Perez-Zoghbi Jose F, Sanderson Michael J
Dept. of Physiology, Univ. of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655, USA.
Am J Physiol Lung Cell Mol Physiol. 2007 Oct;293(4):L1000-11. doi: 10.1152/ajplung.00184.2007. Epub 2007 Jul 6.
Endothelin-1 (ET) induces increases in intracellular Ca(2+) concentration (Ca(2+)), Ca(2+) sensitization, and contraction of both bronchiole and pulmonary arteriole smooth muscle cells (SMCs) and may play an important role in the pathophysiology of asthma and pulmonary hypertension. However, because it remains unclear how changes in Ca(2+) and the Ca(2+) sensitivity regulate SMC contraction, we have studied mouse lung slices with phase-contrast and confocal microscopy to correlate the ET-induced contraction with the changes in Ca(2+) and Ca(2+) sensitivity of bronchiole and arteriole SMCs. In comparison with acetylcholine (ACh) or serotonin (5-HT), ET induced a stronger and long-lasting contraction of both bronchioles and arterioles. This ET-induced contraction was associated with prominent asynchronous Ca(2+) oscillations that were propagated as Ca(2+) waves along the SMCs. These Ca(2+) oscillations were mediated by cyclic intracellular Ca(2+) release and required external Ca(2+) for their maintenance. Importantly, as the frequency of the Ca(2+) oscillations increased, the extent of contraction increased. ET-induced contraction was also associated with an increase in Ca(2+) sensitivity. In "model" slices in which the Ca(2+) was constantly maintained at an elevated level by pretreatment of slices with caffeine and ryanodine, the addition of ET increased bronchiole and arteriole contraction. These results indicate that ET-induced contraction of bronchiole and arteriole SMCs is regulated by the frequency of Ca(2+) oscillations and by increasing the sensitivity of the contractile machinery to Ca(2+).
内皮素-1（ET）可导致细支气管和肺小动脉平滑肌细胞（SMC）的细胞内钙离子浓度（[Ca²⁺]i）升高、钙离子敏化及收缩，可能在哮喘和肺动脉高压的病理生理学中起重要作用。然而，由于尚不清楚[Ca²⁺]i的变化及钙离子敏感性如何调节SMC收缩，我们用相差显微镜和共聚焦显微镜研究了小鼠肺切片，以将ET诱导的收缩与细支气管和小动脉SMC的[Ca²⁺]i变化及钙离子敏感性相关联。与乙酰胆碱（ACh）或5-羟色胺（5-HT）相比，ET诱导细支气管和小动脉产生更强且持久的收缩。这种ET诱导的收缩与显著的异步钙离子振荡相关，该振荡以钙离子波的形式沿SMC传播。这些钙离子振荡由细胞内钙离子的周期性释放介导，且其维持需要细胞外钙离子。重要的是，随着钙离子振荡频率增加，收缩程度增大。ET诱导的收缩还与钙离子敏感性增加相关。在用咖啡因和雷诺丁预处理切片使[Ca²⁺]i持续维持在升高水平的“模型”切片中，添加ET可增加细支气管和小动脉的收缩。这些结果表明，ET诱导的细支气管和小动脉SMC收缩受钙离子振荡频率及收缩机制对钙离子敏感性增加的调节。
