QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: jpet.103.060780v1 309/2/554    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fischbach, P. S. Articles by Lucchesi, B. R. Search for Related Content PubMed PubMed Citation Articles by Fischbach, P. S. Articles by Lucchesi, B. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Arrhythmia

CARDIOVASCULAR

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

Departments of Pediatrics and Communicable Diseases (P.S.F.) and Pharmacology (A.W., T.D.B., B.R.L.), University of Michigan Medical School, Ann Arbor, Michigan

Received October 3, 2003; accepted January 26, 2004.

	Abstract

Top Abstract Materials and Methods Results Discussion References

 
Myocardial ATP-gated potassium channels (K-ATPs) are critical in the intracellular signaling cascade resulting in ischemic preconditioning (IP). Mitochondrial K-ATP channels seem to be responsible for IP, whereas the functions of K-ATP channels in the sarcolemmal membrane are less well understood. The proarrhythmic potential of specific versus nonspecific opening of K-ATP channels has not been investigated. In this study, Langendorff-perfused rabbit hearts were exposed to either pinacidil (1.25 µM), a nonselective K-ATP channel agonist, or selective mitochondrial or sarcolemmal K-ATP channel agonists or antagonists. The hearts were then subjected to 12 min of hypoxic perfusion and 40 min of reoxygenation. Hearts were monitored for the induction of ventricular fibrillation (VF). No heart subjected to hypoxia-reoxygenation without drug treatment developed VF (0 of 5). Pinacidil pretreatment induced VF (12 of 14; p = 0.004 versus control). Pinacidil's effect was blocked by HMR-1098 (1-[5-[2-(5-chloro-o-anisamide)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea) (1 µM), a selective sarcolemmal K-ATP channel antagonist (1 of 7; p = 0.007 versus pinacidil; N.S. versus control). Hearts pretreated with 5-hydroxydecanoate (5-HD) (100 µM), a putatively selective mitochondrial K-ATP channel blocker developed VF in one of eight trials (N.S. versus control). 5-HD did not alter the effects of pinacidil (6 of 8; p < 0.05 versus control; N.S. versus pinacidil alone). Selective mitochondrial K-ATP channel activation with [(3R)-trans-4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride] (BMS-191095) (6 µM) resulted in zero of five hearts developing VF (N.S. versus control). Our data suggest that selective opening of the sarcolemmal K-ATP channel during hypoxia-reoxygenation induced VF, whereas opening of the mitochondrial channel was not associated with VF. The findings suggest that caution should be exercised when developing compounds aimed at inducing IP, and nonspecific opening of the K-ATP channel should be avoided.

Myocardial K-ATP channels may be divided into two distinct populations. One channel type resides in the sarcolemmal membrane (sarcK-ATP), whereas the other is localized in the mitochondrial inner membrane (mitoK-ATP). The mitoK-ATP and sarcK-ATP channels may be differentiated based on their pharmacological sensitivities. The mitoK-ATP channel is purported to be responsible for IP (Garlid et al., 1997; Liu et al., 1998). Although the sarcK-ATP channel may also participate in IP, the exact role that the channel serves remains unclear (Flagg and Nichols, 2001).

Although opening of the mitoK-ATP does not affect the electrophysiological properties of the myocyte, sarcK-ATP channel opening leads to a large outward repolarizing current, shortening the action potential of the individual cell and decreasing the refractory period of the tissue as a whole. The shortening of the refractory period forms a myocardial substrate potentially susceptible to reentrant arrhythmias. The potential for proarrhythmia generated via K-ATP channel opening is important because the ability to pharmacologically precondition the heart and protect it from a future ischemic insult represents an attractive therapeutic target. Patients undergoing cardiac surgery requiring circulatory arrest, donor organs and patients with myocardial ischemia would stand to benefit significantly. This study, therefore, was designed to examine the effects of selective and nonselective opening of the K-ATP channel on the incidence of ventricular arrhythmias in isolated hearts exposed to hypoxia and reoxygenation.

