Cyclic AMP‐mediated inhibition of gallbladder contractility: role of K⁺ channel activation and Ca²⁺ signaling

Abstract

1 We have examined the mechanisms of cAMP-induced gallbladder relaxation by recording isometric tension and membrane potential in the intact tissue, and global intracellular calcium concentrations ([Ca 2 þ ] i ) and F-actin content in isolated myocytes. 2 Both the phosphodiesterase (PDE) inhibitor, IBMX (100 mM) and the adenylate cyclase activator, forskolin (2 mM) caused decreases in basal tone that exhibited similar kinetics. IBMX and forskolin both caused concentration dependent, right-downward shifts in the concentration-response curves of KCl and cholecystokinin (CCK). 3 IBMX and forskolin elicited a membrane hyperpolarization that was almost completely inhibited by the ATP-sensitive K þ channel (K ATP ) channel blocker, glibenclamide (10 mM). IBMX also induced an increase in large-conductance sensitivity of the contractile apparatus. A depolymerization of the thin filament could be reason for this change, as forskolin induced a decrease in F-actin content. 7 In conclusion, these findings suggest that multiple, redundant intracellular processes are affected by cAMP to induce gallbladder relaxation.

Effects of cinacalcet on gastrointestinal hormone release in patients with secondary hyperparathyroidism undergoing dialysis

“…Recent reports have demonstrated that calcium facilitates fatty acid and protein-induced CCK secretion [21,22]. Furthermore, calcium also participates in the mechanism of action of CCK on gallbladder contraction [23][24][25] and pancreatic enzyme production [26][27][28]. Our data suggest that calcimimetics have no relevant role in the release of this hormone.…”

Calcium waves in intact guinea pig gallbladder smooth muscle cells

“…The excitability of GBSM cells is modulated by Ca 2ϩ influx via VDCCs (1, 50) and intracellular Ca 2ϩ mobilization (1,(27)(28)(29)38). We evaluated the role of VDCCs in Ca 2ϩ -wave activity to determine the association among Ca 2ϩ waves, Ca 2ϩ flashes, or APs.…”

Role of mitochondria in spontaneous rhythmic activity and intracellular calcium waves in the guinea pig gallbladder smooth muscle

“…In arterial smooth muscle cells, nanomolar concentration CCCP causes generation of ROS and activation of Ca 2ϩ -activated K ϩ channels (53). Ca 2ϩ -activated K ϩ channels are present in GBSM and are involved with reducing excitability through a hyperpolarization (28,34,54), which may explain the tendency for plasma membrane hyperpolarization observed in some GBSM immediately after the application of CCCP. It is also possible that CCCP and FCCP reduced APs and Ca 2ϩ flashes through transient activation of other types of potassium channels known to exist in GBSM (17,31,34,54).…”