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1 Medicine, McMaster University, Hamilton, Canada; Asthma Research Group, Firestone Institute for Respiratory Health, Hamilton, Canada
2 Asthma Research Group, Firestone Institute for Respiratory Health, Hamilton, Canada; Medicine, McMaster University, Hamilton, Canada
* To whom correspondence should be addressed. E-mail: janssenl{at}mcmaster.ca.
Agonist-induced contraction of airway smooth muscle(ASM) can be triggered by the elevation in the intracellular Ca2+ concentration ([Ca2+]i), primarily through the release of Ca2+ from the sarcoplasmic reticulum(SR). The refilling of the SR is integral for subsequent contractions. It has been suggested that Ca2+ entry via store-operated cation(SOC) and receptor operated cation(ROC) channels may facilitate refilling of the SR. Indeed depletion of the SR activates substantial inward SOC currents in ASM that are composed of both Ca2+ and Na+. Accumulation of Na+ within the cell may regulate Ca2+-handling in ASM by forcing the sodium-calcium exchanger(NCX) into the reverse-mode leading to the influx of Ca2+ from the extracellular domain. Since depletion of the SR activates substantial inward Na+ current, it is conceivable that the reverse-mode of the NCX may contribute to the intracellular Ca2+ pool from which the SR is refilled. Indeed successive contractions of bovine ASM, evoked by various agonists(acetylcholine,3x10-7 M; histamine,5x10-6 M;5-HT,1.5x10-6 M;caffeine,10 mM) were significantly reduced upon removal of extracellular Na+; whereas, contractions evoked by KCl(60mM) were unchanged by Na+ depletion. Ouabain(10-6M), a selective inhibitor of the Na+/K+ pump had no effect on the reductions observed under normal and zero Na+ conditions. KB-R7943(2x10-5M), a selective inhibitor of the reverse-mode of the NCX, significantly reduced successive contractions induced by all three agonists without altering KCl responses. Furthermore, KB-R7943 abolished successive caffeine-induced(10mM) Ca2+ transients in single ASM cells. Together, these data suggest a role for the reverse-mode of the NCX in refilling the SR in ASM following Ca2+ mobilization.
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