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Europace Advance Access originally published online on January 25, 2007
Europace 2007 9(3):154-161; doi:10.1093/europace/eul146
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

VENTRICULAR ARRHYTHMIA

Role of KATP channels in repetitive induction of ventricular fibrillation

Alexander Bauer1,* {dagger}, Ruediger Becker1 {dagger}, Jens Dreyhaupt2, Frederik Voss1, Patricia Kraft1, Kamilla Kelemen1, Julia C. Senges-Becker1, Hugo A. Katus1 and Wolfgang Schoels1

1 Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany; 2 Department of Medical Biometry and Informatics, University of Heidelberg, Germany

Manuscript submitted 12 April 2006. Accepted after revision 2 October 2006.

* Corresponding author. Tel: +49 6221 5638672; fax: +49 6221 565514. E-mail address: alexander_bauer{at}med.uni-heidelberg.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Aim Patients with sustained ventricular tachyarrhythmias are at high risk for sudden cardiac death. The mechanisms leading to multiple temporally related episodes of ventricular fibrillation (VF) are not yet fully elucidated, and treatment options are limited. We investigated whether KATP-channels could be involved in triggering VF.

Methods We determined postarrhythmic changes of monophasic action potentials (MAP) after repetitive induction of VF in 32 Langendorff-perfused rabbit hearts.

Results Postarrhythmic action potential duration (APD) was significantly shorter compared with baseline (100 ± 12 ms vs. 140 ± 8 ms, P < 0.05). With increasing numbers of VF and shortening of recovery intervals between VF episodes (2 min) inducibility of VF increased, and abbreviation of APD became more prominent (90 ± 5 ms vs. 130 ± 4 ms, P < 0.05). Pre-treatment with the selective KATP blocking agent HMR 1883 led to a significant increase of postarrhythmic APDs compared with control hearts (100 ± 12 ms vs. 118 ± 3 ms, P = 0.0013). Moreover, HMR 1883 significantly reduced inducibility of VF and increased the rate of successful defibrillation.

Conclusions Repetitive episodes of VF result in postarrhythmic abbreviation of APDs, a phenomenon thought to be of potential relevance for incessant tachyarrhythmias in patients. Prevention of postarrhythmic MAP-shortening by HMR 1883 might be useful in suppressing VF.

Key Words: KATP channels, HMR 1883, ventricular fibrillation, arrhythmias


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Patients who have survived sustained ventricular arrhythmias are still at considerable risk for recurrence and consequently death.1Go So far the results from studies investigating the reduction of sudden cardiac death by class I or III-antiarrhythmic drugs have been disappointing.2Go–4Go Therefore, implantable cardioverter defibrillators (ICD) are currently the preferred therapy. However, implantation of ICDs is expensive and sometimes associated with severe complications.

Multiple temporally related episodes of ventricular tachyarrhythmias (VT) or ventricular fibrillation (VF) represent the most severe form of arrhythmias. Without an ICD, mortality is very high. However, those secured by an ICD often suffer from multiple painful defibrillations. At present, pharmacological treatment options for recurrent VTs or VFs are limited and the underlying mechanisms are still not fully elucidated.

Ventricular arrhythmias are caused by either rapid focal discharge or by re-entrant wave fronts. One of the conditions of re-entry initiation, the unidirectional block of conduction, can be provided by asymmetries in the substrate, by cardiac conduction disturbances or by shortening and/or heterogeneity of repolarization.5Go,6Go Sustained VT/VF preferentially occurs in patients with an anatomic substrate of extensive healed myocardial infarction or marked fibrosis. Imbalances of electrolytes or ion channel function may also precipitate arrhythmias.

The antiarrhythmic potency of KATP channel-blockers is still not fully elucidated. KATP channels were first described by Noma.7Go In hearts, activation of KATP channels mediates both cardiac preconditioning and shortening of cardiac repolarization.5Go,6Go,8Go Billman and coworkers were the first to demonstrate an antifibrillatory action of the cardioselective KATP blocking agent HMR 1402. In dogs with acute ischaemia, pre-treatment with a selective KATP blocker significantly reduced the incidence of VF.5Go The mechanisms underlying these antifibrillatory effects of HMR 1402 are still unclear. Reduction of postarrhythmic shortening of repolarization might be of importance for suppressing VF. Unfortunately, Billman and coworkers did not test this hypothesis in the in vivo part of their study.

