Risk of Ventricular Proarrhythmia with Selective Opening of the Myocardial Sarcolemmal versus Mitochondrial ATP-Gated Potassium Channel

Fischbach, Peter S.; White, Andrew A.; Barrett, Terrance D.; Lucchesi, Benedict R.

doi:10.1124/jpet.103.060780

Cited by 37 publications

(30 citation statements)

References 32 publications

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“…In the present study, pinacidil pretreatment clearly promoted rapid arrhythmias with characteristics of transmural re-entry. This observation supports findings in perfused heart preparations in which pinacidil treatment promoted very rapid ventricular tachyarrhythmias (D'Alonzo et al, 1998;Fischbach et al, 2003Fischbach et al, , 2004.…”

supporting

confidence: 80%

“…A study in isolated guinea pig free wall preparations reported that pretreatment with pinacidil before no-flow ischemia improved the recovery of developed tension and abolished severe arrhythmias in reperfusion (Cole et al, 1991). In contrast, other studies found that pinacidil pretreatment promoted arrhythmias induced by global ischemia and reperfusion (D'Alonzo et al, 1998) or hypoxia and re-oxygenation (Fischbach et al, 2003(Fischbach et al, , 2004 in Langendorff-perfused hearts.…”

mentioning

confidence: 91%

“…However, the present study used 100 M pinacidil for pretreatment, whereas the study by Cole et al (1991) investigated effects of 1 to 10 M pinacidil. On the other hand, the studies by Fischbach et al (2003Fischbach et al ( , 2004 and D' Alonzo et al (1998) reported proarrhythmic effects in preparations pretreated with 1 to 30 M pinacidil. The mechanism of arrhythmia present in these models also may affect the outcome of pretreatment with pinacidil.…”

mentioning

confidence: 96%

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Pretreatment with Pinacidil Promotes Arrhythmias in an Isolated Tissue Model of Cardiac Ischemia and Reperfusion

Ferrier

Howlett²

2005

J Pharmacol Exp Ther

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It is not clear whether activation of ATP-sensitive potassium channels (K ATP ) with pinacidil in advance of ischemia and reperfusion promotes or suppresses arrhythmias. This study determines the effects of pinacidil pretreatment on arrhythmias and the changes in cellular electrophysiological parameters in segments of guinea pig right ventricular free walls exposed to simulated ischemia and reperfusion. Microelectrode recordings were made from endo-and epicardium during endocardial pacing. Preparations were superfused with Tyrode's solution and then exposed for 5 min to either 100 M pinacidil or its solvent. After a 5-min washout, preparations were exposed to 15 min of ischemic conditions (hypoxia, hypercapnia, hyperkalemia, acidosis, lactate accumulation, and glucose-free) followed by reperfusion with Tyrode's solution. Pinacidil pretreatment increased ischemia-induced abbreviation of endo-and epicardial action potential durations and effective refractory periods. Pinacidil had no effect on endocardial conduction times but greatly prolonged transmural conduction during ischemia and early reperfusion, and it increased the incidence of transmural conduction block. Pinacidil pretreatment caused a significant increase in the incidence of arrhythmias in ischemia and reperfusion. Reperfusion arrhythmias in control preparations had electrophysiological characteristics of activity initiated by afterpotentials; however, arrhythmias with these characteristics were absent in pinacidil-pretreated preparations, and all reperfusion arrhythmias exhibited characteristics of reentry. The increased incidence of re-entrant arrhythmias is likely explained by pinacidil-induced reduction in effective refractory periods in combination with prolonged transmural conduction times. Thus, pinacidil pretreatment enhanced the effects of ischemia and reperfusion on action potential duration, effective refractory period, and transmural conduction, and it promoted re-entrant arrhythmias.

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supporting

confidence: 80%

mentioning

confidence: 91%

mentioning

confidence: 96%

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Pretreatment with Pinacidil Promotes Arrhythmias in an Isolated Tissue Model of Cardiac Ischemia and Reperfusion

Ferrier

Howlett²

2005

J Pharmacol Exp Ther

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“…When K ATP channels open during ischaemia, resultant dispersion of refractoriness and slowing of conduction could predispose to reentrant arrhythmias; by preventing these effects, K ATP channel blockade could be anti-arrhythmic and protective. In fact, some studies have indicated that K ATP channel blockers reduce the propensity for ischaemic arrhythmias [12,13], while K ATP channel openers facilitate induction of ventricular fibrillation [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

