Antiarrhythmic Efficacy of Selective Blockade of the Cardiac Slowly Activating Delayed Rectifier Current,
 I
 
 Ks
 
 , in Canine Models of Malignant Ischemic Ventricular Arrhythmia

Lynch, Joseph J.; Houle, Mélanie; Stump, Gary L.; Wallace, Audrey A.; Gilberto, David B.; Jahansouz, Hossain; Smith, Garry R.; Tebben, Andrew J.; Liverton, Nigel J.; Selnick, Harold G.; Claremon, David A.

doi:10.1161/01.cir.100.18.1917

Cited by 36 publications

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“…The anesthetized canine model of recent anterior myocardial infarction in which ventricular tachyarrhythmias may be induced by programmed ventricular stimulation (PVS) and in which malignant ventricular arrhythmias develop in response to acute coronary artery thrombosis was used to assess the antiarrhythmic efficacy of low-dose I Ks and ␤-adrenergic receptor blockade. This model was used previously to characterize the dose-dependent cardiac electrophysiologic and antiarrhythmic actions of the I Ks blocker L-768673 (Lynch et al, 1999). The present study extends this initial evaluation through a comparison of the following four treatment groups: 1) microemulsion vehicle (n ϭ 10), 2) a subeffective 0.3 g/kg i.v.…”

Section: Methodsmentioning

confidence: 71%

“…In anesthetized dogs 3 to 5 days after anterior myocardial infarction, intravenous chromanol 293b produced forward frequency-dependent, transmurally homogeneous increases in ventricular refractoriness, with greater increases in refractoriness observed in the infarct zone compared with the noninfarct zone (Bauer et al, 2000). The antiarrhythmic potential of I Ks blockade has been addressed through the study of L-768673 in two canine models of myocardial ischemic injury: 1) chloralose-anesthetized dogs in which malignant ventricular arrhythmias develop in response to acute thrombotic coronary ischemia superimposed upon a recent myocardial infarction, and 2) conscious dogs in which malignant ventricular arrhythmias develop in response to acute mechanical coronary ischemia and exercise superimposed upon a healed myocardial infarction (Lynch et al, 1999). Intravenous L-768673 produced modest increases in noninfarct zone and infarct zone refrac- jpet.aspetjournals.org tory periods and ECG QTc interval, and prevented the development of malignant arrhythmia in both preparations.…”

Section: Discussionmentioning

confidence: 99%

“…S 2 to S 4 were applied at 2 times the diastolic threshold voltage or, if ineffective at this level, at 4 times the diastolic threshold voltage. Responses to baseline PVS were categorized as noninducible (NI), sustained ventricular tachycardia (VT, unimorphic or polymorphic), or VT degenerating into ventricular fibrillation (VT/VF) as defined previously (Lynch et al, 1999). PVS was continued until the initiation of either sustained VT or VT/VF, or until reaching S 4 with no VT induction (NI).…”

Section: Methodsmentioning

confidence: 99%

“…We therefore hypothesized that concomitant lowdose I Ks and ␤-adrenergic receptor blockade might provide enhanced and potentially safer antiarrhythmic activity than either mechanism alone. We tested this hypothesis by extending our previous antiarrhythmic assessment of the I Ks blocker L-768673 in dogs with recent myocardial infarction (Lynch et al, 1999). The present study assesses the cardiac electrophysiologic and antiarrhythmic actions of a subeffective dose of L-768673 and a subeffective, minimally ␤-adrenergic blocking dose of timolol, administered individually or in combination.…”

mentioning

confidence: 94%

“…To this point, the benzodiazepine I Ks blocker L-768673 ( Fig. 1) has been shown to prevent the development of malignant ventricular arrhythmia in anesthetized dogs with acute thrombotic coronary ischemia superimposed upon a recent myocardial infarction, and in conscious dogs with acute coronary ischemia and exercise superimposed upon a healed myocardial infarction (Lynch et al, 1999). Antiarrhythmic efficacy in the latter model was noteworthy because this conscious preparation possesses high sympathetic tone, and the I Kr blocker d-sotalol was ineffective in this model (Vanoli et al, 1995).…”

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confidence: 99%

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Antiarrhythmic Efficacy of Combined I_Ks and β-Adrenergic Receptor Blockade

Lynch

Salata²,

Wallace³

et al. 2002

J Pharmacol Exp Ther

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In contrast, coadministration of 0.3 g/kg i.v. L-768673 ϩ 1.0 g/kg i.v. timolol suppressed the induction of VT by PVS (8/10, 80% rendered noninducible versus 1/10, 10% noninducible in vehicle group; p Ͻ 0.01) and prevented the development of acute ischemic lethal arrhythmias (3/10, 30% incidence versus 8/10, 80% incidence in vehicle group; p Ͻ 0.05). Concomitant administration of low-dose L-768673 ϩ timolol produced modest increases in QTc and paced QT intervals (4.5 Ϯ 1.2 and 5.5 Ϯ 1.4%; both p Ͻ 0.01), increases in noninfarct zone relative and effective refractory periods (7.0 Ϯ 1.7 and 12.3 Ϯ 3.0%; both p Ͻ 0.01), and lesser increases in infarct zone relative and effective refractory periods (5.3 Ϯ 1.6 and 5.8 Ϯ 1.4%; both p Ͻ 0.01). These findings suggest that concomitant low-dose I Ks and ␤-adrenergic blockade may constitute a potential pharmacologic strategy for prevention of malignant ischemic ventricular arrhythmias.Delay of myocardial repolarization (class III electrophysiologic activity) via blockade of repolarizing potassium currents has been advanced as a potential antiarrhythmic mechanism. This is based on the premise that sufficient prolongation of myocardial refractoriness results in a wavelength of excitation that exceeds the path length of reentrant circuits, thereby preventing the initiation and/or maintenance of reentrant rhythms (Wellens et al., 1984). Myocardial repolarization in the majority of mammalian species studied, including humans, is controlled mainly by the interplay of the rapidly (I Kr ) and slowly (I Ks ) activating, delayed rectifier potassium currents (Sanguinetti and Jurkiewicz, 1990;Wang et al., 1994;Liu and Antzelevitch, 1995;Li et al., 1996;Salata et al., 1996a;Virag et al., 2001). The clinical assessment of selective blockers of I Kr for the treatment of malignant ventricular arrhythmia has yielded disappointing results. d-Sotalol increased mortality in patients with previous myocardial infarction and left ventricular dysfunction (Waldo et al., 1996), and dofetilide displayed a neutral effect on mortality in patients with reduced left ventricular function and congestive heart failure (Torp-Pedersen et al., 1999). Characteristics of I Kr blockers, which have been proposed to limit clinical antiarrhythmic efficacy, include reverse frequency dependence, whereby class III activity is diminished at faster heart rates and exaggerated at slower rates (Nattel and Zeng, 1984;Hondeghem and Snyders, 1990), and reduction of class III activity in the setting of sympathetic stimulation (Sanguinetti et al., 1991;Schreieck et al., 1997).A number of structurally distinct selective I Ks blockers recently have become available for preclinical assessment. Initial studies indicate that selective I Ks block may provide a profile of class III action differing significantly from that of I Kr block, particularly with regard to frequency dependence

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Section: Methodsmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 94%

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confidence: 99%

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