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Levosimendan is a calcium sensitizer developed for the treatment of heart failure. It increases contractile force by enhancing the sensitivity of myofilaments to calcium. Besides this sensitizing effect, the drug has also been reported to show some inhibitory action on phosphodiesterase 3 (PDE3). The inotropic effects of levosimendan have been studied on guinea pig paced perfused hearts by using modular control analysis (MoCA) (Diolez P, Deschodt-Arsac V, Raffard G, Simon C, Santos PD, Thiandiere E, Arsac L, Franconi JM. Am J Physiol Regul Integr Comp Physiol 293: R13-R19, 2007.), an integrative approach of heart energetics using noninvasive [sup.31]p NMR. The aim was to evaluate quantitatively the respective effects of this drug on energy supply and demand modules. Under our experimental conditions, 0.7 [micro]M levosimendan induced a 45% increase in paced heart output associated with a 7% decrease in phosphocreatine and a negligible increase in oxygen consumption. Because MoCA allows in situ study of the internal regulations in intact beating heart energetics, it was applied to describe quantitatively by which routes levosimendan exerts its inotropic action. MoCA demonstrated the absence of any significant effect of the drug on the supply module, which is responsible for the lower increase in oxygen consumption, compared with epinephrine, which increases the ratio between myocardial oxygen consumption and cardiac contraction. This result evidences that, under our conditions, a possible effect of levosimendan on PDE3 activity and/or intracellular calcium remains very low on mitochondrial activity and insignificant on integrated cardiac energetics. Thus, levosimendan inotropic effect on guinea pig heart depends almost entirely on the calcium[-sensitizing properties leading to myofilament activation and the concomitant activation of energy supply by the decrease in PCr, therefore improving energetic efficiency of contraction. systems biology; modular control analysis; calcium sensitizer; mitochondria; phosphate-31 magnetic resonance spectroscopy; oxygen consumption doi: 10.1152/ajpregu.00184.2010.

Modular control analysis (MoCA; Diolez P, Deschodt-Arsac V, Raffard G, Simon C, Santos PD, Thiaudiere E, Arsac L, Franconi JM. Am J Physiol Regul Integr Comp Physiol 293: R13-R19, 2007) was applied here on perfused hearts to describe the modifications of the regulation of heart energetics induced in mice exposed to 3-wk chronic hypoxia. MoCA combines [sup.31]P-NMR spectroscopy and modular (top down) control analysis to describe the integrative regulation of energy metabolism in the intact beating heart, on the basis of two modules [ATP/phosphocreatine (PCr) production and ATP/PCr consumption] connected by the energetic intermediates. In contrast with previous results in rat heart, in which all control of contraction was on ATP demand, mouse heart energetics presented a shared control of contraction between ATP/PCr-producing and -consuming modules. In chronic hypoxic mice, the decrease in heart contractile activity and PCr-to-ATP ratio was surprisingly associated with an important and significant higher response of ATP/PCr production (elasticity) to PCr changes compared with control hearts (-10.4 vs. -2.46). By contrast, no changes were observed in ATP/PCr consumption since comparable elasticities were observed. Since elasticities determine the regulation of energetics of heart contraction, the present results show that this new parameter may be used to uncover the origin of the observed dysfunctions under chronic hypoxia conditions. Considering the decrease in mitochondrial content reported after exposure to chronic hypoxia, it appears that the improvement of ATP/PCr production response to ATP demand may be viewed as a positive adaptative mechanism. It now appears crucial to understand the very processes responsible for ATP/PCr producer elasticity toward the energetic intermediates, as well as their regulation. perfused mouse heart; systems biology; [sup.31]P-labeled magnetic resonance spectroscopy

Heart contraction is characterized by the absence of changes in energetic intermediates in response to a large increase of activity. Until now no experimental approach could address this question concerning the intact beating heart. [Ca.sup.2+] plays a crucial role in the excitation-contraction coupling, and in vitro studies have evidenced that [Ca.sup.2+] may also directly activate mitochondrial oxidative phosphorylation. We applied our new in situ modular control and regulation analysis on isolated beating rat heart perfused under two different calcium concentrations with pyruvate or glucose as the substrate. Modular control analysis demonstrated experimentally that, although control by energy production was slightly higher under glucose conditions compared with pyruvate, most of the control of heart contraction resides in energy utilization. This behavior is the direct consequence of the high sensitivity (elasticity) of the energy producer processes to ATP utilization. Interestingly, the increase in heart metabolic rate by [Ca.sup.2+] did not significantly change the pattern of control distribution. The regulation analysis performed under the two calcium conditions demonstrated a balanced activation of myofibrils ATPases, and mitochondrial ATP synthesis in response to [Ca.sup.2+] increase. This first study demonstrates in situ the hypothesis that the energetic adequation in heart contraction is mediated by a parallel activation of both processes of energy production and utilization by [Ca.sup.2+]. The results presented here show that modular control and regulation analyses allow in situ study of internal regulations in intact beating heart energetics and function and may now be applied to heart dysfunctions and therapeutic effects. rat perfused heart; [sup.31]P-labeled magnetic resonance spectroscopy; calcium signaling; metabolic control analysis; systems biology doi:10.1152/ajpregu.00189.2007

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