Koning and coworkers, interestingly, were able to demonstrate non-ischaemic activation of KATP channels in pigs after fast ventricular pacing.9Go Due to the fact that induction of VF in vivo is always associated with marked ischaemia, discrimination of non-ischaemic and ischaemic activation of KATP is impossible. We, therefore, tested the impact of non-ischaemic activation of KATP channels on initiation as well as termination of VF in an ex vivo model.

To mimic incessant VF, we used an artificial model, where VF was repetitively induced by ventricular burst pacing. In Langendorff perfused rabbit hearts significant ischaemia during VF induction can be excluded. The goal of the present study was to identify underlying mechanisms of recurrent VF and potential treatment options. Involvement of KATP channels in mechanisms triggering VF was tested during perfusion of the cardioselective KATP blocking agent HMR 1883 (1-[[5-[2-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-methylthiourea).10Go


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All animal experiments conformed to the ‘Position of the American Heart Association on Research Animal Use’ adopted 11 November 1984.

Isolated rabbit heart preparation
Forty-six New Zealand white rabbits males and females, weighing 2–3 kg, were anaesthetized with intravenous propofol (2%). After a median sternotomy, the heart was removed quickly and washed in cold pH 7.4 Tyrode solution of the following composition (mM): NaCl: 140, KCl: 5, CaCl2: 2.2, MgCl2: 1, NaHCO3: 20, NaH2PO4: 0.33, Glucose: 11.1. Human albumin (0.040 mM) was added to the solution. The cut aortic stump was cannulated and the heart transferred to the Langendorff apparatus. Afterwards hearts were perfused with warm and oxygenated (37°C, 95% O2, 5% CO2) Tyrode solution. Base excess, pH, pO2, and pCO2 were continuously monitored and shown to be within the physiological range. Non-recirculating solution was perfused through the aorta at a constant flow of 25.8 ± 4.9 ml/min using a flow roller pump system (Pericor SF70/H33, New York, NY, USA). Coronary flow was measured with a glass flowmeter (Cole Parmer Instrument Company, Vernon Hills, IL, USA) positioned immediately above the retrogradely perfused aorta. The perfusion pressure in the cannulated aorta was kept at 80 mm/Hg during all experiments. Time interval from excision of rabbits' hearts and initiation of Krebs–Henseleit solution was < 80 s.

Experimental protocol
All hearts were allowed to equilibrate for 20 min after instrumentation to confirm stability and viability. To ensure constant heart rates during baseline and postarrhythmic recovery, pacing rate was set at 3.3 Hz (UHS 20, Biotronik, Berlin, Germany). Hearts were stimulated through a pair of pacing electrodes (TME-60-Z, Rheinfelden, Germany) located in the left ventricle. The pacing threshold was stable for all protocols and with different pre-treatments. Epicardial monophasic action potentials (MAP) were recorded from the left ventricle using Ag–/AgCL contact MAP catheters (HSE, March-Hugstetten, Germany) as described by Franz et al.11Go The MAP-catheter was fixed on the epicardial surface of the heart allowing a stable position during induction as well as after termination of VF. Signals were amplified by an AC-Amplifier (Dieffenbacher AC 110, Karlsruhe, Germany) and stored on optical disks (optical disk DC-502, Pioneer Corp., Willich, Germany) using a computer system (EPLab, Quinton Electrophysiology, East Jesus, CA, USA). Action potential duration (APD) was measured as time from rapid depolarization to 90% repolarization.

