Activation of Volume Regulated Chloride Channels Protects Myocardium from Ischemia/reperfusion Damage in Second-window Ischemic Preconditioning

Activation of volume regulated chloride channels (VRCCs) has been shown to be cardioprotective in ischemic preconditioning (IPC) of isolated hearts but the underlying molecular mechanisms remain unclear. Recent independent studies support that ClC-3, a ClC voltage-gated chloride channel, may function as a key component of the VRCCs. Thus, ClC-3 knockout (Clcn3 -/- ) mice and their age-matched heterozygous (Clcn3 +/- ) and wild-type (Clcn3 +/+ ) littermates were used to test whether activation of VRCCs contributes to cardioprotection in early and/or second-window IPC. Targeted disruption of ClC-3 gene caused a decrease in the body weight but no changes in heart/body weight ratio. Telemetry ECG and echocardiography revealed no differences in ECG and cardiac function under resting conditions among all groups. Under treadmill stress (10 m/min for 10 min), the Clcn3 -/- mice had significant slower heart rate (648±12 bpm) than Clcn3 +/+ littermates (737±19 bpm, n=6, P