The mechanism and effect of drug on hypoperfusion injury and reperfusion injury in the hearts with underlying disease (diabetes)

在离体非糖尿病和链脲佐菌素-糖尿病大鼠心脏中，研究了去甲肾上腺素（NE）低灌注时收缩功能障碍与局部心肌能量代谢异常的相关性，以及离体药物对这些功能障碍的影响。(1)NE低流量时，β受体介导的内皮细胞下Ca^2+含量的增加加重了糖尿病心脏的低灌注损伤。（2）糖尿病心脏易受NE的影响，易出现左室僵硬度增加和组织能量代谢异常，尤其是内膜下组织。（3）两组左室僵硬度的增加均与内膜下ATP耗竭和乳酸升高密切相关，但糖尿病组临界ATP水平明显高于对照组，临界乳酸水平明显低于对照组。因此，总ATP降低率本身不能解释左室收缩压的差异。 ...更多信息 糖尿病和非糖尿病心脏之间的差异。（4）糖原含量随糖尿病病程的延长而增加。糖尿病心脏中显著高的糖原含量可能有助于NE低灌注期间LV僵硬度增加的延迟开始，尽管损伤的程度最终取决于糖尿病的持续时间。（5）离体胰岛素对糖尿病心肌NE损伤后低灌注的保护作用更明显，但在高葡萄糖灌流时其保护作用减弱，可能与组织乳酸水平有关。（6）外源性丙酮酸对NE损伤的糖尿病心肌低灌注也有改善作用。二氯乙酸（丙酮酸脱氢酶激活剂）既不影响损伤，也不影响丙酮酸对损伤的影响。(7)Ex体内抗糖尿病药物格列本脲可通过抑制K^+通道而加重糖尿病心肌NE损伤的低灌注。（8）其他生理活性物质对NE损伤后低灌注和局部心肌血流分布的影响仍在研究中。在离体6周的糖尿病主动脉，KCl收缩减弱，但肾上腺素受体介导的反应没有改变。少

Correlation of contractile dysfunction and abnormal regional myocardial energy metabolism, and the effect of ex vivo drugs on the dysfuctions were investigated during hypoperfusion with norepinephrine (NE) in isolated non-diabetic and streptozotocin-diabetic rat hearts.(1)NE during low flow aggravated the hypoperfusion injury more markedly in diabetic hearts together with beta adrenoceptor-mediated increase in subendocardial Ca^<2+> content.(2)Diabetic hearts were more susceptible to flow reduction with NE and easily suffered from an increase in stiffness of the left ventricle (LV) and abnormal tissue energy metabolism, particularly in the subendocardium.(3)The increase in LV stiffness correlated closely with the subendocardial ATP depletion and lactate increase in both groups, the critical ATP level, however, was significantly higher in diabetic hearts and critical lactate level was lower. Therefore, the rate of decrease of total ATP itself cannot explain the difference in the LV stif … More fness between diabetic and non-diabetic hearts.(4)Glycogen content increased depending on the duration of diabetes. Markedly high glycogen content in diabetic hearts probably contributes to delayd start of LV stiffness increase during hypoperfusion with NE, though degree of the injury eventually depended on the duration of diabetes.(5)The beneficial effect of ex vivo insulin on the hypoperfusion with NE injury was more marked in diabetic hearts, but the effect reduced under high perfusate glucose and is probably influenced by the tissue lactate level.(6)Exogenous pyruvate also improved the hypoperfusion with NE injury in diabetic hearts. Dichloroacetate (a pyruvate dehydrogenase activator) affected neither the injury nor the effects of pyruvate on the injury.(7)Ex vivo glyburide (an anti-diabetic drug) aggravated the hypoperfusion with NE injury in diabetic hearts owing to the K^+ channel inhibition.(8)Effects of other physiologically active substances on the hypoperfusion with NE injury and a distribution of regional myocardial flow are still examining. In the isolate 6 week-diabetic aorta, KCl-contraction was attenuated, but the adrenoceptors-mediated responses were not changed. Less