, p < 0.05) of 7 PVs. KB-R7943 (10 mu M) suppressed celecoxib (3 mu M)-induced PV burst firings in 5 (71%, p < 0.05) of 7 PVs. Conclusions: Selective and non-selective NSAIDs differentially modulate PV and atrial electrophysiological characteristics. Celecoxib increased PV triggered activity through enhancement of the NCX current, which contributed to its arrhythmogenesis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.