Chloride Channel Inhibition Blocks the Protection of Ischemic Preconditioning and Hypo-Osmotic Stress in Rabbit Ventricular Myocardium

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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 [micro sign]mol/L) or 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, 1 [micro sign]mol/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. (Circ Res. 1999;84:763-775.)

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