Effects of a Novel Cardioselective ATP-Sensitive Potassium Channel Antagonist, 1-[[5-[2-(5-Chloro-<i>o</i>-anisamido)ethyl]-β-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea, Sodium Salt (HMR 1402), on Susceptibility to Ventricular Fibrillation Induced by Myocardial Ischemia: In Vitro and in Vivo Studies

Houle, Mélanie; Englert, Heinrich C.; Gögelein, Heinz

doi:10.1124/jpet.103.061416

Cited by 20 publications

(6 citation statements)

References 29 publications

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“…In fact, K ATP channel inhibition has been shown to prevent VF after acute myocardial infarction in non-insulin-dependent diabetic patients 33 . Furthermore, K ATP channel inhibition effectively prevented arrhythmias induced by the combination of acute myocardial ischemia and exercise in dogs with healed myocardial infarctions 9,10,34 . Notably, the antiarrhythmic effect was observed with compounds (HMR1883 and congeners) that were designed to selectively inhibit the heart sarcolemmal K ATP channel without affecting pancreatic insulin release or mitochondrial K ATP channels 35 .…”

Section: Discussionmentioning

confidence: 93%

Effects of Regional Mitochondrial Depolarization on Electrical Propagation

Zhou

Solhjoo

Millare

et al. 2014

Circ: Arrhythmia and Electrophysiology

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Background Sudden cardiac death often involves arrhythmias triggered by metabolic stress. Loss of mitochondrial function is thought to contribute to the arrhythmogenic substrate, but how mitochondria contribute to uncoordinated electrical activity is poorly understood. It has been proposed that the formation of “metabolic current sinks”, caused by the non-uniform collapse of mitochondrial inner-membrane potential (ΔΨm), contributes to reentrant arrhythmias because ΔΨm depolarization is tightly coupled to the activation of sarcolemmal ATP-sensitive K+ (KATP) channels, hastening action potential repolarization and shortening the refractory period. Methods and Results Here we use computational and experimental methods to investigate how ΔΨm instability can induce reentrant arrhythmias. We develop the first tissue level model of cardiac electrical propagation incorporating cellular electrophysiology, excitation-contraction coupling, mitochondrial energetics and reactive oxygen species (ROS) balance. Simulations show that reentry and fibrillation can be initiated by regional ΔΨm loss, due to the disparity of refractory periods inside and outside of the metabolic sink. Computational results are compared with the effects of a metabolic sink generated experimentally by local perfusion of a mitochondrial uncoupler in a monolayer of cardiac myocytes. Conclusions The results demonstrate that regional mitochondrial depolarization triggered by oxidative stress activates sarcolemmal KATP currents to form a metabolic sink. Consequent shortening of the action potential inside, but not outside, the sink increases the propensity for reentry. ΔΨm recovery during pacing can lead to novel mechanisms of ectopic activation. The findings highlight the importance of mitochondria as potential therapeutic targets for sudden death associated with cardiovascular disease.

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Section: Discussionmentioning

confidence: 93%

Effects of Regional Mitochondrial Depolarization on Electrical Propagation

Zhou

Solhjoo

Millare

et al. 2014

Circ: Arrhythmia and Electrophysiology

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“…The contradictory involvement of mPTP in CB13-treated NRAM but not CB13-treated NRVM is possibly explained by functional differences of ion complexes within the inner membrane that are involved in ΔΨ m . For example, blocking the inner membrane ion channel, IMAC, was protective against arrhythmias by preventing ΔΨ m reduction, improving left ventricular developed pressure, and preventing action potential shortening ( Billman et al, 1998 ; Aon et al, 2003 ; Brown et al, 2008 ). As noted above, we recently reported that CB13 treatment prevents atrial refractoriness shortening in an ex vivo rat model exposed to atrial tachypacing, suggesting prevention of action potential shortening by CB13 ( Lee et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid receptor agonist attenuates angiotensin II–induced enlargement and mitochondrial dysfunction in rat atrial cardiomyocytes

