MUSCLE CONTRACTION IN HUMAN & PRAIRIE DOG GALLBLADDERS

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DESCRIPTION: (Adapted from the applicant's abstract) Lithogenic bile saturated with cholesterol is thought to contribute to gallbladder hypomotility, but the mechanism whereby cholesterol damages the gallbladder smooth muscle is not known. Human and prairie-dog gallbladders exposed to cholesterol-saturated bile exhibit impaired contraction in response to agonists. This abnormal response precedes the formation of gallstones. Therefore, the investigators propose to characterize the signal transduction pathways mediating contraction and relaxation in gallbladder muscle from man and prairie dog and to determine the abnormalities induced by exposure of gallbladder muscle to bile saturated with cholesterol. First, the investigators will define transduction pathways utilized by normal gallbladder muscle in response to agonists. The investigators will examine the sources of calcium and the second messengers (1,4,5-inositol triphosphate(IP3)-calmodulin or diacylglycerol-protein kinase C) utilized by these agonists. Next, the investigators will determine whether exposure of the muscle to the excess cholesterol in bile causes disruption of specific transduction pathway(s). Preliminary data suggest that cholesterol-induced damage may be initially limited to the membrane, since cholesterol-damaged human gallbladder muscle, after permeabilization with saponin, contracts normally in response to IP3. The investigators will confirm this preliminary finding with IP3 and examine whether the protein kinase C-dependent pathway is similarly involved. The investigators will then explore the various possible mechanisms underlying relaxation in the gallbladder muscle. In this context the investigators will examine the roles of norepinephrine, vasoactive intestinal peptide, and peptide histidine isoleucine as possible neurotransmitters mediating gallbladder relaxation in man and prairie dog. The investigators will determine the relative role of increases in cAMP and cGMP, and/or decreases in IP3 in inducing relaxation, and determine whether any of these second messengers is affected by exposure to cholesterol-saturated bile. The investigators will test in prairie dogs whether cholesterol-induced impairment of contraction is progressive, preventable, or reversible with either ursodeoxycholic acid (UDCA), which solubilizes cholesterol, or with aspirin, which may indirectly prevent formation of gallstones by inhibiting prostaglandin synthesis. The results of these experiments, they believe, may provide a rationale for treating overweight patients with impaired gallbladder contraction and cholesterol microcrystals with UDCA. These data, they believe, may elucidate the pathogenic role of cholesterol in disrupting gallbladder contraction and may ultimately contribute to long-term, nonsurgical treatment of patients with cholesterol stones.