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

This Article Full Text 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.

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

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.

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

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]