Inhibition of cardiac contractility by 5-hydroxydecanoate and tetraphenylphosphonium ion: a possible role of mito[K.sub.ATP] in response to inotropic stress

This study investigates the role of the mitochondrial ATP-sensitive [K.sup.+] channel (mito[K.sub.ATP]) in response to positive inotropic stress. In Langendorff-perfused rat hearts, inotropy was induced by increasing peffusate calcium to 4 mM, by adding 80 [micro]M ouabain or 0.25 [micro]M dobutamine. Each of these treatments resulted in a sustained increase in rate-pressure product (RPP) of ~60%. Inhibition of mito[K.sub.ATP] by perfusion of 5-hydroxydecanoate (5-HD) or tetraphenylphosphonium before induction of inotropic stress resulted in a marked attenuation of RPP. Inhibition of mito[K.sub.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 mito[K.sub.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.sub.1/2] (ADP)]. We conclude that opening of cardiac mito[K.sub.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 mito[K.sub.ATP] in inotropy and, by extension, in heart failure. mitochondria; creatine kinase; calcium; dobutamine; ouabain