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1 Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
* To whom correspondence should be addressed. E-mail: clee{at}mrl.ubc.ca.
Stimulation of the tracheal muscle bundle by acetylcholine (ACh) results in the generation of asynchronous repetitive Ca2+ waves (ACW) in the intact tracheal smooth muscle cells. We have previously shown that the ACW underlie cholinergic excitation-contraction coupling in porcine tracheal smooth muscle (TSM) and that Ca2+ entry through the L-type voltage gated Ca2+ channel (VGCC) contributes partially to the maintenance of the ACW. However, the mechanism of the ACW remains undefined. In this study, we pharmacologically characterized the mechanism of ACh-induced ACW in the intact porcine tracheal muscle bundle. We found that inhibition of the receptor-operated channels/store-operated channels (ROC/SOC) by SKF96365 completely abolished the nifedipine insensitive component of ACh-mediated ACW and tonic contraction. Blockade of Na+-Ca2+ exchange with KB-R7943 or 2',4'-dichlorobenzamil or the removal of extracellular Na+ resulted in nearly complete inhibition of the nifedipine insensitive component of ACh-mediated ACW and tonic contraction. Inhibition of the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) by cyclopiazonic acid abolished the ongoing ACW. Application of 2-aminoethoxydiphenyl borate (2-APB) or xestospongin C to inhibit the inositol 1,4,5-trisphosphate-sensitive sarcoplasmic reticulum (SR) Ca2+ release channels produced no effect on ACh-mediated ACW and tonic contraction. However, pretreatment with caffeine or ryanodine inhibited ACh-induced ACW. Furthermore, application of procaine or tetracaine prevented the generation and abolished the ongoing ACh-mediated ACW and tonic contraction. Collectively, these results indicate that the ACh-stimulated ACW in porcine TSM are produced by repetitive cycles of Ca2+ release from SR through 2-APB and xestospongin C insensitive Ca2+ release channels and plasmalemmal Ca2+ entry involving the reverse-mode Na+-Ca2+ exchange, the ROC/SOC and the L-type VGCC is required to refill the SR via SERCA to support the ongoing ACW.
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