zy-17617b and Cholelithiasis

Smooth muscle from gallbladders with cholesterol stones exhibits impaired response to cholecystokinin (CCK). This study investigated whether the impaired response is mediated by different signal-transduction pathways responsible for CCK-induced contraction in prairie dog and human gallbladders with cholesterol stones. Gallbladder muscle cells were isolated enzymatically to study contraction. Protein kinase C (PKC) activity was measured by examining the phosphorylation of a specific substrate peptide from myelin basic protein Ac-MBP-(4-14). Gallbladder muscle cells from high-cholesterol-fed prairie dogs contracted less in response to CCK octapeptide (CCK-8) than those from the control group. However, inositol-1,4,5-trisphosphate (IP3), diacylglycerol, and guanosine 5'-O-(3-thiotriphosphate) induced the same magnitudes of contraction in these two groups. In control prairie dog and human gallbladders, the maximal contraction caused by 10(-8) M CCK-8 was blocked by the calmodulin antagonist CGS9343B but not by the PKC inhibitor H-7. Conversely, in gallbladders with cholesterol stones from prairie dogs or human patients, the maximal contraction induced by 10(-8) M CCK-8 was blocked by H-7 and chelerythrine but not by CGS9343B. In these gallbladders CCK-8 caused a significant PKC translocation from the cytosol to the membrane. High CCK concentrations may activate the calmodulin-dependent pathway in functionally normal gallbladder muscle and the PKC-dependent pathway in muscle from gallbladders with cholesterol stones. The defect of gallbladder muscle after cholesterol feeding and stones might reside in the steps before G protein activation.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Alkaloids; Animals; Benzimidazoles; Benzophenanthridines; Biological Transport; Calmodulin; Cholecystokinin; Cholelithiasis; Enzyme Inhibitors; Gallbladder; Humans; Male; Muscle Contraction; Muscle, Smooth; Phenanthridines; Protein Kinase C; Reference Values; Sciuridae; Sincalide