The development of evaluating method for oxygen wasting effects by cardiotonic agents

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This head investigator proposed and established Emax (maximal elastance) as a index of cardiac contractility and PVA as a total mechanical energy derived from cardiac contraction in fundamental physiological studies. Furthermore, VO_2, which is a product of arteriovenous oxygen content difference per beat and coronary flow has been presented to be linearly correlated with PVA.In the first year of this project, by using this Emax-PVA-VO_2 framework, we examind the effects of a cardiotonic agent, pimobendan which has a calcium sensitizing effect, on cardiac mechanoenergetics in normral hearts. In the second year of this project we tried to make acute failing heart model to examine the effects of cardiotonic agents. For experiments, we prepared a cross-circulated blood perfused excised heart from a pair of dogs. At first we obtained control Emax, PVA and VO_2 at different end-diastole volume by measuring pressure and volume. VO_2-PVA relation was linear. The reciprocal of the slope of this relation is contractile efficiency converting PVA-dependent VO_2 into total mechanical energy. PVA-independent VO_2 at PVA=0 demonstrates calcium handling energy in excitation-contraction coupling. We obtanined reasonable values in all of those parameters. Pimobendan or pentobarbital dose-dependently increased or decreased Emax, PVA and VO_2 and shifted VO_2-PVA relation upwards or downwords. Neither pimobendan nor pentobarbital changed contractile efficiency, but increased or decreased PVA-independent VO_2. The relation of PVA-independent VO_2 and Emax was linear and its slope demonstrates oxygen cost of contractility ; this cost was similar to calcium. Therefore, pimobendan and pentobarbital increased or decreased Emax without changing oxygen costs of PVA and contractily. Further studies will be done by using failing hearts model to compare with nomal hearts.