Mechanism of ACh-induced asynchronous calcium waves and tonic contraction in porcine tracheal muscle bundle

Abstract

channel (VGCC) contributes partially to 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 receptor-operated channels/store-operated channels (ROC/SOC) by SKF-96365 completely abolished the nifedipine-insensitive component of ACh-mediated ACW and tonic contraction. Blockade of Na ϩ /Ca 2ϩ exchange with KB-R7943 or 2Ј,4Ј-dichlorobenzamil or removal of extracellular Na ϩ resulted in nearly complete inhibition of the nifedipine-insensitive component of ACh-mediated ACW and tonic contraction. Inhibition of the sarco(endo)plasmic reticulum Ca 2ϩ -ATPase 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) Ca 2ϩ 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 AChmediated ACW and tonic contraction. Collectively, these results indicate that the ACh-stimulated ACW in porcine TSM are produced by repetitive cycles of Ca 2ϩ release from SR through 2-APB-and xestospongin C-insensitive Ca 2ϩ release channels, and plasmalemmal Ca 2ϩ entry involving reverse-mode Na ϩ /Ca 2ϩ exchange, ROC/SOC, and L-type VGCC is required to refill the SR via SERCA to support the ongoing ACW.

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

“…As the Ca endothelin) usually consists of Ca 2+ oscillations that propagate along the muscle cells as Ca 2+ waves [254][255][256][257][258]. The frequency of these Ca 2+ oscillations correlate with the muscle's contractile state and this has led to the consensus that ASM cells frequency encode their Ca 2+ signals [259][260][261]. These Ca 2+ oscillations are primarily mediated by repetitive Ca 2+ release from internal stores and require refilling by Ca 2+ influx [255,256,260,261].…”

“…In one hypothesis, the Ca 2+ oscillations are mediated by calciuminduced calcium-release (CICR) via the IP 3 R sensitised by IP 3 [254,260]. Alternatively, Ca 2+ oscillations may be mediated by CICR via the RyR [261][262][263][264], although the initiation of the Ca 2+ oscillations may require an IP 3 -induced Ca 2+ release [265]. The release of Ca 2+ via the RyR may also require sensitisation with cADP-ribose.…”

“…influx, agonist stimulation does not sufficiently depolarise smooth muscle cells to fully activate such channels [266]. Similarly, L-type Ca 2+ channel blockers, such as nifedipine, have variable effects [258,260,261,267,268]. These data indicate that there is a range of involvement of voltage-gated channels in refilling internal stores.…”

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

“…The initial release occurs in the vicinity of the plasma membrane. It spreads into the cell through the regenerative release of Ca 2+ by the RyR and /or the IP3R in the form of an intracellular Ca 2+ wave travelling down the length of the cell [31][32][33]. When [Ca 2+ ]i is integrated over an entire cell with time, these Ca 2+ waves appear as rhythmical oscillations [34].…”

Properties of a store-operated nonselective cation channel in airway smooth muscle

“…The mechanisms responsible for store-refilling remain unclear but seem to include voltage-gated Ca 2+ channels [5], nonselective cation channels (NSCCs) [1,6,7] and/or reverse-mode Na + /Ca 2+ exchange [8,9]. NSCCs formed by proteins of the transient receptor potential (TRP) family have received a great deal of attention, particularly those of the ''canonical'' or ''classical'' subtype (TRPC) [10][11][12].…”