HALOTHANE ALTERS CYTOSOLIC CALCIUM TRANSIENT IN TRACHEAL SMOOTH-MUSCLE

Halothane is a potent bronchodilator that attenuates vagally mediated constriction of canine airways, in part by a direct action on the smoo th muscle cell. In tracheal smooth muscle, acetylcholine (ACh) produce s a transient peak increase in cytosolic ionized calcium concentration ([Ca2+]i), which declines to a sustained plateau concentration that i s higher than that of the unstimulated muscle, and a sustained increas e in force. The transient peak [Ca2+]i is caused primarily by Ca2+ rel ease from the sarcoplasmic reticulum (SR), whereas the plateau [Ca2+]i is caused primarily by influx of extracellular Ca2+ across the plasma membrane. This study was conducted to investigate the effects of halo thane on the 1) transient peak [Ca2+]i during force development (i.e., developed force) and 2) plateau [Ca2+]i during force maintenance (i.e ., sustained force) induced by ACh in isolated strips of canine trache al smooth muscle. Changes in [Ca2+]i were measured with the photoprote in, aequorin. In muscle strips contracted after incubation with 1.1 (n = 5) or 1.5 (n = 5) minimum alveolar concentration (MAC) halothane, h alothane significantly attenuated the transient peak aequorin luminesc ence (AL) and developed force and significantly prolonged the time nec essary to reach peak AL and developed force; these effects were not do se dependent. In muscle strips (n = 3) contracted with ACh, addition o f halothane caused a reduction in sustained force but no decrease in p lateau AL. These results suggest that in canine tracheal smooth muscle in vitro, clinically relevant concentrations of halothane attenuates the increase in both [Ca2+]i and developed force induced by ACh, possi bly by inhibiting Ca2+ release from the SR, whereas during sustained f orce halothane 1) relaxes the tracheal smooth muscle by cellular mecha nisms independent of [Ca2+]i, possibly by interfering with Ca2+- and c almodulin-mediated cellular events or, alternatively, the molecular pr ocesses that modulate the sensitivity of the contractile elements to [ Ca2+]i, and 2) does not interfere with Ca2+ influx across the plasma m embrane.