	Materials and Methods

Top Abstract Materials and Methods Results Discussion References

 
The procedures used in this study were in accordance with the guidelines of the University of Michigan Committee on the Use and Care of Animals and conforms to the standards in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication number 86-23). The University of Michigan Unit for Laboratory Animal Medicine provided veterinary care.

Isolated Heart Preparation. Rabbit hearts were prepared as described previously (Fischbach et al., 2003). Male New Zealand White rabbits (1.9–2.5 kg) were rendered unconscious using cervical dislocation. The heart was removed rapidly via a median sternotomy and placed in iced buffered saline. The hearts were mounted on a Langendorff apparatus and perfused with a modified Krebs-Henseleit solution at a constant flow rate to achieve a coronary perfusion pressure of 50 to 60 mm Hg.

The composition of the perfusion buffer was 117 mM NaCl, 1.9 mM KCl, 2.6 mM CaCl₂, 1.2 mM MgCl₂, 25 mM NaHCO₃, 1.1 mM KH₂PO₄, 5 mM glucose, 5 mM Na-glutamate, and 2 mM Na-pyruvate. The final K⁺ concentration was 3 mM. The pH of the solution was adjusted to 7.4 using HCl. The buffer was gassed continuously with 95% O₂, 5% CO₂ as it passed through an "artificial membrane-lung" (Silastic tubing; Dow Corning, Midland, MI) and maintained at 37°C using a circulating water bath. Pacing leads were attached to the right atrial appendage, and the hearts were paced at twice diastolic threshold at a rate of 150 bpm if their sinus rates fell below 150 bpm. Atrial pacing was used to ensure that each heart was subjected to a comparable metabolic stress. A balloon for monitoring left ventricular developed pressure and generating a constant end diastolic pressure was inserted through the left atrium and advanced across the mitral valve. A polyethylene tube also was advanced across the mitral valve and served as a vent for the left ventricle. Coronary perfusion pressure, a volume conducted ECG, left ventricular end diastolic pressure and left ventricular developed pressure were monitored continuously and recorded on a Grass Instruments model 7 polygraph (AstroMed, Warwick, RI) interfaced to a MacLab (Castle Hill, Australia) data acquisition system. The data were archived on a Macintosh computer (Apple Computer, Inc., Cupertino, CA) for subsequent off-line analysis.

Experimental Protocol. After a 20-min stabilization period, the hearts were treated for an additional 15 min (Fig. 1). In the drug-treated hearts, the test agents were added to the buffer at the conclusion of the stabilization period. For those experiments with both a K-ATP channel opener and blocker, the blocker was added to the buffer 5 min before the activator. Perfusion with the test agent was continued for the length of the experiment. The buffer was then made hypoxemic by changing the gas content in the "membrane-lung" to 95% N₂/5% CO₂. The pO₂ of the solution was checked using a gas analyzer to ensure appropriate hypoxemia. Hearts were perfused with the hypoxic perfusion medium for 12 min and then reoxygenated for 40 min. In those experiments using a pharmacological intervention, the drugs were perfused throughout the entire experiment. Electrocardiographic and hemodynamic monitoring was performed for the duration of the experiment. The occurrence of VF and the time of onset of the VF were recorded.

View larger version (35K): [in this window] [in a new window]   Fig. 1. Experimental protocol. At the completion of the equilibration period, the various test agents were added to the buffer. The hearts were perfused for an additional 15 min before making the perfusion buffer hypoxic. The hearts continued with hypoxic perfusion for 12 min and then were reoxygenated. The test agents were maintained in the buffer for the entire experiment. For those groups that included both an agonist and antagonist (groups IV, VII, IX, X, and XI), the antagonist (5-HD or HMR-1098) was added to the buffer 5 min before the pinacidil.

