© 1999 American Heart Association, Inc.
Original Contribution |
Chloride Channel Inhibition Blocks the Protection of Ischemic Preconditioning and Hypo-Osmotic Stress in Rabbit Ventricular Myocardium
From the Divisions of Cardiovascular Research and Pathology (R.J.D., G.D.M., M.K.F., G.J.W.), Research Institute, The Hospital for Sick Children; Division of Cardiovascular Surgery (G.J.W.) and Department of Medicine (P.H.B.), The Toronto Hospital; and Department of Physiology (P.H.B., G.J.W.), Department of Pathobiology and Laboratory Medicine (G.J.W.), Department of Surgery (G.J.W.), and Institute of Medical Science (V.A.L., G.J.W.), The University of Toronto, Toronto, Ontario, Canada.
Correspondence to Dr Gregory J. Wilson, Cardiovascular Labs, Rm CCRW1-885, The Toronto Hospital, General Division, 200 Elizabeth St, Toronto, Ontario, Canada, M5G 2C4. E-mail diazport{at}sickkids.on.ca
Abstract—The objective of this study was to examine the role of chloride (Cl–) channels in the myocardial protection of ischemic preconditioning (IP). Isolated rabbit ventricular myocytes were preconditioned with 10-minute simulated ischemia (SI) and 20-minute simulated reperfusion (SR) or not preconditioned (control). The myocytes then received 180-minute SI or 45-minute SI/120-minute SR. Indanyloxyacetic acid 94 (IAA-94, 10 µmol/L) or 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, 1 µmol/L) was administered before IP or before SI or SI/SR to inhibit Cl– channels. Electrophysiological studies indicate that these drugs, at the concentrations used, selectively abolished Cl– currents activated under hypo-osmotic conditions (215 versus 290 mOsm). IP significantly (P<0.001) reduced the percentage of dead myocytes after 60-minute (30.8±1.3%, mean±SEM), 90-minute (35.3±1.3%), and 120-minute (39.2±1.7%) SI compared with controls (44.7±1.6%, 54.5±1.3%, and 58.9±1.8%, respectively) and after 45-minute SI/120-minute SR (36.3±0.6%) compared with control (56.6±2.2%). Hypo-osmotic stress also produced protection similar to IP. IAA-94 or NPPB abolished the protection of both IP and hypo-osmotic stress. In buffer-perfused rabbit hearts preconditioned with three 5-minute ischemia/10-minute reperfusion cycles given before the 40-minute long ischemia and 60-minute reperfusion, IP significantly (P<0.0001) reduced infarct size (IP+vehicle, 4.7±0.9%, versus control+vehicle, 26.6±3.3%; mean±SEM). Again, IAA-94 or NPPB abolished the protection of IP. Our results implicate Cl– channels in the IP protection of the myocardium against ischemic/reperfusion injury and demonstrate that hypo-osmotic stress is capable of preconditioning cardiomyocytes.
Key Words: ischemic preconditioning • hypo-osmotic stress • chloride channel • myocardial infarction • cardiomyocyte
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