Calmodulin regulation of gallbladder ion transport becomes dysfunctional during gallstone formation in prairie dogs.
Gallbladder absorption is increased prior to gallstone formation in prairie dogs and may promote cholesterol crystallization. Recent studies indicate that Ca2+-calmodulin (CaM) tonically inhibits gallbladder electrolyte absorption in prairie dogs fed a nonlithogenic diet. We hypothesized that dietary cholesterol alters CaM-dependent regulation of gallbladder ion transport, a possible link between increased gallbladder absorption and gallstone formation. Gallbladders from prairie dogs fed control (N = 24) or 1.2% cholesterol-enriched chow (N = 32) were mounted in Ussing chambers. Electrophysiology and ion flux were measured while exposing the epithelia sequentially to trifluoperazine (TFP), a CaM antagonist, followed by the calcium ionophore A23187. Animals fed the high cholesterol diet developed crystals and gallstones in a time-dependent fashion. Mucosal addition of 50 microM TFP decreased short-circuit current (Isc), transepithelial potential, and tissue conductance in control, crystal, and gallstone animals, but the magnitude of its effect was significantly decreased in animals fed cholesterol. TFP stimulated mucosa-to-serosa Na+ flux by 6.9 +/- 0.9 microeq/cm2/hr in control animals but only 3.1 +/- 0.8 microeq/cm2/hr in gallstone animals. Similarly, TFP increased mucosa-to-serosa Cl- flux by 11.9 +/- 1.4 microeq/cm2/hr in controls but only 4.9 +/- 1.4 microeq/cm2/hr in cholesterol-fed animals. TFP effects were not reversed by A23187, which caused differential effects on Isc and ion transport in cholesterol-fed animals. In conclusion, CaM-mediated inhibition of gallbladder Na+ and Cl- transport is diminished in prairie dogs fed cholesterol. We conclude that gallbladder ion transport is partially released from basal inhibition during gallstone formation and propose that dysfunctional CaM regulation may be a stimulus to increased gallbladder absorption.
Moser
A J
AJ
Department of Surgery, MCP Hahnemann University, Philadelphia VAMC, Pennsylvania, 19102-1192, USA.
Giurgiu
D I
DI
Morgenstern
K E
KE
Abedin
Z R
ZR
Roslyn
J J
JJ
Abedin
M Z
MZ
D000042:Absorption / Q000187:drug effects; D000818:Animals; D001646:Bile / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D000001:Calcimycin / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism; D002769:Cholelithiasis / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D002791:Cholesterol, Dietary / Q000494:pharmacology; D004594:Electrophysiology; D005704:Gallbladder / Q000378:metabolism; D007477:Ions; D050356:Lipid Metabolism; D008297:Male; D012589:Sciuridae; D012964:Sodium / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology
D002147:Calmodulin; D002712:Chlorides; D002791:Cholesterol, Dietary; D007477:Ions; D014268:Trifluoperazine; D000001:Calcimycin; D012964:Sodium