2023

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Pathological remodeling of atrial tissue renders the atria more prone to arrhythmia upon arrival of electrical triggers. Activation of the renin-angiotensin system is an important factor that contributes to atrial remodeling, which may result in atrial hypertrophy and prolongation of P-wave duration. In addition, atrial cardiomyocytes are electrically coupled via gap junctions, and electrical remodeling of connexins may result in dysfunction of coordinated wave propagation within the atria. Currently, there is a lack of effective therapeutic strategies that target atrial remodeling. We previously proposed that cannabinoid receptors (CBR) may have cardioprotective qualities. CB13 is a dual cannabinoid receptor agonist that activates AMPK signaling in ventricular cardiomyocytes. We reported that CB13 attenuates tachypacing-induced shortening of atrial refractoriness and inhibition of AMPK signaling in the rat atria. Here, we evaluated the effects of CB13 on neonatal atrial rat cardiomyocytes (NRAM) stimulated by angiotensin II (AngII) in terms of atrial myocyte enlargement and mitochondrial function. CB13 inhibited AngII-induced enhancement of atrial myocyte surface area in an AMPK-dependent manner. CB13 also inhibited mitochondrial membrane potential deterioration in the same context. However, AngII and CB13 did not affect mitochondrial permeability transition pore opening. We further demonstrate that CB13 increased Cx43 compared to AngII-treated neonatal rat atrial myocytes. Overall, our results support the notion that CBR activation promotes atrial AMPK activation, and prevents myocyte enlargement (an indicator that suggests pathological hypertrophy), mitochondrial depolarization and Cx43 destabilization. Therefore, peripheral CBR activation should be further tested as a novel treatment strategy in the context of atrial remodeling.

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“…Predisposition of the heart to such electrical dysfunction and generation of fatal arrhythmias is high under conditions referred to as metabolic sinks [ 110 ] with compromised energetic status due to hypoxia or ischemia. While these conditions and sarcKATP channel openers predispose the heart to arrhythmogenesis [ 106 , 107 ], the blockers of sarcKATP channels increase ERP [ 111 ] and prevent the occurrence of ventricular arrhythmias [ 112 , 113 , 114 , 115 ]. On the other hand, the opening of sarcKATP channels can be vital to cellular survival in the face of these conditions and in fact, the pharmacological blockade of sarcKATP channels was shown to increase cell death in hearts exposed to ischemia/reperfusion [ 116 , 117 ].…”

Section: Potential Mechanisms Of Oxidative Stress Induced Ventricumentioning

confidence: 99%

Role of Oxidative Stress in the Genesis of Ventricular Arrhythmias

Adameová

Shah

Dhalla

2020

IJMS

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Ventricular arrhythmias, mainly lethal arrhythmias, such as ventricular tachycardia and fibrillation, may lead to sudden cardiac death. These are triggered as a result of cardiac injury due to chronic ischemia, acute myocardial infarction and various stressful conditions associated with increased levels of circulating catecholamines and angiotensin II. Several mechanisms have been proposed to underlie electrical instability of the heart promoting ventricular arrhythmias; however, oxidative stress which adversely affects ion homeostasis due to changes in the ion channel structure and function, seems to play a critical role in eliciting different types of ventricular arrhythmias. Prevention or mitigation of the severity of ventricular arrhythmias due to antioxidants has been indicated as the fundamental contribution in the field of preventive cardiology; however, novel interventions have to be developed for greater effectiveness and specificity in attenuating the adverse effects of oxidative stress. In this review, we have attempted to discuss proarrhythmic effects of oxidative stress differing in time and concentration dependence and highlight a molecular and cellular concept how it alters cardiac cell automaticity and conduction velocity sensitizing the probability of ventricular arrhythmias with resultant sudden cardiac death due to ischemic heart disease and other stressful situations. It is concluded that pharmacological approaches targeting multiple mechanisms besides oxidative stress might be more effective in the treatment of ventricular arrhythmias than current antiarrhythmic therapy.

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Effects of a Novel Cardioselective ATP-Sensitive Potassium Channel Antagonist, 1-[[5-[2-(5-Chloro-o-anisamido)ethyl]-β-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea, Sodium Salt (HMR 1402), on Susceptibility to Ventricular Fibrillation Induced by Myocardial Ischemia: In Vitro and in Vivo Studies

Abstract: In the present study, a novel sulfonylthiourea, 1-

Cited by 20 publications

References 29 publications

Effects of Regional Mitochondrial Depolarization on Electrical Propagation

Effects of Regional Mitochondrial Depolarization on Electrical Propagation

Cannabinoid receptor agonist attenuates angiotensin II–induced enlargement and mitochondrial dysfunction in rat atrial cardiomyocytes

Role of Oxidative Stress in the Genesis of Ventricular Arrhythmias

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