A total of seven groups were included in the first portion of the study. The groups were control, 1.25 µM pinacidil (a nonselective K-ATP channel opener), 100 µM 5-hydroxydecanoate (a selective mitoK-ATP channel blocker), 100 µM 5-hydroxydecanoate + 1.25 µM pinacidil, 6 µM BMS-191095 (in DMSO, a selective mitoK-ATP opener), 1 µM HMR-1098 (a selective sarcK-ATP channel blocker) and 1 µM HMR-1098 + 1.25 µM pinacidil, the concentration of each agent was based upon published studies. An additional group of three hearts (not included in data) treated with DMSO alone was subjected to the hypoxia-reoxygenation protocol to ensure no proarrhythmic effects. To demonstrate that these effects were due to opening of the K-ATP channel, a limited number of rabbit hearts were treated with 5 µM cromakalim, like pinacidil a nonspecific opener of the K-ATP channel. Four groups were included in this portion of the study. The groups were 5 µM cromakalim alone, 5 µM cromakalim + 1 µM HMR-1098, 5 µM cromakalim + 3 µM HMR-1098, and 5 µM cromakalim + 100 µM 5-hydroxydecanoate.

Drugs. Pinacidil (Sigma-Aldrich, St. Louis, MO) was dissolved in acidified buffer. Cromakalim (Sigma-Aldrich) was first dissolved in ethanol to make a stock solution. 5-HD (Sigma-Aldrich) and HMR-1098 (Aventis Pharmaceuticals Inc., Bridgewater, NJ) were dissolved in buffer. BMS-191095 (Bristol-Myers Squibb Co., Princeton, NJ), a selective mitoK-ATP channel opener, was dissolved in 0.04% DMSO.

Statistics. Continuous data are expressed as the mean ± the standard error of the mean. Statistical significance was tested using analysis of variance followed by a Tukey's test for differences. The occurrence of ventricular fibrillation in each group was analyzed using Fisher's exact test. All statistical tests were two-tailed and a p < 0.05 was considered statistically significant.

	Results

Top Abstract Materials and Methods Results Discussion References

 
Hemodynamic data are summarized in Table 1. Reversible third degree atrioventricular block developed in each heart during the period of hypoxia. Normal atrioventricular conduction returned within 5 min after commencing normoxic perfusion. None of the control or pinacidil-treated hearts developed VF during hypoxic perfusion or before the return of normal AV conduction. Of the five hearts treated with cromakalim, three developed VF during hypoxia and the remaining two shortly after beginning reoxygenation. Of the hearts treated with 5-HD and cromakalim, two of five developed VF during hypoxia as did three of three treated with 1 µM HMR-1098 and cromakalim.

In the absence of a pharmacological intervention, ventricular fibrillation was not observed in the hearts (n = 5) exposed to 12 min of hypoxic perfusion followed by reoxygenation (Fig. 2). In contrast, 12 of 14 (86%) hearts pretreated with pinacidil (1.25 µM) developed ventricular fibrillation within an average time of 19.5 min after the reintroduction of normoxic perfusion (p = 0.004 versus control hearts). Hearts pretreated with 5-HD (100 µM) developed VF in one of eight trials (N.S. versus control hearts). In the group of hearts perfused with 5-HD (100 µM) followed by exposure to pinacidil (1.25 µM), six of eight hearts developed VF (p < 0.05 versus control; N.S. versus pinacidil-treated hearts). The results indicate that inhibition of the mitoK-ATP channel does not result in a proarrhythmic effect. In addition, it is noted that 5-HD, a selective inhibitor of the mitoK-ATP channel, did not prevent the proarrhythmic action of pinacidil in hearts subjected to hypoxia and reoxygenation.

View larger version (30K): [in this window] [in a new window]   Fig. 2. Incidence of VF with the different treatment groups. Each heart is represented by the symbol *. The incidence and time to the onset of VF are demonstrated in this figure. Hearts that did not develop VF during the experimental protocol are grouped on the far right of the figure.

