Prakash Y S, Iyanoye Adeyemi, Ay Binnaz, Sieck Gary C, Pabelick Christina M
Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Anesthesiology. 2006 Nov;105(5):976-83. doi: 10.1097/00000542-200611000-00019.
Volatile anesthetics produce bronchodilation in part by depleting sarcoplasmic reticulum Ca stores in airway smooth muscle (ASM). Other bronchodilatory drugs are known to act via cyclic nucleotides (cyclic adenosine 3',5'-cyclic monophosphate, cyclic guanosine 3',5'-cyclic monophosphate). Intracellular Ca regulation in ASM involves plasma membrane Ca influx, including that triggered by sarcoplasmic reticulum Ca depletion (store-operated Ca entry [SOCE]). The authors hypothesized that anesthetics and bronchodilatory agents interact in inhibiting SOCE, thus enhancing ASM relaxation.
In enzymatically dissociated porcine ASM cells imaged using fluorescence microscopy, sarcoplasmic reticulum Ca was depleted by 1 microm cyclopiazonic acid in 0 extracellular Ca, nifedipine, and potassium chloride (preventing Ca influx through L-type channels and SOCE). Extracellular Ca was rapidly reintroduced to selectively activate SOCE in the presence or absence of 1 minimum alveolar concentration (MAC) halothane, isoflurane, or sevoflurane. Anesthetic interference with SOCE regulation by cyclic nucleotides was examined by activating SOCE in the presence of (1) 1 microm acetylcholine, (2) 100 microm dibutryl cyclic adenosine 3',5'-cyclic monophosphate, or (3) 100 microm 8-bromo-cyclic guanosine 3',5'-cyclic monophosphate.
SOCE was enhanced by acetylcholine, whereas volatile anesthetics and both cyclic nucleotides partially inhibited Ca influx. Preexposure to 1 or 2 MAC anesthetic (halothane > isoflurane > sevoflurane) inhibited SOCE. Only halothane and isoflurane inhibited acetylcholine-induced augmentation of Ca influx, and significantly potentiated cyclic nucleotide inhibition such that no influx was observed in the presence of anesthetics and cyclic nucleotides.
These data indicate that volatile anesthetics prevent sarcoplasmic reticulum refilling by inhibiting SOCE and enhancing cyclic nucleotide blunting of Ca influx in ASM. Such interactions likely result in substantial airway relaxation in the presence of both anesthetics and bronchodilatory agents such as beta agonists or nitric oxide.
挥发性麻醉剂部分通过耗尽气道平滑肌（ASM）肌浆网中的钙储备来产生支气管扩张作用。已知其他支气管扩张药物通过环核苷酸（环磷腺苷、环磷鸟苷）发挥作用。ASM中的细胞内钙调节涉及质膜钙内流，包括由肌浆网钙耗竭引发的内流（储存性钙内流[SOCE]）。作者推测麻醉剂和支气管扩张剂在抑制SOCE方面存在相互作用，从而增强ASM舒张。
在使用荧光显微镜成像的酶解离猪ASM细胞中，在无细胞外钙、硝苯地平和氯化钾（防止钙通过L型通道和SOCE内流）的情况下，用1微摩尔环匹阿尼酸耗尽肌浆网钙。在存在或不存在1个最低肺泡浓度（MAC）的氟烷、异氟烷或七氟烷的情况下，迅速重新引入细胞外钙以选择性激活SOCE。通过在存在（1）1微摩尔乙酰胆碱、（2）100微摩尔二丁酰环磷腺苷或（3）100微摩尔8-溴环磷鸟苷的情况下激活SOCE，研究麻醉剂对环核苷酸调节SOCE的干扰。
乙酰胆碱增强SOCE，而挥发性麻醉剂和两种环核苷酸均部分抑制钙内流。预先暴露于1或2MAC麻醉剂（氟烷>异氟烷>七氟烷）可抑制SOCE。只有氟烷和异氟烷抑制乙酰胆碱诱导的钙内流增加，并显著增强环核苷酸抑制作用，以至于在存在麻醉剂和环核苷酸的情况下未观察到内流。
这些数据表明，挥发性麻醉剂通过抑制SOCE和增强ASM中钙内流的环核苷酸钝化作用来阻止肌浆网再充盈。这种相互作用可能在同时存在麻醉剂和支气管扩张剂（如β激动剂或一氧化氮）的情况下导致显著的气道舒张。
