Koike A, Akita T, Hotta Y, Takeya K, Kodama I, Murase M, Abe T, Toyama J
Department of Thoracic Surgery, School of Medicine, Nagoya University, Japan.
J Thorac Cardiovasc Surg. 1996 Sep;112(3):765-75. doi: 10.1016/S0022-5223(96)70063-6.
The effects of 5-(N,N-dimethyl)amiloride, a potent and specific Na(+)-H+ exchange inhibitor, were investigated in isolated perfused rabbit hearts subjected to ischemia and reperfusion. Phosphorus 31-nuclear magnetic resonance spectroscopy was used to monitor intracellular pH, creatine phosphate, beta-adenosine triphosphate, and inorganic phosphate. After cardioplegic arrest with St. Thomas' Hospital solution, normothermic (37 degrees C) global ischemia was induced for 45 minutes, and the hearts were reperfused for 50 minutes. Dimethyl amiloride at 10 mumol/L, which has minimal inotropic and chronotropic effects on the nonischemic heart, was added to the cardioplegic solution. Treatment with dimethyl amiloride reduced the elevation of left ventricular end-diastolic pressure during and after the ischemia and improved the postischemic recovery of developed pressure from 76% +/- 3.2% at 30 minutes of reperfusion in control hearts (n = 6) up to 99% +/- 1.9% in hearts treated with dimethyl amiloride (n = 8). Dimethyl amiloride did not affect the decline in intracellular pH during ischemia for up to 30 minutes but enhanced the intracellular acidosis thereafter. The intracellular pH at the end of ischemia was 6.21 +/- 0.05 in control hearts compared with 5.24 +/- 0.17 in hearts treated with dimethyl amiloride (p < 0.05). During reperfusion, intracellular pH of hearts treated with dimethyl amiloride was less than control for 5 minutes, but subsequent recovery of intracellular pH was similar to control. Treatment with dimethyl amiloride did not affect creatine phosphate breakdown, inorganic phosphate accumulation, and beta-adenosine triphosphate depletion during 45 minutes of ischemia. The creatine phosphate resynthesis and inorganic phosphate reduction during reperfusion were also unaffected. These findings suggest that Na(+)-H+ exchange plays an important role not only during reperfusion but also during ischemia for the development of postischemic cardiac dysfunction most likely by inducing primary Na+ and secondary Ca2+ overload. Specific Na(+)-H+ exchange inhibitors like dimethyl amiloride would have a potential therapeutic profile in cardiac surgery, especially if added before ischemia.
研究了强效特异性Na(+)-H+交换抑制剂5-(N,N-二甲基)氨氯吡脒对离体灌注兔心脏缺血再灌注的影响。采用磷31核磁共振波谱法监测细胞内pH值、磷酸肌酸、β-三磷酸腺苷和无机磷酸盐。用圣托马斯医院溶液进行心脏停搏后，诱导常温（37℃）全心缺血45分钟，然后心脏再灌注50分钟。将对非缺血心脏具有最小变力性和变时性作用的10μmol/L二甲基氨氯吡脒添加到心脏停搏液中。二甲基氨氯吡脒治疗可降低缺血期间及缺血后左心室舒张末期压力的升高，并改善缺血后心室内压的恢复情况：对照组心脏（n = 6）在再灌注30分钟时为76%±3.2%，而用二甲基氨氯吡脒治疗的心脏（n = 8）可达99%±1.9%。二甲基氨氯吡脒在长达30分钟的缺血期间不影响细胞内pH值的下降，但在此后会加剧细胞内酸中毒。缺血结束时，对照组心脏的细胞内pH值为6.21±0.05，而用二甲基氨氯吡脒治疗的心脏为5.24±0.17（p < 0.05）。在再灌注期间，用二甲基氨氯吡脒治疗的心脏的细胞内pH值在5分钟内低于对照组，但随后细胞内pH值的恢复与对照组相似。二甲基氨氯吡脒治疗在45分钟缺血期间不影响磷酸肌酸分解、无机磷酸盐积累和β-三磷酸腺苷消耗。再灌注期间磷酸肌酸的再合成和无机磷酸盐的减少也未受影响。这些发现表明，Na(+)-H+交换不仅在再灌注期间而且在缺血期间对缺血后心脏功能障碍的发生起着重要作用；最可能的机制是诱导原发性Na+和继发性Ca2+超载。像二甲基氨氯吡脒这样的特异性Na(+)-H+交换抑制剂在心脏手术中可能具有潜在的治疗作用，尤其是在缺血前添加时。