Ventricular fibrillation did not occur in any of the hearts subjected to hypoxic perfusion and reoxygenation in the presence of 6 µM BMS-191095 (n = 5) or when perfused in the presence of 1 µM HMR-1098 (n = 5). However, HMR-1098 (1 µM), a selective inhibitor of the sarcK-ATP channel, prevented the proarrhythmic action of pinacidil as demonstrated by only one of seven hearts developing VF when exposed to a combination of HMR-1098 and pinacidil during hypoxia and reoxygenation (p = 0.007 versus pinacidil-treated hearts; N.S. versus control hearts).

In the second series of isolated heart experiments designed to ensure that the proarrhythmic effects were due to the opening of the K-ATP channel and not due to a different effect of pinacidil, VF developed in five of five hearts treated with cromakalim alone and exposed to hypoxia-reoxygenation (p = 0.004 versus control hearts; N.S. versus pinacidil-treated hearts), all during hypoxia or immediately upon reoxygenation. Hearts pretreated with 5-HD (100 µM) were not protected from cromakalim's proarrhythmic effects, and all (five of five) developed VF (p = 0.004 versus control hearts; N.S. versus pinacidil-treated hearts). Pretreatment with 1 µM HMR-1098 did not prevent VF (3 of 3); however, increasing the dose to 3 µM eliminated VF (0 of 3) (p = 0.01 versus pinacidil-treated hearts; N.S. versus control hearts).

	Discussion

Top Abstract Materials and Methods Results Discussion References

 
The nonselective K-ATP channel opener pinacidil exhibits profibrillatory actions when the rabbit isolated heart is subjected to a brief period of hypoxic perfusion followed by reoxygenation (Chi et al., 1990, 1993; Fischbach et al., 2003). The results of the present study demonstrate that the increased propensity to develop VF is prevented by pretreatment with the specific sarcK-ATP channel blocker HMR-1098. Additional studies were conducted using the selective mitoK-ATP blocker 5-HD in combination with pinacidil, or the selective mitoK-ATP channel opener BMS-191095. The results demonstrate that the mitoK-ATP channel does not participate in the induction of proarrhythmic activity in hearts subjected to hypoxia-reoxygenation in the presence of pinacidil. An additional series of experiments were performed using cromakalim, which like pinacidil, is a nonselective opener of the myocardial K-ATP channel. The results of these studies also demonstrated that VF was prevented by selectively inhibiting the sarcK-ATP channel, demonstrating that this was not an effect unique to pinacidil. The results of this study provide compelling evidence to implicate the sarcK-ATP channel as being responsible for the induction of VF in rabbit isolated hearts treated with pinacidil and subjected to hypoxia and reoxygenation.

The induction of an ischemic or hypoxic insult results in the opening of the myocardial K-ATP channel (Noma, 1983), which is accompanied by a shortening of the membrane action potential and the myocardial refractory period. Whereas these effects may contribute to a cardioprotective effect by decreasing the metabolic demands on the heart and decreasing the intracellular calcium accumulation, they also establish an environment leading to a dispersion of refractoriness and altered conduction velocity, both of which favor the genesis of reentrant arrhythmias. It would stand to reason therefore, that blockade of the K-ATP channel should be antiarrhythmic during ischemia-reperfusion and/or hypoxia-reoxygenation. This has been demonstrated in several different animal models (Wolleben et al., 1989; Kantor et al., 1990; Smallwood et al., 1990; Gwilt et al., 1992) in which glibenclamide, a nonselective K-ATP channel blocker, prevented the electrophysiological and arrhythmogenic consequences of myocardial ischemia. However, glibenclamide is many times more specific for the pancreatic K-ATP channel than it is for the myocardial K-ATP channel, resulting in release of insulin. Due to the disproportionate effect on the pancreatic K-ATP channel, when used clinically, glibenclamide's hypoglycemic effects outweigh its potential beneficial effects as an antiarrhythmic agent.