After baseline MAPs were recorded, VF was induced by short burst pacing (3 s, 60 Hz, 2 s time interval between successive burst pacing episodes, Telectronics Defibrillator 4510 120 mF, Sydney, NSW, Australia) applied through a pair of left ventricular pacing electrodes. Ninety seconds after induction of sustained VF, arrhythmias were terminated by a 20 J defibrillation shock (Telectronics Defibrillator 4510 120 mF). Sustained VF was defined as (i) the development of a chaotic, irregular rapid electrogram from the ventricular MAP electrode, (ii) the loss of pulsatile left ventricular pressure,3Go the loss of grossly observable, regular ventricular contraction. Sustained VF was always terminated after 90 s. Inducibility of VF was defined as the total number of burst-pacing attempts required for induction of persistent VF. Immediately after termination of VF, MAPs were continuously recorded to allow further APD measurements. The number of defibrillation attempts required for successful termination was counted and used for statistical analysis. Once APDs had returned to baseline values and a minimum interval of 10 min had passed, repeat cycles of VF initiation and termination were performed (five consecutive VF-episodes). Electrophysiological characteristics were investigated in isolated rabbit hearts without pre-treatment (n = 7) or with pre-treatment of the new KATP blocking agent HMR 1883 (1-[[5-[2-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea, the free acid of HMR1098) (n = 7; 3 x 10–6 M; Fa. Aventis, Frankfurt, Germany) (Figure 1). For evaluation of accumulating effects caused by repetitive episodes of VF, the protocol was repeated with an abbreviated postarrhythmic recovery interval of 2 min in another 14 rabbits (n = 7 without pre-treatment; n = 7 with HMR 1883).


Figure 1
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  		Figure 1 Schematic description of the experimental protocol. Pre-treatment is shown in the first frame.

 
In order to exclude direct effects of electrical defibrillation on refractoriness, MAPs were recorded in four isolated rabbit hearts before and after defibrillation without prior induction of VF. Effluents were collected from the coronary sinus at baseline and after the fifth consecutive episode of VF for analysis of lactate concentrations.

Statistical analysis
Statistical analysis was performed using SAS (version 9.1; SAS Institute Inc., Cary, NC, USA). Linear mixed effects regression models were used for the investigation of the variables of interest. In particular, the following models were fitted.

  1. The influence of drug presence, numbers of VF episodes, and APD baseline value and the mean of postarrhythmic APD was investigated in the group with 10 min recovery time.
  2. The influence of drug presence and numbers of VF episodes on the inducibility of VF was investigated in both recovery time groups.
  3. The influence of drug presence, numbers of VF episodes, and APD baseline value on the time course of postarrhythmic APD was investigated in the group with 2 min recovery time.
  4. The influence of drug presence and number of successful defibrillations on the inducibility of VF in the group with 2 min recovery time.

In all mixed effects regression models, the single heart was included as a random effect. The dependency between the different VF episodes was modelled with a suitable covariance structure.

Statistical significance was accepted at P < 0.05. Because of the hypothesis generating nature of our study, an adjustment for multiple testing was not done.

Student's t-test was employed for the comparison of lactate levels.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Electrophysiological effects of repetitive episodes of VF interrupted by 10 min recovery intervals
In order to exclude a direct effect of electrical defibrillation on post defibrillation repolarization, MAPs were recorded in four hearts after electrical defibrillation without prior induction of VF. As expected, no significant changes in APD were evident (Figure 2).


Figure 2
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  		Figure 2 (A) APDs prior to and after termination of VF in hearts pre-treated with Tyrode-solution (con) or HMR 1883 (HMR). (B) Relative changes of APD in hearts perfused with Tyrode-solution and defibrillation (defi) without prior induction of VF; defi 1–5 means episode 1–5.

 
Repetitive induction of VF with a postarrhythmic recovery period of 10 min resulted in a decrease in APDs (Figures 2 and 3). Using a regression model, a comparison of APDs during episodes 1–4 and 5 revealed moderate but significant differences (Table 1 and Figure 3). Additionally, time dependent and significant differences of APDs occurred after defibrillation (Table 1 and Figure 3). With 10 min postarrhythmic recovery times, inducibility of VF (defined as the total number of burst-pacing attempts required for induction of persistent VF) did not change during consecutive episodes of VF (Tables 2 and 3). In addition, the success rate of electrical defibrillation did not change with increasing numbers of VF.


Figure 3
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  		Figure 3 Left ventricular (LV) APD before induction (base) and after termination of the first until fifth episode of VF (post VF) in hearts pre-treated with Tyrode solution (control) or Tyrode solution with HMR 1883 (HMR 1883). Ventricular fibrillation episodes were separated by 10 min recovery-intervals. Base, baseline APD prior to induction of VF.

