Hui K K, Yu J L
Department of Medicine, School of Medicine, University of California, Los Angeles 90024.
Life Sci. 1988;42(20):2037-45. doi: 10.1016/0024-3205(88)90504-8.
We have investigated the effects of clinically available calcium channel blockers (nifedipine, verapamil and diltiazem) on isoproterenol stimulated cyclic adenosine 3',5'-monophosphate (cyclic AMP) generation in intact human lymphocytes. After preincubation of various calcium antagonists with intact lymphocytes at 37 degrees C for 15 minutes, 10 microM nifedipine or verapamil partially inhibited isoproterenol induced cyclic AMP generation in the presence of cyclic AMP phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine) while they alone had no effect on cyclic AMP level at a concentration of up to 100 microM. In contrast, 10 nM-1.0 microM nifedipine, verapamil or diltiazem potentiated cyclic AMP generation induced by isoproterenol in a dose dependent manner. Similar results were observed in the time course studies of cyclic AMP generation. These effects are somewhat similar to the effect of phenothiazine, a calmodulin inhibitor, which, at 10 microM (close to IC50), also potentiated the effects of isoproterenol. In contrast, lanthanum chloride (LaCl3), an extracellular inorganic calcium antagonist, at 1.0 mM, inhibited isoproterenol induced cyclic AMP generation. The biochemical mechanisms underlying these potentiating effects are unknown. It may be partly related to the effect of calcium channel blockers (at least for nifedipine) on preventing beta 2 adrenergic receptor desensitization. This may provide a potential mechanism for the synergistic effect between calcium channel blockers and beta 2 adrenoceptor agonists on bronchial dilatation.
我们研究了临床可用的钙通道阻滞剂（硝苯地平、维拉帕米和地尔硫䓬）对异丙肾上腺素刺激完整人淋巴细胞中3',5'-环磷酸腺苷（环磷腺苷）生成的影响。在37℃下将各种钙拮抗剂与完整淋巴细胞预孵育15分钟后，10微摩尔硝苯地平或维拉帕米在存在环磷腺苷磷酸二酯酶抑制剂（3-异丁基-1-甲基黄嘌呤）的情况下部分抑制异丙肾上腺素诱导的环磷腺苷生成，而在浓度高达100微摩尔时它们单独对环磷腺苷水平没有影响。相比之下，10纳摩尔至1.0微摩尔的硝苯地平、维拉帕米或地尔硫䓬以剂量依赖方式增强异丙肾上腺素诱导的环磷腺苷生成。在环磷腺苷生成的时间进程研究中也观察到了类似结果。这些作用在某种程度上类似于钙调蛋白抑制剂吩噻嗪的作用，在10微摩尔（接近半数抑制浓度）时，吩噻嗪也增强了异丙肾上腺素的作用。相比之下，细胞外无机钙拮抗剂氯化镧（LaCl3）在1.0毫摩尔时抑制异丙肾上腺素诱导的环磷腺苷生成。这些增强作用背后的生化机制尚不清楚。这可能部分与钙通道阻滞剂（至少对于硝苯地平）防止β2肾上腺素能受体脱敏的作用有关。这可能为钙通道阻滞剂与β2肾上腺素能受体激动剂在支气管扩张方面的协同作用提供一种潜在机制。