Mammalian cells have two discrete types of K-ATP channels; those associated with the sarcolemmal membrane (sarcK-ATP) and others in the mitochondrial inner membrane (mitoK-ATP). Cardiac mitoK-ATP channels are purported to be instrumental in mediating ischemic preconditioning and are viewed as potential drug targets (Oldenburg et al., 2002). The sarcK-ATP channels are composed of a pore-forming, inwardly rectifying potassium channel subunit (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1, SUR2A, or SUR2B). The Kir and SUR subunits coassemble with a 4:4 stoichiometry, creating a hetero-octameric K-ATP channel (Inagaki et al., 1995, 1996). On the other hand, the molecular structure of the mitoK-ATP channel remains unresolved. Investigations into the structure and function of K-ATP channels indicate that the different subpopulations (mitochondrial, sarcolemmal, vascular, and pancreatic) are molecularly distinct.

K-ATP channel activators have been developed for a number of therapeutic indications that include, coronary vasodilators as potential antianginal agents, antispasmodics for urinary incontinence, bronchodilators for bronchial asthma, and vasodilators for the control of hypertension. To date, such agents have not achieved clinical acceptance, in part, due to a lack of specificity. Additional interest exists for developing a therapeutic agent to be used for myocardial preservation during cardiac bypass surgery or for use during organ preservation before transplantation. There are few published reports examining the proarrhythmic potential related to pharmacologically opening the sarcK-ATP and/or mitoK-ATP channel under conditions of myocardial hypoxia or ischemic stress, which would render the channels more susceptible to the action of agonists (Wolleben et al., 1989; Chi et al., 1990; Billman et al., 1993; Chi et al., 1993).

Hypoxic perfusion of the isolated heart leads to a decrease in cellular ATP content and reduced cardiac function, while coronary flow remains unaltered. Under conditions in which coronary flow is maintained constant, it is unlikely that accumulation of K⁺ would occur in the extracellular space. Under normoxic conditions, the ATP-dependent K⁺ channel is blocked by the high intracellular ATP concentration. Hypoxia-induced depletion of cellular ATP releases the blockade of the channel and allows for K⁺ efflux to occur (Conrad et al., 1983; Chi et al., 1993). In contrast to other K-ATP channel subtypes, the cardiac sarcK-ATP channel exhibits high sensitivity to potassium channel openers (Gribble et al., 2000), an effect that is further enhanced by a decrease in tissue ATP content.

Studies in large animal models of myocardial ischemia provide evidence that the opening of K-ATP channels is associated with the development of ventricular fibrillation (Chi et al., 1990; Billman, 1994), which can be prevented by interventions known to inhibit activation of the K-ATP channel (Friedrichs et al., 1996b; Billman et al., 1998; Friedrichs et al., 1998). There is the potential to develop K-ATP channel antagonists to prevent ischemia-induced reductions in refractory period and ventricular fibrillation. Therefore, the cited literature provides evidence to suggest that the activation of sarcK-ATP may play an important role in both the reductions in refractory period and initiation of lethal arrhythmia formation associated with myocardial ischemia. The results of this study support this hypothesis. Previous data also indicate that inhibition of the mitoK-ATP channel does not provide protection from ischemia-induced ventricular fibrillation in the postinfarcted conscious canine (Friedrichs et al., 1996a).

Pinacidil has been demonstrated to nonselectively open K-ATP channels. Interestingly, pinacidil's action upon the atrium and ventricle differs. Pinacidil effectively opens K-ATP channels in the atrium in the basal state as demonstrated by a shortening of the atrial action potential; however, in the ventricle pinacidil requires a coincident metabolic stress to open the K-ATP channel. Our laboratory and others previously demonstrated that isolated rabbit hearts exposed to pinacidil and subjected to hypoxia-reoxygenation reliably develop ventricular fibrillation (Chi et al., 1993; Inagaki et al., 1996; Fischbach et al., 2003). In the series of experiments reported in this article, we have demonstrated that the opening of the sarcK-ATP channel is responsible for the proarrhythmic effect.

