Enhanced cell volume regulation: a key protective mechanism of ischemic preconditioning in rabbit ventricular myocytes

Remote Ischemic Preconditioning Cardio-protection via Enhanced Cell Volume Regulation Requires Activation of Swelling-Activated Chloride (Icl- Swell) Channels

“…Using viral transfection of cardiomyocytes to overexpress dominant negative Kir 2.1 and 2.2 components in the IK1 channel we have demonstrated its essential role in IPC. Also, we have determined that ion channels which remove Cl-from cardiomyocytes are necessary for cell volume control under normoxic conditions and that IPC causes a striking reduction in cardiomyocyte swelling under conditions of simulated ischemia [15]. Our findings further support that cell volume dynamics play an important role in the transition from reversible to irreversible I/R cardiomyocyte injury.…”

“…We have demonstrated that pan chloride channel inhibition blocked the protection of IPC against I/R necrosis in both Langendorff perfused hearts and isolated ventricular myocytes [11]. Furthermore, we have determined that the osmotic equivalent for IPC protection in cultured cardiomyocytes is 50-60 mOsm [15] and by quantitative fluorescence imaging of Cl-in the same model observed that IPC causes a net Cl -efflux of ~30 mOsm [10]. To achieve charge balance across the sarcolemma an osmotic load of ~60mOsm should also require an efflux of about 30 mM of positive ions of which K + are a component.…”

“…However, we have been particularly drawn to the swell-activated Cl-channel because of our previous work showing the importance of cardiomyocyte swelling in cardioprotection by classic, local ischemic preconditioning [14,15]. It is known that ClC-3 most likely underlies swell-activated Cl-channel activity.…”

“…Changes in cell volume at peak swelling between (HS time=8 to 12 min) and at the end of 30-minute HS were measured using a method we have previously described [14,15].…”

Molecular Basis of Cardioprotection

“…406 IPC also attenuates the intracellular volume load which is associated with sodium and calcium overload. 407 The role of chloride channel activation in such attenuation of intracellular edema is contentious. 408,409 Potassium channels may also be involved in cell volume control during IPC to maintain electroneutrality along with chloride efflux.…”