Reiter

et al. 2008

Diabetologia

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Aims/hypothesis Opening of ATP-sensitive potassium (K ATP ) channels during myocardial ischaemia shortens action potential duration and is believed to be an adaptive, energy-sparing response. Thiazolidinedione drugs block K ATP channels in non-cardiac cells in vitro. This study determined whether thiazolidinedione drugs block cardiac K ATP channels in vivo. Methods Experiments in 68 anaesthetised pigs determined: (1) effects of inert vehicle, troglitazone (10 mg/kg i.v.) or rosiglitazone (0.1 or 1.0 mg/kg i.v.) on epicardial monophasic action potential (MAP) during 90 min low-flow ischaemia; (2) effects of troglitazone, rosiglitazone or pioglitazone (1 mg/kg i.v.) on response of MAP to intracoronary infusion of a K ATP channel opener, levcromakalim; and (3) effects of inert vehicle, rosiglitazone (1 mg/kg i.v.) or the sarcolemmal K ATP blocker HMR-1098 on time to onset of ventricular fibrillation following complete coronary occlusion. Results With vehicle, epicardial MAP shortened by 44±9 ms during ischaemia. This effect was attenuated to 12±8 ms with troglitazone and 6±6 ms with rosiglitazone (p<0.01 for both vs vehicle), suggesting K ATP blockade. Intracoronary levcromakalim shortened MAP by 38±10 ms, an effect attenuated to 12±8, 13±4 and 9±5 ms during co-treatment with troglitazone, rosiglitazone or pioglitazone (p<0.05 for each), confirming K ATP blockade. During coronary occlusion, median time to ventricular fibrillation was 29 min in pigs treated with vehicle and 6 min in pigs treated with rosiglitazone or HMR-1098 (p<0.05 for both vs vehicle), indicating that K ATP blockade promotes ischaemic ventricular fibrillation in this model. Conclusions/interpretation Thiazolidinedione drugs block cardiac K ATP channels at clinically relevant doses and promote onset of ventricular fibrillation during severe ischaemia.

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“…The selective benzopyran derivate, BMS 191095, elicited both antinecrotic (Neckar et al 2002) and antiarrhythmic (Fischbach et al 2004) protection in the rodent heart subjected to I/R injury, being recognized as an useful tool for basic research (Grover and Atwal 2002). Accordingly, further studies addressing the role of novel benzopyran analogues in preventing the deleterious effects of reperfusion injury are warranted.…”

Section: Mitochondrial H 2 O 2 Productionmentioning

confidence: 99%

Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues

Mioc

Duicu

Sturza

et al. 2015

Can. J. Physiol. Pharmacol.

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A substantial body of evidence indicates that pharmacological activation of mitochondrial ATP-sensitive potassium channels (mK ATP ) in the heart is protective in conditions associated with ischemia/reperfusion injury. Several mechanisms have been postulated to be responsible for cardioprotection, including the modulation of mitochondrial respiratory function. The aim of the present study was to characterize the dose-dependent effects of novel synthetic benzopyran analogues, derived from a BMS-191095, a selective mK ATP opener, on mitochondrial respiration and reactive oxygen species (ROS) production in isolated rat heart mitochondria. Mitochondrial respiratory function was assessed by high-resolution respirometry, and H 2 O 2 production was measured by the Amplex Red fluorescence assay. Four compounds, namely KL-1487, KL-1492, KL-1495, and KL-1507, applied in increasing concentrations (50, 75, 100, and 150 mol/L, respectively) were investigated. When added in the last two concentrations, all compounds significantly increased State 2 and 4 respiratory rates, an effect that was not abolished by 5-hydroxydecanoate (5-HD, 100 mol/L), the classic mK ATP inhibitor. The highest concentration also elicited an important decrease of the oxidative phosphorylation in a K + independent manner. Both concentrations of 100 and 150 mol/L for KL-1487, KL-1492, and KL-1495, and the concentration of 150 mol/L for KL-1507, respectively, mitigated the mitochondrial H 2 O 2 release. In isolated rat heart mitochondria, the novel benzopyran analogues act as protonophoric uncouplers of oxidative phosphorylation and decrease the generation of reactive oxygen species in a dose-dependent manner.

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Risk of Ventricular Proarrhythmia with Selective Opening of the Myocardial Sarcolemmal versus Mitochondrial ATP-Gated Potassium Channel

Cited by 37 publications

References 32 publications

Pretreatment with Pinacidil Promotes Arrhythmias in an Isolated Tissue Model of Cardiac Ischemia and Reperfusion

Pretreatment with Pinacidil Promotes Arrhythmias in an Isolated Tissue Model of Cardiac Ischemia and Reperfusion

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues

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