There are several limitations to this study. One concern is that the animal model is the rabbit isolated heart. The applicability of arrhythmia models in small mammals to humans should be viewed with caution. Additionally, the metabolic stress imposed on the hearts to induce ventricular fibrillation was global hypoxia. Although this successfully generated metabolic stress that is thought to open the K-ATP channels, it is an unusual clinical condition. The hearts exposed to pinacidil also did not fibrillate until well into reoxygenation. This has been a phenomenon that we have observed consistently. It is likely that this is a result of a heterogenous recovery time of the myocardium with some tissue becoming reoxygenated at different rates. This would therefore establish myocardium with heterogenous electrical properties thereby producing a proarrhythmic substrate. Finally, we were unable to acquire any specific agonist for the sarcK-ATP channel P-1075. Although this shortfall limits the study, the combination of pinacidil with 5-HD should approximate the same stimulus as would be obtained with a selective agonist of the sarcK-ATP channel.

In summary, our data suggest that nonselective opening of the myocardial K-ATP channel is potentially arrhythmogenic. In particular, opening of the sarcK-ATP channel in the face of hypoxia-reoxygenation consistently resulted in the induction of VF. The therapeutic implications are that caution needs to be exercised when developing pharmacological agents for preconditioning the myocardium. Agents should be designed that are selective agonists for the mitoK-ATP channel.

	Footnotes

 
ABBREVIATIONS: IP, ischemic preconditioning; K-ATP, ATP-gated potassium channel; sarcK-ATP, sarcolemmal ATP-gated potassium channel; mitoK-ATP, mitochondrial ATP-gated potassium channel; DMSO, dimethyl sulfoxide; SUR, sulfonylurea; HMR-1098, 1-[5-[2-(5-chloro-o-anisamide) ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea; 5-HD, 5-hydroxydecanoate; BMS-191095, (3R)-trans-4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride.

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

DOI: 10.1124/jpet.103.060780.

Address correspondence to: Dr. Peter S. Fischbach, Department of Pediatrics, University of Michigan Medical School, Women's L1242, Box 0204, 1500 East Medical Center Dr., Ann Arbor, MI 48109-0204. E-mail: petersf{at}umich.edu

	References

Top Abstract Materials and Methods Results Discussion References

 

Billman GE (1994) Role of ATP sensitive potassium channel in extracellular potassium accumulation and cardiac arrhythmias during myocardial ischaemia. Cardiovasc Res 28: 762-769.[Free Full Text]

Billman GE, Avendano CE, Halliwill JR, and Burroughs JM (1993) The effects of the ATP-dependent potassium channel antagonist, glyburide, on coronary blood flow and susceptibility to ventricular fibrillation in unanesthetized dogs. J Cardiovasc Pharmacol 21: 197-204.[Medline]

Billman GE, Englert HC, and Scholkens BA (1998) HMR 1883, a novel cardioselective inhibitor of the ATP-sensitive potassium channel. Part II: Effects on susceptibility to ventricular fibrillation induced by myocardial ischemia in conscious dogs. J Pharmacol Exp Ther 286: 1465-1473.[Abstract/Free Full Text]

Bugge E and Ytrehus K (1996) Endothelin-1 can reduce infarct size through protein kinase C and KATP channels in the isolated rat heart. Cardiovasc Res 32: 920-929.[CrossRef][Medline]

Cason BA, Gamperl AK, Slocum RE, and Hickey RF (1997) Anesthetic-induced preconditioning: previous administration of isoflurane decreases myocardial infarct size in rabbits. Anesthesiology 87: 1182-1190.[CrossRef][Medline]

