Verapamil Prevents Stretch‐Induced Shortening of Atrial Effective Refractory Period in Langendorff‐Perfused Rabbit Heart

Zarse, Markus; Stellbrink, Christoph; Athanatou, Evangelia; Robert, Jens; Schotten, Ulrich; Hanrath, Peter

doi:10.1046/j.1540-8167.2001.00085.x

Cited by 31 publications

(16 citation statements)

References 5 publications

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“…Thus, we show that BRL-32872 has an antifibrillatory effect. This confirms the results by Zarse et al [16], who demonstrated that verapamil (that has also both I Kr and I CaL blocking properties) was responsible for a significant decrease of atrial ERPs at baseline, without further reduction after elevation of intra-atrial pressure, indicating a profibrillatory effect before stretch and an antifibrillatory one after. Nevertheless, it should be mentioned that human and experimental data previously showed an atrial profibrillatory effect of I CaL blockade [25,26].…”

Section: Brl Groupssupporting

confidence: 92%

“…First, Bode et al [4,15] have shown that blocking stretch- activated channels led to a diminished AF inducibility. Also, Zarse et al [16] investigated the effects of verapamil, glibenclamide and cariporide, and concluded that calcium overload plays a crucial role in short-term electrophysiological changes caused by atrial dilatation, as opposed to atrial ischemia or acidosis which have no significant impact. Finally, Eijsbouts et al [17] recently showed that the effects of flecainide on atrial refractoriness were enhanced by acute atrial stretch.…”

Section: Discussionmentioning

confidence: 99%

“…Further, it was also demonstrated that blocking channels or pumps (that are not uniquely stretch-activated) in the presence of acute atrial stretch can modify the effects of stretch-activated channels. For instance, Zarse et al [16] explored this paradigm with verapamil (I CaL and I Kr blocker), glibenclamide (blocker of adenosine-triphosphate-regulated K + channels) and cariporide (blocking Na + /H + exchanger). In this work, verapamil prevented the shortening of atrial refractory periods, whereas glibenclamide and cariporide did not have any effects.…”

Section: Introductionmentioning

confidence: 99%

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Anti-arrhythmic Effects of I Na, I Kr, and Combined I Kr–I CaL Blockade in an Experimental Model of Acute Stretch-Related Atrial Fibrillation

Kalifa

Bernard

Gout

et al. 2007

Cardiovasc Drugs Ther

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Section: Brl Groupssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti-arrhythmic Effects of I Na, I Kr, and Combined I Kr–I CaL Blockade in an Experimental Model of Acute Stretch-Related Atrial Fibrillation

Kalifa

Bernard

Gout

et al. 2007

Cardiovasc Drugs Ther

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“…The resultant leakage of extracellular calcium into the cytosol then compromises calcium clearance during relaxation and renders mdx cardiomyocytes vulnerable to stretch-induced injury (59). In this study of intact perfused hearts, we employed a stretch protocol to mimic cardiomyocyte activity under moderate strain regimes by inflating LV pressure to 80 mmHg, which is similar to that used for investigating fibrillation by several groups (10,21,37,50,78). Under the stretched condition, mdx hearts exhibited regional deficiency in calcium uptake, as evidenced by the prolonged T 50 and decay time constant, at the base where the sheet functional defect was observed.…”

Section: Discussionmentioning

confidence: 99%

Focal but reversible diastolic sheet dysfunction reflects regional calcium mishandling in dystrophicmdxmouse hearts

Cheng

Lang

Caruthers

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiac dysfunction is a primary cause of patient mortality in Duchenne muscular dystrophy, potentially related to elevated cytosolic calcium. However, the regional versus global functional consequences of cellular calcium mishandling have not been defined in the whole heart. Here we sought for the first time to elucidate potential regional dependencies between calcium mishandling and myocardial fiber/sheet function as a manifestation of dystrophin-deficient ( mdx) cardiomyopathy. Isolated-perfused hearts from 16-mo-old mdx ( N = 10) and wild-type (WT; N = 10) were arrested sequentially in diastole and systole for diffusion tensor MRI quantification of myocardial sheet architecture and function. When compared with WT hearts, mdx hearts exhibited normal systolic sheet architecture but a lower diastolic sheet angle magnitude (|β|) in the basal region. The regional diastolic sheet dysfunction was normalized by reducing perfusate calcium concentrations. Optical mapping of calcium transients in isolated hearts (3 mdx and 4 WT) revealed a stretch-inducible regional defect of intracellular calcium reuptake, reflected by a 25% increase of decay times ( T50) and decay constants, at the base of mdx hearts. The basal region of mdx hearts also exhibited greater fibrosis than did the apex, which matched the regional sheet dysfunction. We conclude that myocardial diastolic sheet dysfunction is observed initially in basal segments along with calcium mishandling, ultimately culminating in increased fibrosis. The preservation of relatively normal calcium reuptake and diastolic/systolic sheet mechanics throughout the rest of the heart, together with the rapid reversibility of functional defects by reducing cytosolic calcium, points to the significance of regional mechanical factors in the progression of the disease.

