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

药物对基础疾病（糖尿病）心脏低灌注损伤和再灌注损伤的机制及影响

基本信息

批准号：
04670125
负责人：
HIGUCHI Makie
金额：
$ 0.26万
依托单位：
University of the Ryukyus
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

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

研究了去甲肾上腺素（NE）低灌注对离体非糖尿病和链脲霉素-糖尿病大鼠心脏收缩功能障碍与心肌能量代谢异常的相关性，以及体外药物对心肌功能障碍的影响。(1)低血流时NE更明显加重糖尿病心脏低灌注损伤，同时β肾上腺素受体介导的心内膜下Ca^<2+>含量升高。(2)糖尿病心脏更易发生NE引起的血流减少，易出现左心室（LV）僵硬度增加和组织能量代谢异常，尤其是心内膜下。(3)两组左室僵硬度的增加与心内膜下ATP消耗和乳酸升高密切相关，但糖尿病心脏的临界ATP水平明显较高，临界乳酸水平较低。因此，总ATP下降速率本身并不能解释糖尿病与非糖尿病心脏左室僵硬度的差异。(4)糖原含量随糖尿病病程的延长而增加。糖尿病心脏中糖原含量明显升高可能导致低灌注NE时左室僵硬度增加的延迟开始，尽管损伤程度最终取决于糖尿病的持续时间。(5)离体胰岛素对低灌注合并NE损伤的有益作用在糖尿病心脏中更为明显，但在高灌注葡萄糖下作用减弱，可能受组织乳酸水平的影响。(6)外源性丙酮酸还能改善糖尿病心脏NE损伤后的低灌注。二氯乙酸（一种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)体外抗糖尿病药物格列本脲通过抑制K^+通道，加重糖尿病心脏低灌注伴NE损伤。(8)其他生理活性物质对NE损伤低灌注和局部心肌血流分布的影响仍在研究中。在分离的6周糖尿病主动脉中，kcl收缩减弱，但肾上腺素受体介导的反应没有改变。少