Chi L, Black SC, Kuo PI, Fagbemi SO, and Lucchesi BR (1993) Actions of pinacidil at a reduced potassium concentration: a direct cardiac effect possibly involving the ATP-dependent potassium channel. J Cardiovasc Pharmacol 21: 179-190.[Medline]

Chi L, Uprichard AC, and Lucchesi BR (1990) Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death. J Cardiovasc Pharmacol 15: 452-464.[Medline]

Cohen MV, Yang XM, Liu GS, Heusch G, and Downey JM (2001) Acetylcholine, bradykinin, opioids and phenylephrine, but not adenosine, trigger preconditioning by generating free radicals and opening mitochondrial K(ATP) channels. Circ Res 89: 273-278.[Abstract/Free Full Text]

Conrad CH, Mark RG, and Bing OH (1983) Outward current and repolarization in hypoxic rat myocardium. Am J Physiol 244: H341-H350.

Cope DK, Impastato WK, Cohen MV, and Downey JM (1997) Volatile anesthetics protect the ischemic rabbit myocardium from infarction. Anesthesiology 86: 699-709.[Medline]

Fischbach PS, Barrett TD, Reed NJ, and Lucchesi BR (2003) SNC-80-induced preconditioning: selective activation of the mitochondrial adenosine triphosphategated potassium channel. J Cardiovasc Pharmacol 41: 744-750.[CrossRef][Medline]

Flagg TP and Nichols CG (2001) Sarcolemmal K(ATP) channels in the heart: molecular mechanisms brought to light, but physiologic consequences still in the dark. J Cardiovasc Electrophysiol 12: 1195-1198.[CrossRef][Medline]

Friedrichs GS, Abreu JN, Black SC, Chi L, and Lucchesi BR (1996a) 5-Hydroxydecanoate fails to attenuate ventricular fibrillation in a conscious canine model of sudden cardiac death. Eur J Pharmacol 306: 99-106.[CrossRef][Medline]

Friedrichs GS, Abreu JN, Cousins GR, Chi L, Borlak J, and Lucchesi BR (1996b) Tedisamil attenuates ventricular fibrillation in a conscious canine model of sudden cardiac death. J Cardiovasc Pharmacol Ther 1: 313-324.

Friedrichs GS, Abreu JN, Driscoll EM Jr, Borlak J, and Lucchesi BR (1998) Antifibrillatory efficacy of long-term tedisamil administration in a postinfarcted canine model of ischemic ventricular fibrillation. J Cardiovasc Pharmacol 31: 56-66.[CrossRef][Medline]

Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D'Alonzo AJ, Lodge NJ, Smith MA, and Grover GJ (1997) Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res 81: 1072-1082.[Abstract/Free Full Text]

Gribble FM, Reimann F, Ashfield R, and Ashcroft FM (2000) Nucleotide modulation of pinacidil stimulation of the cloned K(ATP) channel Kir6.2/SUR2A. Mol Pharmacol 57: 1256-1261.[Abstract/Free Full Text]

Gwilt M, Henderson CG, Orme J, and Rourke JD (1992) Effects of drugs on ventricular fibrillation and ischaemic K+ loss in a model of ischaemia in perfused guinea-pig hearts in vitro. Eur J Pharmacol 220: 231-236.[Medline]

Inagaki N, Gonoi T, Clement JP, Wang CZ, Aguilar-Bryan L, Bryan J, and Seino S (1996) A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron 16: 1011-1017.[CrossRef][Medline]

Inagaki N, Gonoi T, Clement JPt, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, and Bryan J (1995) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science (Wash DC) 270: 1166-1170.[Abstract/Free Full Text]

Kantor PF, Coetzee WA, Carmeliet EE, Dennis SC, and Opie LH (1990) Reduction of ischemic K+ loss and arrhythmias in rat hearts. Effect of glibenclamide, a sulfonylurea. Circ Res 66: 478-485.[Abstract/Free Full Text]

