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

这位首席研究员在基础生理学研究中提出并建立了Emax（最大弹性）作为心脏收缩力的指标，PVA作为心脏收缩产生的总机械能。此外，VO_2（每跳动静脉氧含量差与冠状动脉血流的乘积）与PVA呈线性相关。在这个项目的第一年，通过Emax-PVA-VO_2框架，我们检查了一种心脏强心剂，具有钙敏化作用的匹莫苯丹，对正常心脏的机械能量学的影响。在这个项目的第二年，我们尝试制作急性心力衰竭模型来检验强心剂的作用。为了实验，我们从一对狗身上准备了一个经交叉循环血液灌注的切除心脏。首先通过测量压力和容积得到不同舒张末期容积下的对照Emax、PVA和VO_2。VO_2-PVA呈线性关系。该关系斜率的倒数是将依赖于pva的VO_2转化为总机械能的收缩效率。PVA=0时不依赖于PVA的VO_2表明钙在激发-收缩耦合中的处理能量。我们得到了所有这些参数的合理值。匹莫苯丹和戊巴比妥剂量依赖性地升高或降低Emax、PVA和VO_2，并使VO_2-PVA关系升高或降低。匹莫苯丹和戊巴比妥都没有改变收缩效率，但增加或降低了pva无关的VO_2。与pva无关的VO_2与Emax呈线性关系，其斜率反映了收缩性氧成本；这个成本和钙的成本差不多。因此，在不改变PVA氧耗的情况下，匹莫苯丹和戊巴比妥均可增加或降低Emax。进一步的研究将采用衰竭心脏模型与正常心脏进行比较。

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.