 


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  		Table 1 Impact of drug presence (HMR 1883), number of VF-episodes and baseline-APDs on postarrhythmic APDs in the group with 10 min recovery time between consecutive VF-episodes

 


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  		Table 2 Number of burst-pacing attempts required to induce persistent VF (VF 1, first episode of VF) in the group with 10 min recovery intervals between consecutive VF-episodes

 
With perfusion of HMR 1883, the postarrhythmic shortening of APD observed in control hearts was diminished (Figures 2 and 3). Further, HMR 1883 significantly prolonged APDs compared with control hearts (Table 1). In addition, inducibility of VF was significantly reduced in HMR 1883 hearts (Tables 2 and 3; Figures 2 and 3). However, regarding the defibrillation success, no significant changes were observed in this group.

Electrophysiological effects of repetitive episodes of VF interrupted by 2 min recovery intervals
In search for cumulative effects, we repeated this protocol with a shorter postarrhythmic recovery interval (2 min). APDs preceding episodes of VF served as baseline values. During 2 min recovery intervals, shortening of postarrhythmic APDs seemed to be more marked compared with 10 min recovery intervals (Figure 4). This effect was even further accentuated with repetitive episodes of VF (Figure 4 and Table 4). Additionally, time-dependent postarrhythmic shortening of APDs was evident (Table 3). Further differences in inducibility with repetitive VF-episodes and a lower success rate of electrical defibrillation were found (Tables 5 and 6). With repetitive VF-episodes, fewer burst-pacing attempts were needed to induce VF (Tables 5 and 6), and more defibrillation attempts were needed to terminate VF (Tables 7 and 8).


Figure 4
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  		Figure 4 Left ventricular (LV) APD before induction (base) and after termination of the first until fifth episode of VF (post VF) in hearts pre-treated with Tyrode solution (control) or Tyrode solution with HMR 1883 (HMR 1883). Ventricular fibrillation episodes were separated by 2 min recovery-intervals. Base, baseline APD prior to induction of VF.

 


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  		Table 3 Impact of drug presence (HMR 1883), number of VF-episodes on inducibility of VF in the group with 10 min recovery time between consecutive VF-episodes

 


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  		Table 4 Impact of drug presence (HMR 1883), number of VF-episodes and baseline-APDs on postarrhythmic APDs in the group with 2 min recovery time between consecutive VF-episodes

 


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  		Table 5 Number of burst-pacing attempts required to induce persistent VF (VF 1, first episode of VF) in the group with 2 min recovery intervals between consecutive VF-episodes

 


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  		Table 6 Impact of drug presence (HMR 1883), number of VF-episodes on inducibility of VF in the group with 2 min recovery time between consecutive VF-episodes

 


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  		Table 7 Number of defibrillation attempts required to terminate persistent VF in the group with 2 min recovery intervals between consecutive VF-episodes

 
In hearts perfused with HMR 1883, postarrhythmic shortening of APDs was not as marked as in control hearts (Figure 4). During perfusion with Tyrode and HMR 1883 APDs were significantly longer than in control hearts (Table 4). Additionally, the diminished shortening of APD seemed to exert preventive effects on induction and successful termination of VF (Tables 5, 6, 7 and 8). More burst-pacing attempts to induce VF (Tables 5, 6, 7 and 8), and fewer defibrillation attempts to terminate VF were needed when HMR 1883 had been added.


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  		Table 8 Impact of drug presence (HMR 1883), number of VF-episodes on successful defibrillation of VF in the group with 2 min recovery time between consecutive VF-episodes

 
Myocardial lactate production indicative of myocardial ischaemia was analysed in coronary sinus effluent collected at baseline and after the fifth consecutive episode of VF. As in comparable studies,12Go,13Go VF had no effects on lactate concentrations (baseline: 0.25 ± 0.19 mmol/l vs. VF: 0.26 ± 0.16 mmol/l, P = 0.81).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present study demonstrates that the KATP channel is one potential candidate responsible for a marked shortening of ventricular repolarization after termination of VF. It could be shown that: (i) repetitive induction of sustained VF was associated with a significant shortening of postarrhythmic repolarization. These effects accumulated when recovery intervals were abbreviated between VF-episodes and (ii) the cardioselective KATP blocker HMR 1883 attenuated postarrhythmic shortening of APD, resulting in a decreased inducibility of VF and an increased success rate of electrical defibrillation.