Kersten JR, Schmeling TJ, Hettrick DA, Pagel PS, Gross GJ, and Warltier DC (1996) Mechanism of myocardial protection by isoflurane. Role of adenosine triphosphate-regulated potassium (KATP) channels. Anesthesiology 85: 794-807; discussion 727A.[CrossRef][Medline]

Liang BT and Gross GJ (1999) Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels. Circ Res 84: 1396-1400.[Abstract/Free Full Text]

Liu GS, Thornton J, Van Winkle DM, Stanley AW, Olsson RA, and Downey JM (1991) Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 84: 350-356.[Abstract/Free Full Text]

Liu Y, Sato T, O'Rourke B, and Marban E (1998) Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? Circulation 97: 2463-2469.[Abstract/Free Full Text]

Murry CE, Jennings RB, and Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124-1136.[Abstract/Free Full Text]

Nakano A, Cohen MV, and Downey JM (2000) Ischemic preconditioning: from basic mechanisms to clinical applications. Pharmacol Ther 86: 263-275.[CrossRef][Medline]

Noma A (1983) ATP-regulated K+ channels in cardiac muscle. Nature (Lond) 305: 147-148.[CrossRef][Medline]

Oldenburg O, Cohen MV, Yellon DM, and Downey JM (2002) Mitochondrial K(ATP) channels: role in cardioprotection. Cardiovasc Res 55: 429-437.[Abstract/Free Full Text]

Schultz JE and Gross GJ (2001) Opioids and cardioprotection. Pharmacol Ther 89: 123-137.[CrossRef][Medline]

Smallwood JK, Ertel PJ, and Steinberg MI (1990) Modification by glibenclamide of the electrophysiological consequences of myocardial ischaemia in dogs and rabbits. Naunyn-Schmiedeberg's Arch Pharmacol 342: 214-220.[CrossRef][Medline]

Wall TM, Sheehy R, and Hartman JC (1994) Role of bradykinin in myocardial preconditioning. J Pharmacol Exp Ther 270: 681-689.[Abstract/Free Full Text]

Wang P, Gallagher KP, Downey JM, and Cohen MV (1996) Pretreatment with endothelin-1 mimics ischemic preconditioning against infarction in isolated rabbit heart. J Mol Cell Cardiol 28: 579-588.[CrossRef][Medline]

Wolleben CD, Sanguinetti MC, and Siegl PK (1989) Influence of ATP-sensitive potassium channel modulators on ischemia-induced fibrillation in isolated rat hearts. J Mol Cell Cardiol 21: 783-788.[CrossRef][Medline]

This article has been cited by other articles:

				T. P. Flagg, B. Patton, R. Masia, C. Mansfield, A. N. Lopatin, K. A. Yamada, and C. G. Nichols Arrhythmia susceptibility and premature death in transgenic mice overexpressing both SUR1 and Kir6.2[{Delta}N30,K185Q] in the heart Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H836 - H845. [Abstract] [Full Text] [PDF]

				T. Sato, A. D. T. Costa, T. Saito, T. Ogura, H. Ishida, K. D. Garlid, and H. Nakaya Bepridil, an Antiarrhythmic Drug, Opens Mitochondrial KATP Channels, Blocks Sarcolemmal KATP Channels, and Confers Cardioprotection J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 182 - 188. [Abstract] [Full Text] [PDF]

				G. R. Ferrier and S. E. Howlett Pretreatment with Pinacidil Promotes Arrhythmias in an Isolated Tissue Model of Cardiac Ischemia and Reperfusion J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 823 - 830. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: jpet.103.060780v1 309/2/554    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fischbach, P. S. Articles by Lucchesi, B. R. Search for Related Content PubMed PubMed Citation Articles by Fischbach, P. S. Articles by Lucchesi, B. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Arrhythmia