Janssen L J, Wattie J
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
J Pharmacol Exp Ther. 1996 Nov;279(2):813-21.
Cyclopiazonic acid (selective blocker of the internal Ca+2 pump) evoked tonic contraction in canine bronchial smooth muscle (BSM) and tracheal smooth muscle. This contraction was biphasic, including an initial component that was relatively insensitive to blockade of Ca+2 influx (e.g., removal of external Ca+2; nifedipine; hyperpolarization using lemakalim) followed by a component that was sensitive to all such interventions. In BSM, but not in tracheal smooth muscle, electrical field stimulation (EFS) evoked relaxations that were not affected by interventions designed to prevent release of autacoids from nerve endings or the epithelium, Na+/Ca+2 exchange or Ca(+2)-ATPase activities (internal or plasmalemmal). EFS evoked little or no relaxant response in carbachol-precontracted BSM in the presence of propranolol. After Ca+2 was replaced with Sr+2, however, carbachol evoked comparable contraction after which EFS evoked non-neurogenic relaxations. We found that the EFS-evoked relaxations were abolished by TEA or high KCI, were reduced significantly by charydotoxin or quinine, were reduced partially by ouabain and were unaffected by removal of external K+, by apamin or by glybenclamide. In addition, the relaxations were reduced significantly by the free radical scavenger N-acetylcysteine, were mimicked by H2O2 but were unaffected by superoxide dismutase or catalase. These observations suggest that the cyclopiazonic acid-evoked contraction involves pharmacomechanical coupling mechanisms (i.e., Ca(+2)-release) initially, followed by electromechanical coupling (i.e., voltage-dependent Ca+2 influx). After depletion of the internal Ca+2 store (e.g., by cyclopiazonic acid or Sr+2), EFS is able to evoke in BSM (but not in tracheal smooth muscle) relaxations that seem to involve opening of K+ channels (including those of the large-conductance Ca(+2)-dependent type) by EFS-liberated free radicals.
环匹阿尼酸（内质网钙泵的选择性阻滞剂）可引起犬支气管平滑肌（BSM）和气管平滑肌的强直性收缩。这种收缩是双相的，包括一个初始成分，该成分对钙内流的阻断相对不敏感（例如，去除细胞外钙；硝苯地平；使用雷马卡林进行超极化），随后是一个对所有此类干预敏感的成分。在BSM中，而非气管平滑肌中，电场刺激（EFS）可引起舒张，这种舒张不受旨在阻止自分泌物质从神经末梢或上皮释放、钠/钙交换或钙（+2）-ATP酶活性（内质网或质膜）的干预影响。在普萘洛尔存在的情况下，EFS在卡巴胆碱预收缩的BSM中引起的舒张反应很小或没有。然而，在用锶+2替代钙+2后，卡巴胆碱引起类似的收缩，之后EFS引起非神经源性舒张。我们发现，EFS引起的舒张可被TEA或高钾氯酸盐消除，可被蜂毒明肽或奎宁显著降低，可被哇巴因部分降低，且不受去除细胞外钾、阿帕明或格列本脲的影响。此外，自由基清除剂N-乙酰半胱氨酸可显著降低这种舒张，H2O2可模拟这种舒张，但超氧化物歧化酶或过氧化氢酶对其无影响。这些观察结果表明，环匹阿尼酸引起的收缩最初涉及药理机械偶联机制（即钙释放），随后是机电偶联（即电压依赖性钙内流）。在内质网钙储存耗尽后（例如，通过环匹阿尼酸或锶+2），EFS能够在BSM中（而非气管平滑肌中）引起舒张，这种舒张似乎涉及EFS释放的自由基打开钾通道（包括大电导钙依赖性类型的钾通道）。
