© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Pharmacological preconditioning in rabbit myocardium is blocked by chloride channel inhibition
aDivision of Cardiovascular Research, Research Institute, The Hospital for Sick Children; Department of Medicine, The Toronto Hospital, Toronto, Ontario, Canada
bDivision of Pathology, The Hospital for Sick Children, Department of Medicine, The Toronto Hospital, Toronto, Ontario, Canada
cDepartment of Medicine, The Toronto Hospital, Toronto, Ontario, Canada
dDepartment of Physiology, The University of Toronto, Toronto, Ontario, Canada
diazport{at}sickkids.on.ca
* Corresponding author. Division of Cardiovascular Research, McMaster Building, Room 7019C, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. Tel.: +1-416-813-5965; fax: +1-416-813-7480
Objectives: We have recently proposed that chloride (Cl–) channels contribute to ischemic preconditioning (IPC) in the myocardium. To further evaluate this hypothesis, we investigated the role of Cl– channels in pharmacological preconditioning. Methods: Isolated rabbit cardiomyocytes and isolated buffer-perfused rabbit hearts were initially preconditioned with a 10 min exposure to either an adenosine receptor agonist [2-chloro-N6-cyclopentyladenosine (CCPA, 200 nM) and/or N6-2-(4-aminophenyl)ethyladenosine (APNEA, 1 µM)] or the PKC activator phorbol 12-myristate 13-acetate (PMA, 1 µM) followed by a 10 or 20 min washout or not preconditioned (control). Cardiomyocytes or whole hearts were then subjected to prolonged ischemic period (45 min simulated ischemia or 40 min of regional myocardial ischemia, respectively) followed by 60 min reperfusion (resuspension in oxygenated medium or release of the transient coronary occlusion, respectively). Results: Indanyloxyacetic acid 94, a selective Cl– channel inhibitor that produced substantial inhibition of the regulatory volume decrease (RVD) when given at 10 µM concentration in cultured cardiomyocytes, was administered before ischemia to block RVD through Cl– channel inhibition. CCPA, APNEA and PMA significantly (P<0.01) reduced the % of dead cardiomyocytes (by trypan blue staining) after 45 min SI/60 min SR, as compared to controls, while IAA-94 abolished this protection but did not affect PKC
translocation by IPC. We confirmed that IAA-94 blocked IPC-, APNEA- and PMA-induced protection against infarction in the isolated heart model. Conclusions: These findings support our contention that Cl– channels are downstream effectors of IPC.
KEYWORDS Hypoxia/anoxia; Ischemia; Myocytes; Preconditioning
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