Gandhi Manoj, Finegan Barry A, Clanachan Alexander S
Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2576-86. doi: 10.1152/ajpheart.00942.2007. Epub 2008 Apr 11.
The role of proton (H+) production from glucose metabolism in the recovery of myocardial function during postischemic reperfusion and its alteration by insulin and other metabolic modulators were examined. Rat hearts were perfused in vitro with Krebs-Henseleit solution containing palmitate (1.2 mmol/l) and glucose (11 mmol/l) under nonischemic conditions or during reperfusion following no-flow ischemia. Perfusate contained normal insulin (n-Ins, 50 mU/l), zero insulin (0-Ins), or supplemental insulin (s-Ins, 1,000 mU/l) or other metabolic modulators [dichloroacetate (DCA) at 3 mmol/l, oxfenicine at 1 mmol/l, and N6-cyclohexyladenosine (CHA) at 0.5 micromol/l]. Relative to n-Ins, 0-Ins depressed rates of glycolysis and glucose oxidation in nonischemic hearts and impaired recovery of postischemic function. Relative to n-Ins, s-Ins did not affect aerobic glucose metabolism and did not improve recovery when present during reperfusion. When present during ischemia and reperfusion, s-Ins impaired recovery. Combinations of metabolic modulators with s-Ins stimulated glucose oxidation approximately 2.5-fold in nonischemic hearts and reduced H+ production. DCA and CHA, in combination with s-Ins, improved recovery of function, but addition of oxfenicine to this combination provided no further benefit. Although DCA and CHA were each partially protective in hearts perfused with n-Ins, optimal protection was achieved with DCA + CHA; recovery of function was inversely proportional to H+ production during reperfusion. Although supplemental insulin is not beneficial, elimination of H+ production from glucose metabolism by simultaneous inhibition of glycolysis and stimulation of glucose oxidation optimizes recovery of postischemic mechanical function.
研究了葡萄糖代谢产生的质子（H+）在缺血后再灌注期间心肌功能恢复中的作用，以及胰岛素和其他代谢调节剂对其的影响。在非缺血条件下或无血流缺血后的再灌注期间，用含有棕榈酸（1.2 mmol/l）和葡萄糖（11 mmol/l）的 Krebs-Henseleit 溶液对大鼠心脏进行体外灌注。灌注液中含有正常胰岛素（n-Ins，50 mU/l）、零胰岛素（0-Ins）、补充胰岛素（s-Ins，1000 mU/l）或其他代谢调节剂[3 mmol/l 的二氯乙酸（DCA）、1 mmol/l 的奥芬尼辛和 0.5 μmol/l 的 N6-环己基腺苷（CHA）]。相对于 n-Ins，0-Ins 降低了非缺血心脏中的糖酵解和葡萄糖氧化速率，并损害了缺血后功能的恢复。相对于 n-Ins，s-Ins 不影响有氧葡萄糖代谢，并且在再灌注期间存在时不会改善恢复情况。当在缺血和再灌注期间存在时，s-Ins 会损害恢复。代谢调节剂与 s-Ins 的组合在非缺血心脏中刺激葡萄糖氧化约 2.5 倍，并减少 H+产生。DCA 和 CHA 与 s-Ins 组合可改善功能恢复，但在此组合中添加奥芬尼辛并无进一步益处。尽管 DCA 和 CHA 各自对用 n-Ins 灌注的心脏有部分保护作用，但 DCA + CHA 可实现最佳保护；功能恢复与再灌注期间的 H+产生成反比。尽管补充胰岛素无益，但通过同时抑制糖酵解和刺激葡萄糖氧化消除葡萄糖代谢产生的 H+可优化缺血后机械功能的恢复。
