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

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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