Kai Y Xu1, Eiki Takimoto, Neal S Fedarko. 1. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA. kxu002@umaryland.edu
Abstract
OBJECTIVE: We have recently identified an activation site on (Na+ + K+)-ATPase and found that binding of antibody SSA412 to this specific site of the enzyme markedly augments (Na+ + K+)-ATPase catalytic activity. Demonstration of whether activation of (Na+ + K+)-ATPase affects heart function in animal in vivo was the object of this investigation. METHODS: Male wild-type CD-1 mouse and specific antibody SSA412 were used for the study. A pressure-volume micromanometer-conductance catheter in anesthetized mouse assessed in vivo cardiac functions. RESULTS: Specific antibody SSA412 infusion in mouse shifted pressure-volume loop leftward with increased stroke volume and enhanced end-systolic elastance. Global systolic parameters such as ejection fraction and cardiac output, and load independent contractile parameters including dP/dtmax/IP, PMX/EDV, Ees, and PRSW, were all increased without any effect on relaxation following administration of SSA412. Cardiac preload indexed by EDV and afterload by ESP did not alter, suggesting that SSA412-enhanced myocardial performance is a direct cardiac effect caused by the activation of (Na+ + K+)-ATPase. CONCLUSION: Our study provides the first in vivo physiological evidence to demonstrate that activation of (Na+ + K+)-ATPase induces significant positive inotropic effect in intact animal heart. The finding may lead to new therapeutic strategies for the treatment of heart failure.
OBJECTIVE: We have recently identified an activation site on (Na+ + K+)-ATPase and found that binding of antibody SSA412 to this specific site of the enzyme markedly augments (Na+ + K+)-ATPase catalytic activity. Demonstration of whether activation of (Na+ + K+)-ATPase affects heart function in animal in vivo was the object of this investigation. METHODS: Male wild-type CD-1 mouse and specific antibody SSA412 were used for the study. A pressure-volume micromanometer-conductance catheter in anesthetized mouse assessed in vivo cardiac functions. RESULTS: Specific antibody SSA412 infusion in mouse shifted pressure-volume loop leftward with increased stroke volume and enhanced end-systolic elastance. Global systolic parameters such as ejection fraction and cardiac output, and load independent contractile parameters including dP/dtmax/IP, PMX/EDV, Ees, and PRSW, were all increased without any effect on relaxation following administration of SSA412. Cardiac preload indexed by EDV and afterload by ESP did not alter, suggesting that SSA412-enhanced myocardial performance is a direct cardiac effect caused by the activation of (Na+ + K+)-ATPase. CONCLUSION: Our study provides the first in vivo physiological evidence to demonstrate that activation of (Na+ + K+)-ATPase induces significant positive inotropic effect in intact animal heart. The finding may lead to new therapeutic strategies for the treatment of heart failure.
Authors: Juan Carlos Almagro; Gary L Gilliland; Felix Breden; Jamie K Scott; Devin Sok; Matthias Pauthner; Janice M Reichert; Gustavo Helguera; Raiees Andrabi; Robert Mabry; Mathieu Bléry; James E Voss; Juha Laurén; Lubna Abuqayyas; Stefan Barghorn; Eshel Ben-Jacob; James E Crowe; James S Huston; Stephen Albert Johnston; Eric Krauland; Fridtjof Lund-Johansen; Wayne A Marasco; Paul W H I Parren; Kai Y Xu Journal: MAbs Date: 2014-03-03 Impact factor: 5.857
Authors: Kai Y Xu; Weizhong Zhu; Ling Chen; Christopher DeFilippi; Jin Zhang; Rui-Ping Xiao Journal: Biochem Biophys Res Commun Date: 2011-02-15 Impact factor: 3.575
Authors: Dong I Lee; Michael G Klein; Weizhong Zhu; Rui-Ping Xiao; Volodymyr Gerzanich; Kai Y Xu Journal: Mol Pharmacol Date: 2009-01-02 Impact factor: 4.436