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This Article Full Text Full Text (PDF) All Versions of this Article: 291/1/H152    most recent 01233.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Garlid, K. D. Articles by Santos, P. D. Search for Related Content PubMed PubMed Citation Articles by Garlid, K. D. Articles by Santos, P. D.

Inhibition of cardiac contractility by 5-hydroxydecanoate and tetraphenylphosphonium ion: a possible role of mitoK_ATP in response to inotropic stress

¹Portland State University, Portland, Oregon; ²Department of the Heart and Great Vessels "Attilio Reale," University "La Sapienza": UOC Biotechnologies Applied to Cardiovascular Diseases, Rome, Italy; ³Institut National de la Santé et de la Recherche Médicale, Athérosclérose, Pessac, France; and ⁴Université Victor Ségalen Bordeaux 2, and ⁵Centre National de la Recherche Scientifique, Université Victor Ségalen Bordeaux 2, and ⁶Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France

Submitted 21 November 2005 ; accepted in final form 29 January 2006

This study investigates the role of the mitochondrial ATP-sensitive K⁺ channel (mitoK_ATP) in response to positive inotropic stress. In Langendorff-perfused rat hearts, inotropy was induced by increasing perfusate calcium to 4 mM, by adding 80 µM ouabain or 0.25 µM dobutamine. Each of these treatments resulted in a sustained increase in rate-pressure product (RPP) of 60%. Inhibition of mitoK_ATP by perfusion of 5-hydroxydecanoate (5-HD) or tetraphenylphosphonium before induction of inotropic stress resulted in a marked attenuation of RPP. Inhibition of mitoK_ATP after induction of stress caused the inability of the heart to maintain a high-work state. In human atrial fibers, the increase in contractility induced by dobutamine was inhibited 60% by 5-HD. In permeabilized fibers from the Langendorff-perfused rat hearts, inhibition of mitoK_ATP resulted, in all cases, in an alteration of adenine nucleotide compartmentation, as reflected by a 60% decrease in the half-saturation constant for ADP [K_1/2 (ADP)]. We conclude that opening of cardiac mitoK_ATP is essential for an appropriate response to positive inotropic stress and propose that its involvement proceeds through the prevention of stress-induced decrease in mitochondrial matrix volume. These results indicate a physiological role for mitoK_ATP in inotropy and, by extension, in heart failure.

mitochondria; creatine kinase; calcium; dobutamine; ouabain

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