TY - JOUR
T1 - Increased pancreatic acinar content and secretion of cationic trypsinogen following 30-day continuous ethanol intoxication in rats
AU - Tsukamoto, Hidekazu
AU - Sankaran, Hariharan
AU - Delgado, George
AU - Reidelberger, Roger D.
AU - Deveney, Clifford W.
AU - Largman, Corey
N1 - Funding Information:
Cholecystokinin (CCK) is a major gastrointestinal hormone which regulates both secretion \[1,2\] and synthesis \[3, 4\] of pancreatic exocrine enzymes. Ethanol has been shown to exert an acute inhibitory effect on CCK-stimulated pancreatic secretion in dogs \[5\]a nd in humans \[6\]. The binding of CCK to acinar receptors is inhibited in vitro by high concentrations of ethanol in a dose-dependent manner, and this inhibition correlates with an ethanol-induced reduction in CCK-stimulated amylase secretion \[7\]. On the other hand, chronic alcohol intake augments the pancreatic sensitivity to CCK stimulation in dogs \[8\]a s well as in humans \[9, 10\]. Of different secretory proteins examined, trypsinogen levels have been shown to increase in the pancreatic secretion of rats chronically given ethanol \[11-13\] and of human alcoholics \[10, 14\]. In addition, the injection of secretin produced a significantly greater response * Supported by the Medical Research Service of the Veterans Administration and United States Public Health Service Grants HL25408 to C. L. and AA06603-02 to H. T. t Address reprint requests to: Dr. H. Tsukamoto, Hepa-topancreatic Research Laboratory, Research Bldg., VA Medical Center, 150 Muir Road, Martinez, CA 94553.
PY - 1986/10/15
Y1 - 1986/10/15
N2 - The effects of sustained, high blood alcohol levels (216 ± 120 mg/100 ml, S.D.) for 30 days on cholecystokinin (CCK)-mediated pancreatic exocrine function were studied in a rat model that achieves both maximally controlled, optimal nutrition and high alcohol intake (∼40.5% of total calories). In alcohol-fed rats, basal plasma levels of immunoreactive cationic trypsinogen (ICT) were reduced by 50% (P < 0.05), but intravenous doses (0-30 IDU/kg/hr; 1 IDU = ∼62.5 ng CCK-8) of cholecystokinin octapeptide (CCK-8) resulted in a 3-fold greater maximal concentration of ICT and an 80% steeper slope of the dose-response curve compared to those of pair-fed control animals. Basal plasma levels of amylase were not different in the two groups at basal conditions and did not change significantly following CCK-8 administration. In vitro studies with isolated pancreatic acini have shown that basal secretion of ICT into the media was similar in the two groups. However, ICT secretion in response to CCK-8 (30-3000 pM) was 2-fold greater in alcohol-fed rats than in pair-fed controls, resulting in a CCK-8ec50 which was about half that of controls. On the contrary, the basal and maximal amylase secretion from acini isolated from alcohol-fed rats was reduced by 67 and 43%, respectively, causing a reduction in the magnitude of the response curve with almost identical ec50 and slopes. Despite the marked alterations in CCK-stimulated enzyme secretion, radioiodinated CCK-33 binding to receptors on acini isolated from both control and alcohol-fed rats was similar. Cellular concentrations of ICT and amylase, however, revealed similar patterns of alterations: 2 to 3-fold increase in ICT and 70% reduction in amylase in alcoholic acini compared to controls. These results indicate that the inverse changes in amylase and ICT secretions following continuous ethanol administration are probably due to differential effects on enzyme synthesis.
AB - The effects of sustained, high blood alcohol levels (216 ± 120 mg/100 ml, S.D.) for 30 days on cholecystokinin (CCK)-mediated pancreatic exocrine function were studied in a rat model that achieves both maximally controlled, optimal nutrition and high alcohol intake (∼40.5% of total calories). In alcohol-fed rats, basal plasma levels of immunoreactive cationic trypsinogen (ICT) were reduced by 50% (P < 0.05), but intravenous doses (0-30 IDU/kg/hr; 1 IDU = ∼62.5 ng CCK-8) of cholecystokinin octapeptide (CCK-8) resulted in a 3-fold greater maximal concentration of ICT and an 80% steeper slope of the dose-response curve compared to those of pair-fed control animals. Basal plasma levels of amylase were not different in the two groups at basal conditions and did not change significantly following CCK-8 administration. In vitro studies with isolated pancreatic acini have shown that basal secretion of ICT into the media was similar in the two groups. However, ICT secretion in response to CCK-8 (30-3000 pM) was 2-fold greater in alcohol-fed rats than in pair-fed controls, resulting in a CCK-8ec50 which was about half that of controls. On the contrary, the basal and maximal amylase secretion from acini isolated from alcohol-fed rats was reduced by 67 and 43%, respectively, causing a reduction in the magnitude of the response curve with almost identical ec50 and slopes. Despite the marked alterations in CCK-stimulated enzyme secretion, radioiodinated CCK-33 binding to receptors on acini isolated from both control and alcohol-fed rats was similar. Cellular concentrations of ICT and amylase, however, revealed similar patterns of alterations: 2 to 3-fold increase in ICT and 70% reduction in amylase in alcoholic acini compared to controls. These results indicate that the inverse changes in amylase and ICT secretions following continuous ethanol administration are probably due to differential effects on enzyme synthesis.
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U2 - 10.1016/0006-2952(86)90635-0
DO - 10.1016/0006-2952(86)90635-0
M3 - Article
C2 - 3768045
AN - SCOPUS:0023004146
SN - 0006-2952
VL - 35
SP - 3623
EP - 3629
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 20
ER -