title: Cholesterol inhibits spontaneous action potentials and calcium currents in guinea pig gallbladder smooth muscle.
abstract: Elevated cholesterol decreases agonist-induced contractility and enhances stone formation in the gallbladder. The current study was conducted to determine if and how the electrical properties and ionic conductances of gallbladder smooth muscle are altered by elevated cholesterol. Cholesterol was delivered as a complex with cyclodextrin, and effects were evaluated with intracellular recordings from intact gallbladder and whole cell patch-clamp recordings from isolated cells. Cholesterol significantly attenuated the spontaneous action potentials of intact tissue. Furthermore, calcium-dependent action potentials and calcium currents were reduced in the intact tissue and in isolated cells, respectively. However, neither membrane potential hyperpolarizations induced by the ATP-sensitive potassium channel opener, pinacidil, nor voltage-activated outward potassium currents were affected by cholesterol. Hyperpolarizations elicited by calcitonin gene-related peptide were reduced by cholesterol enrichment, indicating potential changes in receptor ligand binding and/or second messenger interactions. These data indicate that excess cholesterol can contribute to gallbladder stasis by affecting calcium channel activity, whereas potassium channels remained unaffected. In addition, cholesterol enrichment may also modulate receptor ligand behavior and/or second messenger interactions.
authors.affiliation: Department of Anatomy, College of Medicine, The University of Vermont, Burlington, Vermont 05405, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Jennings
authors.forename: Q W
authors.initials: QW
authors.lastname: Xu
authors.forename: T A
authors.initials: TA
authors.lastname: Firth
authors.forename: M T
authors.initials: MT
authors.lastname: Nelson
authors.forename: G M
authors.initials: GM
authors.lastname: Mawe
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001659:Biliary Tract / Q000503:physiopathology; D001896:Boron Compounds; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002769:Cholelithiasis / Q000503:physiopathology; D002779:Cholestasis / Q000503:physiopathology; D002784:Cholesterol / Q000494:pharmacology*; D004553:Electric Conductivity; D004558:Electric Stimulation; D005260:Female; D005456:Fluorescent Dyes; D005704:Gallbladder / Q000737:chemistry / Q000502:physiology*; D016473:Gallbladder Emptying / Q000502:physiology; D006168:Guinea Pigs; D008297:Male; D009130:Muscle, Smooth / Q000737:chemistry / Q000502:physiology*; D018408:Patch-Clamp Techniques; D020110:Pinacidil / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D000959:Antihypertensive Agents; D001896:Boron Compounds; D002120:Calcium Channel Agonists; D015220:Calcium Channels; D005456:Fluorescent Dyes; D015221:Potassium Channels; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D020110:Pinacidil; D002784:Cholesterol; D015740:Calcitonin Gene-Related Peptide; D011188:Potassium; D002118:Calcium