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SK Current, beta-3 adrenoceptor activation and Sex Differences in Ventricular Arrhythmogenesis

SK 电流、β3 肾上腺素受体激活和室性心律失常发生的性别差异

基本信息

批准号：
10734708
负责人：
PENG-SHENG CHEN
金额：
$ 59.43万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734708
关键词：
Acetylcholine Action Potentials Adrenergic Agents Adrenergic Receptor Agonist Anti-Arrhythmia Agents Apamin Arrhythmia Arteries Atrioventricular Block Autonomic nervous system Brain Buffers Cardiac Catecholamines Cells Charybdotoxin Chemicals Computer Simulation Coronary Disease Electric Countershock Embryo Endothelium FDA approved Female Funding Goals Heart Heart Atrium Human Infusion procedures Isoproterenol Left Maps Mediating Messenger RNA Modeling Myocardial Infarction Myocardium Na(+)-K(+)-Exchanging ATPase Nerve Nerve Growth Factors Neurons Nitric Oxide Synthase Optics Oryctolagus cuniculus Ouabain Overactive Bladder Patients Pharmaceutical Preparations Phase Play Proteins Recurrence Relaxation Reporting Research Project Grants Resistance Role Sex Differences Shock Structure of stellate ganglion Sudden Death Syndrome Testing Translations Vasodilation Ventricular Ventricular Arrhythmia Ventricular Fibrillation Ventricular Tachycardia antagonist beta-2 Adrenergic Receptors canine model clinically significant experimental study heart rhythm indium arsenide kidney cell male patch clamp response sudden cardiac death

项目摘要

Project Summary The broad and long-term goal of this research project is to test the hypothesis that (1) the response of apamin- sensitive small conductance Ca2+-activated K+ (SK) current (IKAS) to sympathetic stimulation plays an important role in the mechanisms of sex differences in cardiac arrhythmogenesis and that (2) beta-3 adrenoceptor (AR) activation is antiarrhythmic and eliminates the sex difference of IKAS activation during sympathetic stimulation. In the current funding period, we discovered a significant sex difference of both the SK protein and IKAS at baseline and that the magnitudes of sex differences are amplified during isoproterenol or acetylcholine infusion. Apamin reduces the phase singularities (PSs) in ventricular fibrillation (VF) more effectively in the female than in the male ventricles. It is unclear which AR is responsible for the isoproterenol-induced IKAS activation. Isoproterenol activates the beta-1 and beta-2 ARs at lower concentrations than the beta-3 AR. Contrary to the effects of beta-1 and beta-2 AR activation, beta-3 AR activation exerts negative inotropic effects in the myocardium. Beta-3 ARs likely served as a buffer or rescuer of the excess catecholamines. We showed in a canine model of ventricular tachycardia that BRL-37344 (a beta-3 agonist) is antiarrhythmic. We hypothesize that beta-3 AR activation is antiarrhythmic and eliminates the sex difference of IKAS activation during sympathetic stimulation in the rabbit model. Specific Aim 1: SK current, beta-3 adrenoceptor activation, and Sex Differences in Ventricular Arrhythmogenesis. We will perform optical mapping and patch clamp studies with specific beta-1 and beta-2 antagonists in the presence of isoproterenol. We also will perform optical mapping studies to determine the effects of mirabegron on phase singularities (PSs) during VF with and without isoproterenol. In additional experiments, we will use BRL-37344 instead of mirabegron to test the hypothesis that this antiarrhythmic mechanism is a class effect shared by other beta-3 agonists. The antiarrhythmic action of mirabegron will then be tested in a rabbit model of myocardial infarction. These findings will be used to test the hypothesis that beta-3 AR activation rescues the proarrhythmic effects of beta- 1 and beta-2 stimulation, indirectly reduce IKAS, and eliminates the sex differences of PSs in VF. Specific Aim 2: Na+-K+ ATPase (NKA) activation during beta3 stimulation contributes to the sex differences of antiarrhythmic action. Beta-3 AR activates NKA, which may reduce Ca2+ overload-induced cardiac arrhythmias. We hypothesize that NKA activation plays a vital role in the antiarrhythmic effects of beta-3 AR activation. We will first perform studies to determine if there is a sex difference in beta-3 AR, NKA protein, and mRNA in rabbit ventricles. Optical mapping studies will be done in the presence of ouabain, a specific NKA blocker, to determine if the company of NKA is required for the antiarrhythmic effects of beta-3 activation. Rabbit ventricular action potential models will be used for computer simulation studies to assess the importance of NKA activation in the antiarrhythmic mechanisms of beta-3 AR activation.

