Short exposure to low concentrations of digitalis drugs like
ouabain protects the rat heart against
ischemia/reperfusion injury through the activation of the Na/K-
adenosine triphosphatase (
ATPase)/Src receptor complex and subsequent stimulation of key intracellular cardioprotective signals. Rat Na/K-
ATPase, however, is relatively insensitive to digitalis, and it is not known if similar results could be obtained in species with higher sensitivity. Thus, to determine whether
ouabain pretreatment protects against ischemic injury and activates the Na/K-
ATPase signaling cascade in a species with
cardiac glycoside sensitivity comparable to humans, the present study was conducted in the rabbit model. In Langendorff perfused rabbit hearts, 20-minute exposure to 500-nM
ouabain resulted in positive inotropy as evidenced by a significant increase in +dP/dt, and this increase was accompanied by the activation of several well-characterized downstream mediators of the cardiac Na/K-
ATPase receptor pathway, including Src, Akt, ERK1/2, and
protein kinase Cepsilon. A short (4 minutes) administration of a subinotropic dose of
ouabain (100 nM) followed by an 8-minute washout before 30 minutes of global
ischemia and 120 minutes of reperfusion resulted in protection against cell death, as evidenced by a significant decrease in
infarct size. These data indicate that
ouabain administration activates the Na/K-
ATPase signaling cascade and protects against ischemic injury in a species with high cardiac Na/K-
ATPase sensitivity.