Store-operated Ca2+ Influx in Airway Smooth Muscle: Interactions between Volatile Anesthetic and Cyclic Nucleotide Effects

Background: Volatile anesthetics produce bronchodilation in part by depleting sarcoplasmic reticulum Ca2+ 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 Ca2+ regulation in ASM involves plasma membrane Ca2+ influx, including that triggered by sarcoplasmic reticulum Ca2+ depletion (store-operated Ca2+ entry SOCE]). The authors hypothesized that anesthetics and bronchodilatory agents interact in inhibiting SOCE, thus enhancing ASM relaxation.

Methods: In enzymatically dissociated porcine ASM cells imaged using fluorescence microscopy, sarcoplasmic reticulum Ca2+ was depleted by 1 mu]m cyclopiazonic acid in 0 extracellular Ca2+, nifedipine, and potassium chloride (preventing Ca2+ influx through L-type channels and SOCE). Extracellular Ca2+ 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 mu]m acetylcholine, (2) 100 mu]m dibutryl cyclic adenosine 3',5'-cyclic monophosphate, or (3) 100 mu]m 8-bromo-cyclic guanosine 3',5'-cyclic monophosphate.

Results: SOCE was enhanced by acetylcholine, whereas volatile anesthetics and both cyclic nucleotides partially inhibited Ca2+ influx. Preexposure to 1 or 2 MAC anesthetic (halothane > isoflurane > sevoflurane) inhibited SOCE. Only halothane and isoflurane inhibited acetylcholine-induced augmentation of Ca2+ influx, and significantly potentiated cyclic nucleotide inhibition such that no influx was observed in the presence of anesthetics and cyclic nucleotides.