The KATP channel is formed by physical association of the Kir 6.1/6.2 and SUR1/2A/B subunits. Its function is best described as metabolic sensors in pancreatic ß-cells.14Go–18Go Additionally, KATP channels are also involved in mechanisms of cardiac preconditioning and shortening of repolarization. Opening of as few as 1% of KATP channels is sufficient to produce a significant shortening of cardiac repolarization.18Go

The sulfonylurea glibenclamide is one of the first agents discovered to exhibit KATP blocking effects that abolish ischaemic preconditioning in the heart. One drawback of glibenclamide is the fact that inhibition of ischaemia-induced shortening of repolarization is accompanied by a suppression of ischaemic preconditioning in the heart. In contrast, the selective KATP blocker HMR 1883 prevents ischaemia-induced shortening of repolarization without affecting ischaemic preconditioning.10Go,19Go Therefore, HMR 1883 can be used in patients with ischaemia or myocardial infarction without compromising ischaemic preconditioning. Moreover, Jung and coworkers demonstrated that HMR 1883 selectively blocks the KATP channel without affecting other ion-channels such as the fast Na+ –, transient Ca2+ –, I K1 –, IKr – or IKs –channels.10Go

Antiarrhythmic effects of the selective KATP blocking agent HMR 1402 were first described by Billman and coworkers.5Go They demonstrated suppression of VF in dogs with acute ischaemia. Unfortunately, no underlying mechanisms for the antifibrillatory actions of KATP blocking agents could be identified from their data, since further in vivo exploration, e.g. determination of postarrhythmic changes of cardiac electrophysiology, was not performed.5Go

The present study might provide a potential explanation. It could be shown that postarrhythmic shortening of APDs results in improved inducibility of VF as well as a lower success rate of electrical defibrillation. In addition, with HMR 1883, a drug was identified that significantly diminished abbreviation of repolarization, resulting in decreased inducibility and improved successful termination of VF. In a clinical situation, these findings could possibly be interpreted as a stabilizing effect of the drug to avoid recurrence of VF/VT.

How does KATP induced shortening of repolarization induce a substrate for re-entry? It is well known that stability of re-entrant activity varies with the circuit size, activation pattern, and wave length. Any approach to prolong repolarization, e.g. blockade of KATP channels by the selective blocker HMR 1883,10Go should decrease the number of circuits, which might result in reduced stability and inducibility of VF.20Go–22Go Surprisingly, in the present study effects of HMR 1883 occurred independently from cardiac ischaemia. Our study was conducted in Langendorff perfused rabbits hearts, where ischaemia after repetitive induction of VF was lacking. Findings from the present study confirm the results from Koning and co-workers reporting non-ischaemic activation of KATP channels in open chest pigs.9Go

Several mechanisms might underlie non-ischaemic activation of KATP channels are as follows. (i) One possible mechanism could be rapid and irregular ventricular excitation activating KATP channels. Fast heart rates might decrease ATP production, which could be a trigger for KATP channels; (ii) There is a large body of functional data that supports the existence of subcellular compartmentalization of the components of cyclic AMP in the heart.23Go In myocytes, it could be shown that not all cAMP gains access to subsequent protein kinases, which means that cAMP is present in the cell but not as an active compound.24Go During stress, this effect might be more accentuated with a further loss of ‘active’ cAMP. (iii) Other factors that affect the cellular supply with ATP/cAMP might also be conceivable.

Clinical implications
Although the mechanisms underlying incessant tachyarrhythmias are generally poorly understood, it seems reasonable to assume that KATP channels play a significant role. Postarrhythmic APD shortening and its suppression by blockade of KATP channels, as shown in the present study, are well in line with this hypothesis and could provide potential treatment options for patients at high risk for ‘electrical storm’. Whether these theoretical considerations will hold true in a clinical setting needs to be confirmed in future studies.

Limitations
The time available during the 2 min protocol was too short to determine APDs from different left ventricular sites. Thus, we were not able to elucidate whether heterogenous repolarization might be a trigger for the increased inducibility of VF and whether HMR1883 reduces dispersion of refractoriness.


   Footnotes
 
{dagger} These authors contributed equally to this work. Back


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
[1] Exner DV, Pinski SL, Wyse DG, et al. Electrical storm presages nonsudden death: the antiarrhythmics versus implantable defibrillators (AVID) trial. Circulation 2001; 103: 2066–71.

