Pre- and Post-conditioning by Cardiac Glycosides in the Mouse Heart.

Ouabain preconditioning (OPC) initiated by low concentrations of the cardiac glycoside (CG) ouabain binding to Na/K-ATPase is relayed by a unique intracellular signaling and protects cardiac myocytes against ischemia/reperfusion (IR) injury. To explore more clinically applicable protocols based on CG properties, we tested whether the FDA-approved CG digoxin could trigger cardioprotective effects comparable to those of ouabain using PC and PostC protocols in the Langendorff-perfused mouse heart subjected to global ischemia and reperfusion. Ouabain or digoxin at 10 μmol/L inhibited Na/K-ATPase activity by about 30% and activated PKCε translocation by about 50%. Digoxin-induced preconditioning (DigPC), initiated by a transient exposure prior to 40 min of ischemia, was as effective as OPC as suggested by the recovery of left ventricle developed pressure (LVDP), end-diastolic pressure (EDP) and cardiac Na/K-ATPase activity after 30 min of reperfusion. DigPC also significantly decreased LDH release and reduced infarct size, comparable to OPC. PostC protocols consisting of a single bolus injection of 100 nmoles of ouabain or digoxin in the coronary tree at the beginning of reperfusion both improved significantly the recovery of LVDP and decreased LDH release, demonstrating a functional and structural protection comparable to the one provided by OPC. Given the unique signaling triggered by OPC, these results suggest that DigPostC could be considered for patients with risk factors and/or concurrent treatments that may limit effectiveness of Ischemic PostC.