Original ArticlePreconditioning by Subinotropic Doses of Ouabain in the Langendorff perfused Rabbit HeartMorgan, Eric E PhD*; Li, Zhichuan PhD*; Stebal, Cory PhD*; Belliard, Aude PhD*; Tennyson, Glen BSc*; Salari, Bijan BSc*; Garlid, Keith D PhD†; Pierre, Sandrine V PhD*Author Information From the *Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, OH; and †Department of Biology, Portland State University, Portland, Oregon, OR. Received for publication October 5, 2009; accepted December 7, 2009. Supported by National Heart, Lung, and Blood Institute Grant HL-36573. The authors report no conflicts of interest. Reprints: Sandrine Pierre, PhD, Department of Physiology and Pharmacology, College of Medicine, University of Toledo, 3035 Arlington Avenue, Toledo, OH 43614-5804 (e-mail: [email protected]). Journal of Cardiovascular Pharmacology: March 2010 - Volume 55 - Issue 3 - p 234-239 doi: 10.1097/FJC.0b013e3181ce5e14 Buy Metrics Abstract 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 Cε. 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. © 2010 Lippincott Williams & Wilkins, Inc.