CARDIOSTIMULATORY AND ANTIARRHYTHMIC ACTIVITY OF TUBULIN-BINDING AGENTS
CARDIOSTIMULATORY AND ANTIARRHYTHMIC ACTIVITY OF TUBULIN-BINDING AGENTS
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DOI：
10.1073/pnas.89.4.1256
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发表时间：
1992-02-15
影响因子：
11.1
通讯作者：
RUBIN, RW
中科院分区：
文献类型：
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作者：
LAMPIDIS, TJ;KOLONIAS, D;RUBIN, RW
从新生大鼠培养的有节奏的、自发搏动的心脏细胞，通过添加一些微管蛋白结合剂而不是它们的非微管蛋白结合类似物，立即刺激心跳加快。测试的微管蛋白结合剂包括长春花碱、长春新碱、长春花碱、长春花碱的两种类似物（S12362和S12363）、诺可达唑、秋水仙碱和鬼臼毒素。除了结合微管蛋白外，上述所有药物还能解聚微管。相反，紫杉醇，一种稳定微管的微管蛋白结合剂，不会刺激心脏细胞。此外，0.05 mu-g/ml长春花碱的立即和随后的心脏刺激被1.0 mu-g/ml紫杉醇预处理和共处理完全阻断。逆转长春碱的心脏刺激作用所需的时间明显长于诺可达唑所需的时间，这进一步暗示了这些药物在心脏活动中的微管解聚。所有测试的微管蛋白结合剂（包括紫杉醇）也能立即逆转阿霉素引起的心律失常。利用α -微管蛋白单克隆抗体，通过免疫荧光法在心肌和共培养的非肌肉细胞中观察到典型的丝状微管。用0.05 μ g/ml长春花碱处理细胞2小时后，心肌细胞呈横纹状荧光。总的来说，这些数据开启了揭示细胞骨架元素（除肌动蛋白和肌球蛋白外）与心肌收缩性之间的额外关系的可能性。他们还提出了在体外影响心脏细胞功能的另一种机制（即通过微管蛋白结合剂）。如果这些药物在体内被证明具有心脏活性，它们可能为心律失常的治疗和管理提供另一种方法。
Rhythmic, spontaneously pulsating cardiac cells cultured from newborn rats are immediately stimulated to beat faster by addition of a number of tubulin-binding agents but not by their non-tubulin-binding analogues. The tubulin-binding agents tested include vinblastine, vincristine, navel-bine, two analogs of vinblastine (S12362 and S12363), nocodazole, colchicine, and podophyllotoxin. In addition to binding tubulin, all of the above agents also depolymerize microtubules. In contrast, taxol, a tubulin-binding agent that stabilizes microtubules, does not stimulate cardiac cells. Moreover, the immediate and ensuing cardiac stimulation by vinblastine at 0.05-mu-g/ml is completely blocked by pre- and cotreatment with taxol at 1.0-mu-g/ml. The time necessary to reverse the cardio-stimulatory effect of vinblastine is significantly longer than that required for nocodazole, further implicating depolymerization of microtubules in the cardiac activity of these agents. All of the tubulin-binding agents tested (including taxol) also immediately reverse adriamycin-induced arrhythmias. By using a monoclonal antibody to alpha-tubulin, typical filamentous microtubules are visualized in cardiac muscle and cocultured non-muscle cells by immunofluorescence. When cells are treated for 2 hr with vinblastine at 0.05-mu-g/ml, fluorescence is detected in cross-striated patterns in cardiac muscle cells. Overall, these data open the possibility of uncovering an additional relationship between cytoskeletal elements (other than actin and myosin) and the contractility of cardiac muscle. They also suggest an alternative mechanism for affecting cardiac cell function in vitro (namely, by tubulin-binding agents). If these agents are shown to be cardioactive in vivo, they may provide another approach to the treatment and management of cardiac arrhythmias.