Browsing by Author "Yang, Na"

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Effects of ondansetron on apamin-sensitive small conductance calcium-activated potassium currents in pacing-induced failing rabbit hearts
(2020-02-01)
Yin, Dechun
;
Yang, Na
;
Tian, Zhipeng
;
Wu, Adonis Z.
;
Xu, Dongzhu
BACKGROUND Ondansetron, a widely prescribed antiemetic, has been implicated in drug-induced long QT syndrome. Recent patch clamp experiments have shown that ondansetron inhibits the apamin-sensitive small conductance calcium-activated potassium current (I-KAS). OBJECTIVE The purpose of this study was to determine whether ondansetron causes action potential duration (APD) prolongation by I-KAS inhibition. METHODS Optical mapping was performed in rabbit hearts with pacing-induced heart failure (HF) and in normal hearts before and after ondansetron (100 nM) infusion. APD at 80% repolarization (APD(80)) and arrhythmia inducibility were determined. Additional studies with ondansetron were performed in normal hearts perfused with hypokalemic Tyrode's (2.4 mM) solution before or after apamin administration. RESULTS The corrected QT interval in HF was 326 ms (95% confidence interval [CI] 306-347 ms) at baseline and 364 ms (95% CI 351-378 ms) after ondansetron infusion (P < .001). Ondansetron significantly prolonged APD(80) in the HF group and promoted early afterdepolarizations, steepened the APD restitution curve, and increased ventricular vulnerability. Ventricular fibrillation was not inducible in HF ventricles at baseline, but after ondansetron infusion, ventricular fibrillation was induced in 5 of the 7 ventricles (P = .021). In hypokalemia, apamin prolonged APD(80) from 163 ms (95% CI 146-180 ms) to 180 ms (95% CI 156-204 ms) (P = .018). Subsequent administration of ondansetron failed to further prolong APD(80) (180 ms [95% CI 156-204 ms] vs 179 ms [95% CI 165-194 ms]; P = .789). The results were similar when ondansetron was administered first, followed by apamin. CONCLUSION Ondansetron is a specific I-KAS blocker at therapeutic concentrations. Ondansetron may prolong the QT interval in HF by inhibiting small conductance calcium-activated potassium channels, which increases the vulnerability to ventricular arrhythmias.
Phospholamban is concentrated in the nuclear envelope of cardiomyocytes and involved in perinuclear/nuclear calcium handling
(2016-11)
Wu, Adonis Z.
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Xu, Dongzhu
;
Yang, Na
;
Lin, Shien-Fong
;
Chen, Peng-Sheng
Aims: Phospholamban (PLB) regulates the cardiac Ca2+-ATPase (SERCA2a) in sarcoplasmic reticulum (SR). However, the localization of PLB at subcellular sites outside the SR and possible contributions to Ca2+ cycling remain unknown. We examined the intracellular distribution of PLB and tested whether a pool of PLB exists in the nuclear envelope (NE) that might regulate perinuclear/nuclear Ca2+ (nCa(2+)) handling in cardiomyocytes (CMs). Methods and results: Using confocal immunofluorescence microscopy and immunoblot analyses of CMs and CM nuclei, we discovered that PLB was highly concentrated in NE. Moreover, the ratio of PLB levels to SERCA levels was greater in NE than in SR. The increased levels of PLB in NE were a consistent finding using a range of antibodies, tissue samples, and species. To address a possible role in affecting Ca2+ handling, we used Fluo-4 based con focal Ca2+ imaging, with scan-lines across cytosol and nuclei, and evaluated the effects of PLB on cytosolic and nCa(2+) uptake and release in mouse CMs. In intact CMs, isoproterenol increased amplitude and decreased the decay time of Ca2+ transients not only in cytosol but also in nuclear regions. In saponin-permeabilized mouse CMs ([Ca2+]; = 400 nM), we measured spontaneous Ca2+ waves after specific reversal of PLB activity by addition of the Fab fragment of an anti-PLB monoclonal antibody (100 mu g/ml).This highly selective immunological reagent enhanced Ca2+ uptake (faster decay times) and Ca2+ release (greater intensity) in both cytosol and across the nuclear regions. Conclusions: Besides SR, PLB is concentrated in NE of CMs, and may be involved in modulation of nCa(2+) dynamics. (C) 2016 Elsevier Ltd. All rights reserved.
