Abstract 18734: Inhibition of KCNQ Channels Provides Coronary Flow Dependent Protection against Myocardial Ischemia and Reperfusion Injury Additive to Ischemic Preconditioning
Objectives: The delayed rectifier potassium channels KCNQ (KV7) are activated under ischemic conditions and mediates hypoxic vasodilatation. We investigated the influence of KCNQ channel modulation on cardiac ischemia and reperfusion (IR) injury and its interaction with cardioprotection by ischemic preconditioning (IPC).
Methods: Using isolated, retrogradely perfused Wistar rat hearts (n=4-9) in a constant pressure controlled Langendorff setup, we evaluated the effects of the KCNQ channel inhibitors XE991 and linopirdine, and the KCNQ channel opener, flupirtine, on myocardial IR injury. Hearts were subjected to 40 min of no-flow, global ischemia and 120 min of reperfusion with and without concurrent IPC. The isolated vasomotor effects of XE991 and IPC on IR injury were evaluated by gently reperfusing hearts with reduced initial coronary flow rate at 12ml/min in a flow controlled setup. Cardioprotection was evaluated by infarct size (IS) quantification using 2,3,5-Triphenyltetrazolium chloride staining and hemodynamic measurements using a balloon tipped catheter inserted in the left ventricle.
Results: As shown in the figure, IPC and KCNQ channel inhibition by XE991 and linopirdine reduced infarct size in constant pressure perfused hearts. IPC yielded additive protection to both compounds (p<0.0001 compared to each blocker alone), while flupirtine abolished infarct size reduction by IPC. Controlled gentle reflow reduced infarct size and abolished the infarct size reduction by XE991 (p=0.77) but not by IPC (p=0.004). Similar results were obtained when cardioprotection was evaluated by postischemic hemodynamic recovery.
Conclusion: Pharmacological and mechanical reduction of myocardial blood flow during initial reperfusion yield cardioprotection additive to the protection achieved by IPC alone.
Author Disclosures: J. Johnsen: None. E.R. Hedegaard: None. J.A. Povlsen: None. N.R. Jespersen: None. J.A. Shanmuganathan: None. S.B. Kristiansen: None. U. Simonsen: None. H.E. Bøtker: Ownership Interest; Significant; Shareholder in CellAegis Inc..
- © 2014 by American Heart Association, Inc.