Sodium Calcium Exchange as a Target for Antiarrhythmic Therapy

Sipido, Karin R.; Varró, András; Eisner, David

doi:10.1007/3-540-29715-4_6

Cited by 43 publications

(38 citation statements)

References 178 publications

(170 reference statements)

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“…The increased activity of the NCX has been implicated in triggered arrhythmias in a number of conditions, especially when the AP is prolonged and at membrane potentials negative to -35 mV, a potential at which activation of the I CaL window current is unlikely. 4,29) Taken together, these concepts support the hypothesize that blocking the reverse mode of NCX might be an effective strategy to suppress TdP in the failing heart rabbit. In the present study, KB-R7943 did not demonstrate an inhibitory effect on dofetilide-induced TdP.…”

Section: Prevention Of Dofetilide-induced Tdp By Verapamil Ryanodinesupporting

confidence: 61%

Effects of Sarcolemmal Ca2+ Entry, Ryanodine Function, and Kinase Inhibitors on a Rabbit Model of Heart Failure

et al. 2010

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SummaryQT prolongation may increase the risk of torsades de pointes (TdP). Early afterdepolarizations (EADs) and transmural dispersion of repolarization have been known to serve as physiological substrates and predictors for TdP. Abnormal Ca 2+ cycling is the proximate cause of EADs, and Ca 2+ cycling is abnormal in heart failure (HF). However, the mechanisms for drug-induced TdP in HF are poorly understood. The purpose of this study was to search for torsadogenic-modifying effects of verapamil, ryanodine, KB-R7943, W-7, KN-93, and H-8 on ventricular premature depolarizations (VPD) and TdP in rabbits with HF. Rabbits with HF were pretreated with propranolol followed by test articles before continuous infusion of dofetilide to induce TdP.In the control hearts, VPD and TdP were induced in all rabbits and the onsets of VPD and TdP were 3.6 ± 1.3 minutes and 10.3 ± 1.4 minutes, respectively. Dofetilide lengthened RR, QT and QTc. Verapamil, ryanodine and H-8 significantly delayed onset of VPD (P < 0.05) and suppressed TdP (P < 0.01 Key words: Calcium, QT, Heart failure, Protein kinase A, Rabbit, Torsades de Pointes P rolongation of the action potential duration (APD), the result of a reduction in net repolarizing current or an increase in depolarizing current, translates to lengthening of the QTc interval on the electrocardiogram, the culprit marker for torsades de pointes (TdP). It has been shown previously that early afterdepolarizations (EADs) and transmural dispersion of repolarization (TDR) are the candidates for causes of TdP.1,2) While TDR serves as a substrate for the initial EADs and subsequent re-entrant tachycardia, 2) EADs can trigger a new action potential (AP) and augment electrical heterogeneity in neighboring regions of myocardium. Thus, EADs can provide not only the trigger but also the substrate for the initiation and perpetuation of TdP.3)It was suggested that EADs are associated with reactivation of long lasting Ca 2+ channels (I CaL ) in the setting of APD prolongation.4) A Ca 2+ entry blocker has been shown to attenuate clofilium-induced TdP in anesthetized rabbits. 5) Recently, the Na + /Ca 2+ exchange (NCX) was suggested to produce triggered arrhythmias in heart failure (HF) by prolonging the plateau phase of the AP, thereby providing time for the reactivation of I CaL which then causes the EADs.6) The effects of NCX blocker on ventricular arrhythmias are still controversial; however, KB-R7943, a specific blocker of the reverse mode of NCX, has been shown to suppress arrhythmia in guinea pigs. 7)In the setting of HF, abnormalities in Ca 2+ handling, reduction in cardiac contractility, and diminution in β-adrenergic receptor responsiveness due to an increase in circulating catecholamine were reported in both humans and animals. [8][9][10] The underlying mechanisms of HF are still unclear; however, protein kinases (eg, cAMP dependent protein kinase, PKA; Ca 2+ /calmodulin dependent protein kinase II, CaMKII) are known to regulate cardiac function and it is possible that altered activity of pro...

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Section: Prevention Of Dofetilide-induced Tdp By Verapamil Ryanodinesupporting

confidence: 61%

Effects of Sarcolemmal Ca2+ Entry, Ryanodine Function, and Kinase Inhibitors on a Rabbit Model of Heart Failure

et al. 2010

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“…Yet, in the clinical perspective, a concomitant block of I CaL may be an advantage and part of the therapeutic profile of antiarrhythmic drugs. 11,16,32 Our data strongly suggest that NCX block can have adverse effects in heart failure, because it raises resting Ca 2ϩ and slows down relaxation. Yet, there is also a potential benefit from increasing SR Ca 2ϩ load.…”

Section: Perspectives For Ncx Inhibitorsmentioning

confidence: 67%

Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca ²⁺ Load Attributable to the Predominance of Forward Mode Block

Özdemir

Bito

Holemans

et al. 2008

Circulation Research

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Abstract-Block of Na/Ca exchange (NCX) has potential therapeutic applications, in particular, if a mode-selective block could be achieved, but also carries serious risks for disturbing the normal Ca 2ϩ balance maintained by NCX. We have examined the effects of partial inhibition of NCX by SEA-0400 (1 or 0.3 mol/L) in left ventricular myocytes from healthy pigs or mice and from mice with heart failure (MLP Ϫ/Ϫ handling by refining mode dependence and/or including additional targets.

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“…No patients in this study had alterations in blood pressure. Specific acetylcholine-regulated K ϩ current inhibition 74,75 Abnormal calcium handling 76,77 Gap junction modification 78 Na ϩ /Ca ϩ exchanger inhibition 79 Stretch-induced or ischemia-induced ATP-sensitive K ϩ current inhibitors 80 Gene and cellular therapy 81 An animal study of tecadenoson for rate control of atrial fibrillation has shown promising results. 62 In combination with metoprolol, rate control was improved with tecadenoson compared with either agent alone.…”

Section: Adenosine a 1 Receptor Agonistsmentioning

confidence: 99%

New Pharmacological Agents for Arrhythmias

Mason

DiMarco

2009

Circ: Arrhythmia and Electrophysiology

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Sodium Calcium Exchange as a Target for Antiarrhythmic Therapy

Cited by 43 publications

References 178 publications

Effects of Sarcolemmal Ca2+ Entry, Ryanodine Function, and Kinase Inhibitors on a Rabbit Model of Heart Failure

Effects of Sarcolemmal Ca2+ Entry, Ryanodine Function, and Kinase Inhibitors on a Rabbit Model of Heart Failure

Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca ²⁺ Load Attributable to the Predominance of Forward Mode Block

New Pharmacological Agents for Arrhythmias

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Sodium Calcium Exchange as a Target for Antiarrhythmic Therapy

Cited by 43 publications

References 178 publications

Effects of Sarcolemmal Ca2+ Entry, Ryanodine Function, and Kinase Inhibitors on a Rabbit Model of Heart Failure

Effects of Sarcolemmal Ca2+ Entry, Ryanodine Function, and Kinase Inhibitors on a Rabbit Model of Heart Failure

Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca 2+ Load Attributable to the Predominance of Forward Mode Block

New Pharmacological Agents for Arrhythmias

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Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca ²⁺ Load Attributable to the Predominance of Forward Mode Block