Pharmacological Evidence for the Persistent Activation of ATP-Sensitive K
            <sup>+</sup>
            Channels in Early Phase of Reperfusion and Its Protective Role Against Myocardial Stunning

Shigematsu, Sakuji; Sato, Toshiaki; Abe, Takeji; Saikawa, Tetsunori; Sakata, Toshiie; Arita, Makoto

doi:10.1161/01.cir.92.8.2266

Cited by 81 publications

(45 citation statements)

References 29 publications

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“…These adaptive effects of K ATP channel opening lead to the prediction that blockade of K ATP channels during myocardial ischaemia would impair contractile recovery. In fact, some in vitro studies have shown that glibenclamide impairs contractile recovery after simulated ischaemia [49].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…5 Although a number of studies have investigated this phenomenon, its mechanism is still not fully understood. Recent studies reported that the ATP-sensitive potassium channel opener plays an important role in the process, [6][7][8] so the present study investigated whether IPC and nicorandil, an ATPsensitive potassium channel opener, have protective effects for the myocardium during prolonged heart preservation in an isolated rat heart model.…”

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confidence: 99%

Ischemic Preconditioning and Nicorandil Pretreatment Improve Donor Heart Preservation

Zhang

Kaneda

et al. 2001

Jpn Circ J

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The present study investigated the effects of ischemic preconditioning (IPC) and nicorandil pretreatment on myocardial storage in a donor heart preservation model. Isolated rat hearts were separated into groups: group 1, non-preconditioned control group; group 2, 2.5 min of normothermic ischemia followed by 15 min of normothermic Langendorff perfusion (one IPC cycle); and group 3, 2 cycles of IPC. All hearts were subsequently stored in University of Wisconsin solution at 4°C for 2, 4 and 6 h, and the concentrations of high-energy phosphate metabolites were measured for each time point. Heart function parameters (aortic flow, coronary flow and cardiac output) were measured when the heart was reperfused following the 2, 4 or 6 h of preservation. The effects of nicorandil, an ATP-sensitive potassium channel opener, on heart function following preservation were also evaluated. Nicorandil was injected intravenously before heart harvesting. The results showed that the energy status was well preserved in the IPC groups. The 2-cycle IPC group showed better recovery of heart function following preservation. Pretreatment with nicorandil also improved functional recovery of the heart following preservation. The present study showed that IPC of the rat heart resulted in improved myocardial energy metabolism and functional recovery after hypothermic preservation, and that nicorandil has potential for pharmacological preconditioning in heart preservation for transplantation. (Jpn Circ J 2001; 65: 678 -682)

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“…Because the redox state of the mitochondria improved in the EAM+Nic groups in comparison with the control EAM group, protection of the mitochondrial function during the acute phase seemed to be the mechanism of the cardioprotection by Nic, similar to the acute ischemia model. [3][4][5][6]22) Clinical implications: The results of this study indicate the possibility of a reduction in myocardial or mitochondrial calcium overload as a cardioprotective therapy even in acute myocarditis as it is in acute ischemia. Therefore, this kind of therapeutic approach might result in better cardiac function in the later phase of clinical myocarditis.…”

Section: Mechanisms Of the Cardioprotection Of K-atp Channel Openersmentioning

confidence: 82%

“…This response is considered to be an auto-cardioprotective effect during ischemic conditions, which is known to be enhanced by sarcolemmal K-ATP channel openers. [3][4][5][6][7] However, K-ATP channels are found not only in the sarcolemma of myocytes, but also in the mitochondrial membrane, and openers of these mitochondrial K-ATP channels, such as nicorandil, have been proven to play an important role in its cardioprotective effect by protecting mitochondrial function, especially in short-term acute ischemia. [8][9][10] It has been reported that an increase in ventricular wall stress causes prolongation of the action potential duration, particularly in damaged myocardium with heart failure.…”

mentioning

confidence: 99%

Cardioprotective Effects of Sarcolemmal and Mitochondrial K-ATP Channel Openers in an Experimental Model of Autoimmune Myocarditis

et al. 2012

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SummaryIt has been reported that K-ATP channel openers have a cardioprotective effect in acute ischemia as a pharmacological preconditioning effect. In the present study, the chronic effects of clinical K-ATP channel openers, ie, nicorandil (Nic) and mexiletine (Mex), on cardiac function were evaluated in a rat model of experimental autoimmune myocarditis (EAM). Nicorandil (3 or 10 mg/kg/day) or Mex (10 or 25 mg/kg/day) was administered to the EAM rats, and the effects were compared with those in untreated EAM rats (control EAM) and sham rats without EAM on day 21 (acute phase) or day 60 (chronic phase). In the acute phase, the control EAM rats exhibited a reduced left ventricular ejection fraction (LVEF) and prolonged monophasic action potential duration (MAPD). Neither drug had an affect on the LVEF or degree of myocarditis, but Mex 25 mg suppressed the MAPD prolongation. In the chronic phase, EAM+Nic and EAM+Mex 25 mg exhibited a higher LVEF than the control EAM. Although the control EAM exhibited sustained MAPD prolongation, the other groups showed recovery of the MAPD in the chronic phase. The mitochondorial redox state was lower in the control EAM than in the sham, and EAM+Nic exhibited a similar level of the redox state as the sham in the chronic phase. Nicorandil exhibited a cardioprotective effect through the protection of mitochondrial function. Mexiletine exhibited a cardioprotective effect possibly through a reduction in the calcium overload by shortening the MAPD in the acute phase. (Int Heart J 2012; 53: 139-145)

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Pharmacological Evidence for the Persistent Activation of ATP-Sensitive K ⁺ Channels in Early Phase of Reperfusion and Its Protective Role Against Myocardial Stunning

Abstract: Cardiac ATP-sensitive potassium channels are activated by ischemia, and a fraction of these channels remains activated during the early reperfusion phase. The resulting shortening of the APD prevents the heart from developing myocardial stunning.

Cited by 81 publications

References 29 publications

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

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

Ischemic Preconditioning and Nicorandil Pretreatment Improve Donor Heart Preservation

Cardioprotective Effects of Sarcolemmal and Mitochondrial K-ATP Channel Openers in an Experimental Model of Autoimmune Myocarditis

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Pharmacological Evidence for the Persistent Activation of ATP-Sensitive K + Channels in Early Phase of Reperfusion and Its Protective Role Against Myocardial Stunning

Abstract: Cardiac ATP-sensitive potassium channels are activated by ischemia, and a fraction of these channels remains activated during the early reperfusion phase. The resulting shortening of the APD prevents the heart from developing myocardial stunning.

Cited by 81 publications

References 29 publications

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

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

Ischemic Preconditioning and Nicorandil Pretreatment Improve Donor Heart Preservation

Cardioprotective Effects of Sarcolemmal and Mitochondrial K-ATP Channel Openers in an Experimental Model of Autoimmune Myocarditis

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Pharmacological Evidence for the Persistent Activation of ATP-Sensitive K ⁺ Channels in Early Phase of Reperfusion and Its Protective Role Against Myocardial Stunning