Role of Apamin-Sensitive Calcium-Activated Small-Conductance Potassium Currents on the Mechanisms of Ventricular Fibrillation in Pacing-Induced Failing Rabbit Hearts
(2017-02-01)
Yin, Dechun
;
Hsieh, Yu-Cheng
;
Tsai, Wei-Chung
;
Wu, Adonis Zhi-Yang
;
Jiang, Zhaolei
Background-Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small-conductance calcium-activated potassium currents (I-KAS) are heterogeneously upregulated in failing hearts. We hypothesized that I-KAS influences the location and stability of rotors during VF. Methods and Results-Optical mapping was performed on 9 rabbit hearts with pacing-induced heart failure. The epicardial right ventricular and left ventricular surfaces were simultaneously mapped in a Langendorff preparation. At baseline and after apamin (100 nmol/L) infusion, the action potential duration (APD(80)) was determined, and VF was induced. Areas with a >50% increase in the maximum action potential duration (Delta APD) after apamin infusion were considered to have a high I-KAS distribution. At baseline, the distribution density of phase singularities during VF in high I-KAS distribution areas was higher than in other areas (0.0035 +/- 0.0011 versus 0.0014 +/- 0.0010 phase singularities/pixel; P=0.004). In addition, high dominant frequencies also colocalized to high I-KAS distribution areas (26.0 versus 17.9 Hz; P=0.003). These correlations were eliminated during VF after apamin infusion, as the number of phase singularities (17.2 versus 11.0; P=0.009) and dominant frequencies (22.1 versus 16.2 Hz; P=0.022) were all significantly decreased. In addition, reentrant spiral waves became unstable after apamin infusion, and the duration of VF decreased. Conclusions-The I-KAS current influences the mechanism of VF in failing hearts as phase singularities, high dominant frequencies, and reentrant spiral waves all correlated to areas of high I-KAS. Apamin eliminated this relationship and reduced VF vulnerability.
Role of apamin-sensitive small conductance calcium-activated potassium currents in long-term cardiac memory in rabbits
(2018-05-01)
Yin, Dechun
;
Chen, Mu
;
Yang, Na
;
Wu, Adonis Z.
;
Xu, Dongzhu
BACKGROUND Apamin-sensitive small conductance calcium-activated K current (I-KAS) is up-regulated during ventricular pacing and masks short-term cardiac memory (CM). OBJECTIVE The purpose of this study was to determine the role of I-KAS in long-term CM. METHODS CM was created with 3-5 weeks of ventricular pacing and defined by a flat or inverted T wave off pacing. Epicardial optical mapping was performed in both paced and normal ventricles. Action potential duration (APD(80)) was determined during right atrial pacing. Ventricular stability was tested before and after I-KAS blockade. Four paced hearts and 4 normal hearts were used for western blotting and histology. RESULTS There were no significant differences in either echocardiographic parameters or fibrosis levels between groups. Apamin induced more APD(80) prolongation in CM than in normal ventricles (mean [95% confidence interval]: 9.6% [8.8%-10.5%] vs 3.1% [1.9%-4.3%]; P <.001). Apamin significantly lengthened APD(80) in the CM model at late activation sites, indicating significant I-KAS up-regulation at those sites. The CM model also had altered Ca2+ handling, with the 50% Ca2+ transient duration and amplitude increased at distal sites compared to a proximal site (near the pacing site). After apamin, the CM model had increased ventricular fibrillation (VF) inducibility (paced vs control: 33/40 (82.5%) vs 7/20 (35%); P < .001) and longer VF durations (124 vs 26 seconds; P < .001). CONCLUSION Chronic ventricular pacing increases Ca2+ transients at late activation sites, which activates I-KAS to maintain repolarization reserve. I-KAS blockade increases VF vulnerability in chronically paced rabbit ventricles.