Williamson J R, Schaffer S W, Ford C, Safer B
Circulation. 1976 Mar;53(3 Suppl):I3-14.
The isolated perfused working rat heart preparation has been used to study the effects of respiratory acidosis on myocardial metabolism and contractilly. Hearts were perfused with 5 mM glucose and 10(-2) U/ml of insulin in order to enhance metabolsim of glucose relative to that of fatty acids. After perfusion with Krebs bicarbonate medium at pH 6.6, hearts rapidly ceased performing external work and peak left ventricular pressure fell by 75% after 5 minutes. Oxygen consumption, rate of ATP generation and overall glycolytic flux also declined rapidly. After about 2 minutes of perfusion, the fall of glycolytic flux showed a partial reversal, which was largely accounted for by increased lactate production, so that glucose oxidation decreased further. The reversal of glycoltic flux could be accounted for by partial release of H+ inhibition of phospho-fructokinase by increased tissue levels of adenosine 5'-diphosphate (ADP), adenosine monophosphate (AMP) and P1 and decreased levels of adenosine triphosphate (ATP) and creatine phosphate. The increased proportion of glucose uptake converted to lactate together with an increase of the tissue lactate/pyruvate ratio could be accounted for by inhibition of the malate-aspartate cycle combined with tissue hypoxia. Lactate accumulated in the tissue as a result of a decreased permeability of the plasma membrane to lactate. Decreased oxygen delivery to the myocardium was caused by secondary constriction of the coronary vessels. In further experiments, the coronary flow was regulated by an external pump which delivered fluid at a controlled rate into the aortic cannula above the coronary arteries, and the degree of tissue hypoxia was monitored by measuring changes of pyridine nucleotide reduction state by surface fluorescence techniques. The effects of acidosis uncomplicated by possible hypoxia were compared directly with those produced by ischemic hypoxia. The effects of acidosis under these conditions were similar to those described above, and to those produced by ischemia. From these and other data it is concluded that the effects of ischemia are caused by a lowering of the intracellular pH, which decreases the rate of energy production relative to the rate of energy demand. However, it is suggested that the primary cause of the decreased peak systolic pressure with either acidosis or ischemia is not a result of a defect of energy metabolism, but is due to alteration of the calcium cycle of the heart. Possible causes of irreversible heart failure after prolonged ischemia are discussed.
离体灌注的工作大鼠心脏标本已被用于研究呼吸性酸中毒对心肌代谢和收缩功能的影响。心脏用5 mM葡萄糖和10(-2) U/ml胰岛素灌注，以增强葡萄糖相对于脂肪酸的代谢。在pH 6.6的 Krebs碳酸氢盐培养基中灌注后，心脏迅速停止进行外部工作，5分钟后左心室峰值压力下降75%。耗氧量、ATP生成速率和整体糖酵解通量也迅速下降。灌注约2分钟后，糖酵解通量的下降出现部分逆转，这主要是由于乳酸生成增加，从而使葡萄糖氧化进一步减少。糖酵解通量的逆转可归因于组织中腺苷5'-二磷酸（ADP）、腺苷一磷酸（AMP）和P1水平升高以及三磷酸腺苷（ATP）和磷酸肌酸水平降低，导致H+对磷酸果糖激酶的抑制作用部分解除。葡萄糖摄取转化为乳酸的比例增加以及组织乳酸/丙酮酸比值升高，可能是由于苹果酸-天冬氨酸循环受抑制并伴有组织缺氧。由于质膜对乳酸的通透性降低，乳酸在组织中积累。心肌氧输送减少是由冠状动脉继发性收缩引起的。在进一步的实验中，冠状动脉血流由一个外部泵调节，该泵以可控速率将液体输送到冠状动脉上方的主动脉插管中，并通过表面荧光技术测量吡啶核苷酸还原状态的变化来监测组织缺氧程度。将单纯酸中毒而无可能缺氧情况下的影响与缺血性缺氧产生的影响直接进行比较。在这些条件下酸中毒的影响与上述情况以及缺血产生的影响相似。从这些及其他数据可以得出结论，缺血的影响是由细胞内pH降低引起的，这降低了能量产生速率相对于能量需求速率。然而，有人认为，无论是酸中毒还是缺血导致的收缩期峰值压力降低，其主要原因不是能量代谢缺陷，而是心脏钙循环的改变。讨论了长时间缺血后不可逆心力衰竭的可能原因。