[2] Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324: 781–8.[Abstract]

[3] The Cardiac Arrhythmia suppression trial (CAST) investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321: 406–12.[Abstract]

[4] Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival with oral d-sotalol. Lancet 1996; 348: 7–12.[CrossRef][ISI][Medline]

[5] Billman GE, Houle MS, Englert HC, Gögelein H. Effects of a novel cardioselective ATP-sensitive potassium channel antagonist, 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-beta-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea, sodium salt (HMR 1402), on susceptibility to ventricular fibrillation induced by myocardial ischemia: in vitro and in-vivo studies. J Pharmacol Exp Ther 2004; 309: 182–92.[Abstract/Free Full Text]

[6] Coronel R. Heterogeneity in extracellular potassium concentration during early myocardial ischemia and reperfusion: implications for arrhythmogenesis. Cardiovasc Res 1994; 28: 770–7.[Free Full Text]

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[8] Billman GE. The role of the ATP-sensitive K+channel in K+accumulation and cardiac arrhythmias during myocardial ischaemia. Cardiovasc Res 1994; 28: 762–9.[Free Full Text]

[9] Koning MM, Gho BCG, Klaarwater van E, Opstal RLJ, Duncker DJ, Verdouw PD. Rapid ventricular pacing produces myocardial protection by nonischemic activation of KATP-channels. Circulation 1996; 93: 178–86.

[10] Gogelein H, Hartung J, Englert HC, Scholkens BA. HMR 1883, a novel cardioselective inhibitor of the ATP-sensitive potassium channel. Part I: effects on cardiomyocytes, coronary flow and pancreatic beta-cells. J Pharmacol Exp Ther 1998; 286: 1453–64.[Abstract/Free Full Text]

[11] Franz MR, Burkhoff D, Spurgeon H, Weisfeldt ML, Lakatta EG. In vitro validation of a new cardiac catheter technique for recording monophasic action potentials. Eur Heart J 1986; 7: 34–41.[Abstract/Free Full Text]

[12] Koretsune Y and Marban E. Cell calcium in the pathophysiology of ventricular fibrillation and in the pathogenesis of postarrhythmic contractile dysfunction. Circulation 1989; 80: 369–79.

[13] Merillat JC, Lakatta EG, Hano O, Guarnieri T. Role of calcium and the calcium channel in the initiation and maintenance of ventricular fibrillation. Circ Res 1990; 67: 1115–23.[Abstract/Free Full Text]

[14] Aguilar-Bryan L, Nichols CG, Wechsler S, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995; 268: 423–6.[Abstract/Free Full Text]

[15] Ashcroft FM, Harrison DE, Ashcroft SJ. Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 1984; 312: 446–8.[CrossRef][Medline]

[16] Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CG. Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell 2000; 100: 645–54.[CrossRef][ISI][Medline]

[17] Miki T, Liss B, Minami K, et al. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 2001; 4: 507–12.[ISI][Medline]

[18] Nichols CG and Lederer WJ. Adenosine triphosphate-sensitive potassium channels in the cardiovascular system. Am J Physiol 1991; 261: H1675–86.

[19] Jung O, Englert HC, Jung W, Gogelein H, Scholkens BA, Busch AE, et al. The KATP channel blocker HMR 1883 does not abolish the benefit of ischemic preconditioning on myocardial infarct mass in anesthetized rabbits. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 445–51.[CrossRef][ISI][Medline]

[20] Epstein AE and Ideker RE. Ventricular fibrillation. In Zipes DP and Jalife J (Eds.). Cardiac Electrophysiology: From Cell to Bedside 1995; 2nd ed. Philadelphia Saunders pp. 927–33.

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[23] Rybin VO, Pak E, Alcott S, Steinberg SF. Developmental changes in beta 2-adrenergic receptor signaling in ventricular myocytes: the role of Gi proteins and caveolae microdomains. Mol Pharmacol 2003; 63: 1338–48.[Abstract/Free Full Text]

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O. Aydin, R. Becker, P. Kraft, F. Voss, M. Koch, K. Kelemen, H. A. Katus, and A. Bauer
Effects of protein kinase C activation on cardiac repolarization and arrhythmogenesis in Langendorff-perfused rabbit hearts
Europace, November 1, 2007; 9(11): 1094 - 1098.
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