Submitted on November 21, 2005
Accepted on January 29, 2006
INHIBITION OF CARDIAC CONTRACTILITY BY 5-HYDROXYDECANOATE AND TETRAPHENYLPHOSPHONIUM ION: A POSSIBLE ROLE OF MITOKATP IN THE RESPONSE TO INOTROPIC STRESS
Keith D Garlid1, Paolo E Puddu2, Philippe Pasdois3, Alexandre D. T. Costa1, Bertrand Beauvoit4, Anna Criniti2, Liliane Tariosse3, Philippe Diolez5, and Pierre Dos Santos6*
1 PORTLAND STATE UNIVERSITY, Portland, Oregon, USA
2 UOC BIOTECHNOLOGIES APPLIED TO CARDIOVASCULAR DISEASES, UNIVERSITY LA SAPIENZA, Rome, Italy
3 U.441, Inserm, Pessac, France
4 U.441, Inserm, Pessac, France; UNIVERSIT E VICTOR SEGALEN BORDEAUX 2, Bordeaux, France
5 UMR 5536, CNRS, Bordeaux, France
6 U.441, Inserm, Pessac, France; CENTRE HOSPITALIER UNIVERSITAIRE DE BORDEAUX, Bordeaux, France
* To whom correspondence should be addressed. E-mail: pierre.dossantos{at}wanadoo.fr.
This study investigates the role of the mitochondrial ATP-sensitive potassium channel (mitoKATP) in the 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 by adding 0.25 µM dobutamine. Each of these treatments resulted in a sustained increase in rate-pressure product of about 60%. Inhibition of mitoKATP by perfusion of 5-hydroxydecanoate (5-HD) or tetraphenylphosphonium before induction of inotropic stress, resulted in a marked attenuation of RPP. Inhibition of mitoKATP after the induction of the 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 by 60% by 5-HD. In permeabilized fibers from the Langendorff-perfused rat hearts, inhibition of mitoKATP resulted, in all cases, in an alteration of adenine nucleotide compartmentation, as reflected by a 60 % decrease in K1/2(ADP). We conclude that opening of cardiac mitoKATP 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 mitoKATP in inotropy and, by extension, in heart failure.
