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Endothelin-induced contraction of bronchiole and pulmonary arteriole smooth muscle cells is regulated by intracellular Ca²⁺ oscillations and Ca²⁺ sensitization

Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts

Submitted 8 May 2007 ; accepted in final form 3 July 2007

Endothelin-1 (ET) induces increases in intracellular Ca²⁺ concentration ([Ca²⁺]_i), Ca²⁺ 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 [Ca²⁺]_i and the Ca²⁺ 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 [Ca²⁺]_i and Ca²⁺ 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 Ca²⁺ oscillations that were propagated as Ca²⁺ waves along the SMCs. These Ca²⁺ oscillations were mediated by cyclic intracellular Ca²⁺ release and required external Ca²⁺ for their maintenance. Importantly, as the frequency of the Ca²⁺ oscillations increased, the extent of contraction increased. ET-induced contraction was also associated with an increase in Ca²⁺ sensitivity. In "model" slices in which the [Ca²⁺]_i 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 Ca²⁺ oscillations and by increasing the sensitivity of the contractile machinery to Ca²⁺.

confocal microscopy; blood vessels; airways; lung slices; acetylcholine; serotonin