• Sebastian Vogt, Rabia Ramzan, Petra Weber, Dirk Troitzsch, Annika Rhiel, Alexander Sattler, Marc Irqsusi, Volker Ruppert, and Rainer Moosdorf.
• Cardiovascular Research Lab, Biomedical Research Center of the Philipps-University Marburg, Marburg, Germany.
• Shock. 2013 Nov 1;40(5):407-13.

PurposeThis study addresses the effect of short myocardial ischemia on inhibitory effect of ATP for mitochondrial cytochrome c oxidase (CytOx) activity in myocardium and subsequent hemodynamic alterations. The activity of CytOx is inhibited by ATP (primary substrate control). This additional mechanism was proposed to be switched off at higher mitochondrial membrane potential values in case of stress. The ATP-dependent allosteric enzyme inhibition (second respiratory control) is suggested to reduce the formation of reactive oxygen species and thus is pivotal for cytoprotection. This report addresses the possible involvement of this mechanism in case of myocardial preconditioning.MethodsRat hearts were perfused in a Langendorff system (n = 5 each group). The first two groups underwent short recurrent ischemic periods (three times 5 min) and subsequent high or low reperfusion for 40 min. Besides four control groups, hearts were exposed to an ischemia of 15 min and high flow reperfused for 30 min, in addition. Hemodynamic data were evaluated in parallel. Mitochondria were separated for the polarographic respiration measurements in the presence of ADP or ATP, respectively. Phosphorylation patterns of the CytOx subunits were studied by immunoblotting with P-Ser, P-Thr, and P-Tyr antibodies.ResultsShort recurrent episodes of ischemia result in an ATP-dependent inhibition of CytOx. Electrophoretic analysis and blotting techniques reveal different phosphorylation patterns of the enzyme. Frequent short-lasting ischemic impacts and subsequent increased coronary flow seem to be essential for this effect.ConclusionThe procedure of preconditioning is likely to be dependent on the mechanism of ATP-dependent inhibition of CytOx activity.

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