Greif F, Anais D, Frei L, Arbeit L, Sorroff H S
Department of Surgery, State University of New York, Stony Brook.
Isr J Med Sci. 1990 Jun;26(6):301-5.
Calcium is believed to be responsible for initiating a deleterious cascade of events that leads to irreversible cell injury during prolonged ischemia. Theoretically, the calcium-dependent cascade of events can be interrupted at three distinct points: a) by reducing calcium inflow into the cytosol using a calcium channel blocker such as verapamil, b) by increasing the mitochondrial capacity to sequester calcium using ethane-1-hydroxy-1:1-diphosphonic acid (EHDP), and c) by inhibiting the activation of the calcium-calmodulin complex using trifluoperazine (TFP). To evaluate the protective role of these agents in prolonged ischemia, 190 unilaterally nephrectomized rats underwent total occlusion of the renal artery for 90 min. One hour before surgery, all the rats received an i.p. injection of either saline or one of the drugs. Of the 190 rats, 130 were used to determine survival and optimal drug doses; the remaining 60 rats were used to determine blood urea nitrogen and serum creatinine at 40 h and 5 days after surgery. Only 33% of the rats in the control group survived for 10 days. However, 87.5% (P less than 0.005), 90% (P less than 0.005), and 60% (P less than 0.01) of the rats pretreated with verapamil, TFP and EHDP respectively survived for 10 days. No differences, however, were seen in renal function tests among the control, TFP or EHDP groups. This suggests that calcium antagonists are successful in protecting the kidney from prolonged ischemic injury despite impaired renal function tests. It may also indicate that these agents delay or prevent the ischemic cells from undergoing irreversible damage.
钙被认为是引发一系列有害事件的原因，这些事件会在长时间缺血期间导致不可逆的细胞损伤。从理论上讲，钙依赖性事件级联反应可在三个不同点被阻断：a）使用钙通道阻滞剂（如维拉帕米）减少钙流入细胞质；b）使用乙烷-1-羟基-1:1-二膦酸（EHDP）增加线粒体摄取钙的能力；c）使用三氟拉嗪（TFP）抑制钙-钙调蛋白复合物的激活。为了评估这些药物在长时间缺血中的保护作用，对190只单侧肾切除的大鼠进行了90分钟的肾动脉完全阻断。手术前一小时，所有大鼠腹腔注射生理盐水或其中一种药物。在190只大鼠中，130只用于确定存活率和最佳药物剂量；其余60只大鼠用于在手术后40小时和5天测定血尿素氮和血清肌酐。对照组中只有33%的大鼠存活了10天。然而，分别用维拉帕米、TFP和EHDP预处理的大鼠中，87.5%（P<0.005）、90%（P<0.005）和60%（P<0.01）存活了10天。然而，对照组、TFP组或EHDP组之间的肾功能测试没有差异。这表明钙拮抗剂成功地保护了肾脏免受长时间缺血损伤，尽管肾功能测试受损。这也可能表明这些药物延迟或防止了缺血细胞发生不可逆损伤。
