Mozaffari Mahmood S, Schaffer Stephen W
Department of Oral Biology, Medical College of Georgia School of Dentistry, Augusta, Georgia, USA.
Am J Hypertens. 2008 May;21(5):570-5. doi: 10.1038/ajh.2008.25. Epub 2008 Mar 20.
The mitochondrial permeability transition (MPT) pore may serve as the end-effector of cardioprotective mechanisms, namely the mitochondrial K(ATP) channels and glycogen synthase kinase-3beta (GSK-3beta). We recently showed that augmented MPT pore induction contributes to pressure overload-induced exacerbation of infarct size. This study tests the hypotheses that (i) elevation in perfusion pressure attenuates cardioprotection associated with activation of mitochondrial KATP channels or inhibition of GSK-3beta and (ii) perfusion pressure modulates the regulation of the MPT pore by mitochondrial KATP channels and/or GSK-3beta.
Langendorff-perfused hearts were subjected to a regional ischemia-reperfusion insult at a perfusion pressure of either 80 or 160 cm H2O. The perfusion medium contained no drug, diazoxide (80 micromol/l; mitochondrial KATP channel opener), lithium chloride (LiCl, 1 mmol/l; nonselective inhibitor of GSK-3beta), SB-216763 (3 micromol/l; selective inhibitor of GSK-3beta), cyclosporine A (0.2 micromol/l; inhibitor of MPT pore induction), glibenclamide (50 micromol/l; inhibitor of KATP channels), and the combination of cyclosporine A and glibenclamide or the combination of glibenclamide and LiCl.
The increase in perfusion pressure in the absence of a drug caused larger infarcts, an effect associated with poorer recovery of function following ischemia reperfusion. Treatment with either diazoxide or cyclosporine A reduced infarct size at both perfusion pressures but in contrast to diazoxide, cyclosporine A was more protective at the higher pressure. On the other hand, LiCl and SB-216763 reduced infarct size at both pressures, with the effect more marked at the higher perfusion pressure. Glibenclamide did not affect infarct size but eliminated the cardioprotective effect of cyclosporine A while having no effect on LiCl-induced cardioprotection.
Perfusion pressure primarily affects GSK-3beta-mediated regulation of MPT pore formation in the ischemic reperfused heart.
线粒体通透性转换（MPT）孔可能是心脏保护机制的终效应器，即线粒体ATP敏感性钾（KATP）通道和糖原合酶激酶-3β（GSK-3β）。我们最近发现，增强的MPT孔诱导作用会导致压力超负荷引起的梗死面积扩大。本研究检验以下假设：（i）灌注压力升高会减弱与线粒体KATP通道激活或GSK-3β抑制相关的心脏保护作用；（ii）灌注压力通过线粒体KATP通道和/或GSK-3β调节MPT孔的调控。
采用Langendorff灌注心脏，在80或160 cm H2O的灌注压力下进行局部缺血再灌注损伤。灌注液中不含药物、二氮嗪（80 μmol/l；线粒体KATP通道开放剂）、氯化锂（LiCl，1 mmol/l；GSK-3β非选择性抑制剂）、SB-216763（3 μmol/l；GSK-3β选择性抑制剂）、环孢素A（0.2 μmol/l；MPT孔诱导抑制剂）、格列本脲（50 μmol/l；KATP通道抑制剂），以及环孢素A与格列本脲的组合或格列本脲与LiCl的组合。
在无药物情况下灌注压力升高会导致梗死面积增大，这一效应与缺血再灌注后功能恢复较差相关。在两种灌注压力下，二氮嗪或环孢素A治疗均可减小梗死面积，但与二氮嗪不同的是，环孢素A在较高压力下更具保护作用。另一方面，LiCl和SB-216763在两种压力下均可减小梗死面积，在较高灌注压力下效果更明显。格列本脲不影响梗死面积，但消除了环孢素A的心脏保护作用，而对LiCl诱导的心脏保护作用无影响。
灌注压力主要影响缺血再灌注心脏中GSK-3β介导的MPT孔形成调控。
