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Role of apamin-sensitive small conductance calcium-activated potassium currents in long-term cardiac memory in rabbits.

ABSTRACT: BACKGROUND:Apamin-sensitive small conductance calcium-activated K current (IKAS) 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 IKAS 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 (APD80) was determined during right atrial pacing. Ventricular stability was tested before and after IKAS 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 APD80 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 APD80 in the CM model at late activation sites, indicating significant IKAS 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 IKAS to maintain repolarization reserve. IKAS blockade increases VF vulnerability in chronically paced rabbit ventricles.

SUBMITTER: Yin D

PROVIDER: S-EPMC5930041 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Role of apamin-sensitive small conductance calcium-activated potassium currents in long-term cardiac memory in rabbits.

Yin Dechun D Chen Mu M Yang Na N Wu Adonis Z AZ Xu Dongzhu D Tsai Wei-Chung WC Yuan Yuan Y Tian Zhipeng Z Chan Yi-Hsin YH Shen Changyu C Chen Zhenhui Z Lin Shien-Fong SF Weiss James N JN Chen Peng-Sheng PS Everett Thomas H TH

Heart rhythm 20180108 5

<h4>Background</h4>Apamin-sensitive small conductance calcium-activated K current (I<sub>KAS</sub>) is up-regulated during ventricular pacing and masks short-term cardiac memory (CM).<h4>Objective</h4>The purpose of this study was to determine the role of I<sub>KAS</sub> in long-term CM.<h4>Methods</h4>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 potent ...[more]

PMID: 29325977

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Project description:Background and purposeControlling vascular tone involves K(+) efflux through endothelial cell small- and intermediate-conductance calcium-activated potassium channels (K(Ca)2.3 and K(Ca)3.1, respectively). We investigated the expression of these channels in astrocytes and the possibility that, by a similar mechanism, they might contribute to neurovascular coupling.Experimental approachTransgenic mice expressing enhanced green fluorescent protein (eGFP) in astrocytes were used to assess K(Ca)2.3 and K(Ca)3.1 expression by immunohistochemistry and RT-PCR. K(Ca) currents in eGFP-positive astrocytes were determined in situ using whole-cell patch clamp electrophysiology. The contribution of K(Ca)3.1 to neurovascular coupling was investigated in pharmacological experiments using electrical field stimulation (EFS) to evoke parenchymal arteriole dilatation in FVB/NJ mouse brain slices and whisker stimulation to evoke changes in cerebral blood flow in vivo, measured by laser Doppler flowmetry.Key resultsK(Ca)3.1 immunoreactivity was restricted to astrocyte processes and endfeet and RT-PCR confirmed astrocytic K(Ca)2.3 and K(Ca)3.1 mRNA expression. With 200 nM [Ca(2+)](i) , the K(Ca)2.1-2.3/K(Ca)3.1 opener NS309 increased whole-cell currents. CyPPA, a K(Ca)2.2/K(Ca)2.3 opener, was without effect. With 1 µM [Ca(2+)](i) , the K(Ca)3.1 inhibitor TRAM-34 reduced currents whereas apamin (K(Ca)2.1-2.3 blocker) had no effect. CyPPA also inhibited currents evoked by NS309 in HEK293 cells expressing K(Ca)3.1. EFS-evoked Fluo-4 fluorescence confirmed astrocyte endfoot recruitment into neurovascular coupling. TRAM-34 inhibited EFS-evoked arteriolar dilatation by 50% whereas charybdotoxin, a blocker of K(Ca)3.1 and the large-conductance K(Ca) channel, K(Ca)1.1, inhibited dilatation by 82%. TRAM-34 reduced the cortical hyperaemic response to whisker stimulation by 40%.Conclusion and implicationsAstrocytes express functional K(Ca)3.1 channels, and these contribute to neurovascular coupling.

Dataset Information

Role of apamin-sensitive small conductance calcium-activated potassium currents in long-term cardiac memory in rabbits.

Publications

Role of apamin-sensitive small conductance calcium-activated potassium currents in long-term cardiac memory in rabbits.

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