McPherson C D, Pierce G N, Cole W C
Department of Physiology, St. Boniface Research Centre, University of Manitoba, Winnipeg, Canada.
Am J Physiol. 1993 Nov;265(5 Pt 2):H1809-18. doi: 10.1152/ajpheart.1993.265.5.H1809.
We previously demonstrated that ATP-sensitive K+ channels (KATP) protect the guinea pig myocardium against ischemia-reperfusion injury (Cole et al., Circ. Res. 69: 571-581, 1991), but the cellular alterations leading to ischemic injury affected by KATP remain to be defined. This study investigates the relationship between activation of KATP and preservation of high-energy phosphates during global no-flow ischemia in arterially perfused guinea pig right ventricular walls. Electrical and mechanical activity were recorded via intracellular microelectrodes and a force transducer. Glibenclamide (10 and 50 microM) and pinacidil (10 microM) were used to modulate KATP. ATP and creatine phosphate (CP) levels were determined at the end of no-flow ischemia by enzymatic analysis. Preparations were subjected to 1) 20 min no-flow +/- glibenclamide (10 or 50 microM), 2) 30 min no-flow +/- pinacidil (10 microM) or pinacidil (10 microM) and glibenclamide (50 microM), or 3) 40 or 50 min of control perfusion before rapid freezing in liquid nitrogen. Pinacidil (10 microM) enhanced ischemic shortening of action potential duration (APD) and early contractile failure, prevented ischemic contracture, and inhibited high-energy phosphate depletion during ischemia. Glibenclamide (50 microM) inhibited the effects of pinacidil (10 microM) on electromechanical function and preservation of ATP and CP. Glibenclamide (10 microM) alone inhibited the early decline in APD and produced earlier ischemic contracture but did not enhance ATP or CP depletion compared with untreated tissues during 20 min of no-flow. Glibenclamide (50 microM) produced a greater inhibition of APD shortening in early ischemia, further decreased the latency to ischemic contracture, and caused enhanced ischemic depletion of ATP. The data indicate the changes in electrical activity induced by KATP indirectly preserve high-energy phosphates and reduce injury associated with ischemia. However, the data also suggest the possible presence of additional mechanisms for cardioprotection by KATP.
我们先前已证明，ATP敏感性钾通道（KATP）可保护豚鼠心肌免受缺血再灌注损伤（Cole等人，《循环研究》69: 571 - 581, 1991），但KATP影响缺血性损伤的细胞改变仍有待明确。本研究探讨了在动脉灌注的豚鼠右心室壁全心无复流缺血期间，KATP激活与高能磷酸盐保存之间的关系。通过细胞内微电极和力传感器记录电活动和机械活动。使用格列本脲（10和50微摩尔）和匹那地尔（10微摩尔）来调节KATP。在无复流缺血结束时，通过酶分析测定ATP和磷酸肌酸（CP）水平。将标本进行以下处理：1）20分钟无复流±格列本脲（10或50微摩尔），2）30分钟无复流±匹那地尔（10微摩尔）或匹那地尔（10微摩尔）加格列本脲（50微摩尔），或3）在液氮中快速冷冻前进行40或50分钟的对照灌注。匹那地尔（10微摩尔）增强了缺血时动作电位时程（APD）的缩短和早期收缩功能衰竭，预防了缺血性挛缩，并抑制了缺血期间高能磷酸盐的耗竭。格列本脲（50微摩尔）抑制了匹那地尔（10微摩尔）对电机械功能以及ATP和CP保存的作用。单独使用格列本脲（10微摩尔）可抑制APD的早期下降并导致更早的缺血性挛缩，但与未处理的组织相比，在20分钟无复流期间并未增强ATP或CP的耗竭。格列本脲（50微摩尔）在早期缺血时对APD缩短的抑制作用更大，进一步缩短了缺血性挛缩的潜伏期，并导致ATP的缺血性耗竭增强。数据表明，KATP诱导的电活动变化间接保存了高能磷酸盐并减少了与缺血相关的损伤。然而，数据也提示KATP可能存在其他心脏保护机制。