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“…Mechanoelectric feedback has long been suspected to modulate the hypertensive AF substrate (10,69,94). Acute atrial stretch has been demonstrated to affect ERP (10,11,48).…”

Section: Discussionmentioning

confidence: 99%

Remodeling of atrial ATP-sensitive K⁺ channels in a model of salt-induced elevated blood pressure

Lader

Vásquez²,

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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of atrial ATPsensitive K ϩ channels in a model of salt-induced elevated blood pressure. Am J Physiol Heart Circ Physiol 301: H964 -H974, 2011. First published July 1, 2011; doi:10.1152/ajpheart.00410.2011.-Hypertension is associated with the development of atrial fibrillation; however, the electrophysiological consequences of this condition remain poorly understood. ATP-sensitive K ϩ (KATP) channels, which contribute to ventricular arrhythmias, are also expressed in the atria. We hypothesized that salt-induced elevated blood pressure (BP) leads to atrial KATP channel activation and increased arrhythmia inducibility. Elevated BP was induced in mice with a high-salt diet (HS) for 4 wk. High-resolution optical mapping was used to measure atrial arrhythmia inducibility, effective refractory period (ERP), and action potential duration at 90% repolarization (APD90). Excised patch clamping was performed to quantify KATP channel properties and density. KATP channel protein expression was also evaluated. Atrial arrhythmia inducibility was 22% higher in HS hearts compared with control hearts. ERP and APD90 were significantly shorter in the right atrial appendage and left atrial appendage of HS hearts compared with control hearts. Perfusion with 1 M glibenclamide or 300 M tolbutamide significantly decreased arrhythmia inducibility and prolonged APD90 in HS hearts compared with untreated HS hearts. KATP channel density was 156% higher in myocytes isolated from HS animals compared with control animals. Sulfonylurea receptor 1 protein expression was increased in the left atrial appendage and right atrial appendage of HS animals (415% and 372% of NS animals, respectively). In conclusion, KATP channel activation provides a mechanistic link between salt-induced elevated BP and increased atrial arrhythmia inducibility. The findings of this study have important implications for the treatment and prevention of atrial arrhythmias in the setting of hypertensive heart disease and may lead to new therapeutic approaches. action potentials; arrhythmia mechanisms; cardiac remodeling; potassium channel; salt sensitivity hypertension ATRIAL FIBRILLATION (AF) is the most prevalent cardiac arrhythmia and is a major risk factor for stroke, congestive heart failure, and mortality (8,33,46). Although remodeling in response to AF has been a subject of intense investigation (1, 62), relatively few studies have focused on the mechanisms responsible for the substrate changes that underlie the initiation of atrial tachyarrhythmias. Hypertension is widely recognized as an important independent risk factor for AF (7,46). Animal models of hypertension have been shown to have significant structural and electrophysiological remodeling and increased atrial arrhythmia inducibility (19,24,49,53). However, the cellular mechanisms responsible for these effects remain poorly understood. Importantly, the contribution of ATP-sensitive K ϩ (K ATP ) channel currents (I K,ATP ) to hypertensioninduced electrophysiological remodeling has not been investigated.K ATP ch...

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Verapamil Prevents Stretch‐Induced Shortening of Atrial Effective Refractory Period in Langendorff‐Perfused Rabbit Heart

Cited by 31 publications

References 5 publications

Anti-arrhythmic Effects of I Na, I Kr, and Combined I Kr–I CaL Blockade in an Experimental Model of Acute Stretch-Related Atrial Fibrillation

Anti-arrhythmic Effects of I Na, I Kr, and Combined I Kr–I CaL Blockade in an Experimental Model of Acute Stretch-Related Atrial Fibrillation

Focal but reversible diastolic sheet dysfunction reflects regional calcium mishandling in dystrophicmdxmouse hearts

Remodeling of atrial ATP-sensitive K⁺ channels in a model of salt-induced elevated blood pressure

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Verapamil Prevents Stretch‐Induced Shortening of Atrial Effective Refractory Period in Langendorff‐Perfused Rabbit Heart

Cited by 31 publications

References 5 publications

Anti-arrhythmic Effects of I Na, I Kr, and Combined I Kr–I CaL Blockade in an Experimental Model of Acute Stretch-Related Atrial Fibrillation

Anti-arrhythmic Effects of I Na, I Kr, and Combined I Kr–I CaL Blockade in an Experimental Model of Acute Stretch-Related Atrial Fibrillation

Focal but reversible diastolic sheet dysfunction reflects regional calcium mishandling in dystrophicmdxmouse hearts

Remodeling of atrial ATP-sensitive K+ channels in a model of salt-induced elevated blood pressure

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Remodeling of atrial ATP-sensitive K⁺ channels in a model of salt-induced elevated blood pressure