项目摘要本研究项目的广泛和长期目标是检验以下假设：（1）apamin的反应- 对交感神经刺激敏感的小电导Ca ~（2+）激活K ~+（SK）电流（IKAS）在交感神经系统中起重要作用在心脏血管发生性别差异机制中的作用，以及（2）β-3肾上腺素受体（AR） IKAS激活是抗抑郁的，并且消除了交感神经刺激期间IKAS激活的性别差异。在目前的资助期间，我们发现SK蛋白和IKAS在性别上存在显著差异，在异丙肾上腺素或乙酰胆碱治疗期间，输液Apamin降低心室颤动（VF）中的相位奇异性（PS），比男性的脑室更大。目前尚不清楚哪种AR负责异丙肾上腺素诱导的IKAS activation.异丙肾上腺素激活β-1和β-2 AR的浓度低于β-3 AR。与β-1和β-2 AR激活的作用相反，β-3 AR激活发挥负性肌力作用。对心肌的影响。β-3 AR可能充当过量儿茶酚胺的缓冲剂或拯救剂。我们在室性心动过速犬模型中显示，BRL-37344（β-3激动剂）具有抗心律失常作用。我们假设β-3 AR激活具有抗肿瘤作用，并消除了IKAS激活的性别差异在兔子模型中的交感神经刺激期间。具体目标1：SK电流、β-3肾上腺素受体激活，室性心律失常发生的性别差异我们将进行光学标测和膜片钳在异丙肾上腺素存在下，使用特异性β-1和β-2拮抗剂的研究。我们还将表演光学映射研究，以确定米拉贝隆对VF期间相位奇点（PS）的影响，没有异丙肾上腺素。在另外的实验中，我们将使用BRL-37344代替米拉贝隆来测试假设这种抗肿瘤机制是其他β-3激动剂共有的类效应。的然后在心肌梗塞的兔模型中测试米拉贝隆的抗心律失常作用。这些研究结果将用于检验β-3 AR激活挽救β-3 AR的促肾上腺皮质激素作用的假设。 1和β 2刺激，间接降低IKAS，消除VF PS的性别差异。具体目标二： β_3刺激时Na ~+-K ~+ ATP酶（NKA）的激活有助于抗血小板聚集性的性别差异行动上β-3 AR激活NKA，这可能减少Ca 2+过载诱导的心律失常。我们假设NKA激活在β-3 AR激活的抗肿瘤作用中起重要作用。我们将首先进行研究以确定在兔中β-3 AR、NKA蛋白和mRNA是否存在性别差异心室光学映射研究将在哇巴因（一种特定的NKA阻断剂）存在下进行，确定NKA公司是否需要β-3激活的抗肿瘤作用。兔心室动作电位模型将用于计算机模拟研究，以评估 NKA激活在β-3 AR激活的抗肿瘤机制中的作用。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modeling Calcium Cycling in the Heart: Progress, Pitfalls, and Challenges.

DOI：
10.3390/biom12111686
发表时间：
2022-11-14
期刊：
Biomolecules
影响因子：
5.5
作者：
通讯作者：

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

DOI：
10.1016/j.hrthm.2018.01.016
发表时间：
2018-05
期刊：
Heart rhythm
影响因子：
5.5
作者：
Yin D;Chen M;Yang N;Wu AZ;Xu D;Tsai WC;Yuan Y;Tian Z;Chan YH;Shen C;Chen Z;Lin SF;Weiss JN;Chen PS;Everett TH 4th
通讯作者：
Everett TH 4th

Skin sympathetic nerve activity as a biomarker of fitness.

DOI：
10.1016/j.hrthm.2021.08.031
发表时间：
2021-12
期刊：
Heart rhythm
影响因子：
5.5
作者：
Liu X;Kumar A;O'Neil J;Wong J;Saadoon O;Kadire S;Mitscher GA;Li X;Chen PS;Emery MS;Everett TH 4th
通讯作者：
Everett TH 4th

Bistable nerve conduction.