Schaffer S W, Burton K P, Jones H P, Oei H H
Am J Physiol. 1983 Mar;244(3):H328-34. doi: 10.1152/ajpheart.1983.244.3.H328.
The effect of several phenothiazines on the extent of cellular damage resulting from the calcium paradox was examined. Hearts treated with trifluoperazine, a potent calmodulin inhibitor, exhibited less cellular damage than untreated myocardium as reflected by light microscopy, high-energy phosphate content and the loss of protein and creatine phosphokinase into the perfusate. A dose response of this effect revealed a maximal response at about 1 microM trifluoperazine, a concentration which lies well within the range generally attributed to calmodulin inhibition. Several other lines of evidence were also obtained suggesting a possible role for calmodulin in calcium-overload induced necrosis. First, the phenothiazines had little influence on membrane changes believed responsible for altered calcium permeability. Second, trifluoperazine was without major effect unless included in the reperfusion buffer, indicating that the drug is only effective during the phase associated with calcium overload. Finally, less protection was afforded hearts exposed to phenothiazines such as chlorpromazine and promethazine, which are weaker inhibitors of calmodulin, than those treated with the potent inhibitor trifluoperazine. While other interpretations are possible, these studies are consistent with a role for calmodulin in calcium overload-induced heart failure.
研究了几种吩噻嗪对钙反常所致细胞损伤程度的影响。用强效钙调蛋白抑制剂三氟拉嗪处理的心脏，通过光学显微镜、高能磷酸含量以及蛋白质和肌酸磷酸激酶向灌注液中的流失情况反映出，其细胞损伤程度比未处理的心肌轻。这种效应的剂量反应显示，在约1微摩尔三氟拉嗪时出现最大反应，该浓度处于通常认为与钙调蛋白抑制作用相关的范围内。还获得了其他几条证据，提示钙调蛋白在钙超载诱导的坏死中可能发挥作用。首先，吩噻嗪对被认为是钙通透性改变原因的膜变化影响很小。其次，三氟拉嗪没有主要作用，除非包含在再灌注缓冲液中，这表明该药物仅在与钙超载相关的阶段有效。最后，与用强效抑制剂三氟拉嗪处理的心脏相比，暴露于氯丙嗪和异丙嗪等钙调蛋白较弱抑制剂的心脏受到的保护较少。虽然可能有其他解释，但这些研究与钙调蛋白在钙超载诱导的心力衰竭中的作用是一致的。
