Contribution of angiotensin II to alcohol-induced pancreatic fibrosis in rats.
The mechanisms by which alcohol causes pancreatic fibrosis remain unknown. Recent studies have demonstrated that angiotensin II contributes to the development of fibrosis in liver, kidney, and heart injury. Here, the effects of angiotensin-converting enzyme inhibitor (captopril) and angiotensin II receptor antagonist (losartan) on alcohol-induced pancreatic fibrosis were examined in an intragastric ethanol-feeding model. Male rats were fed a high-fat liquid diet with either ethanol (16-20 g/kg/day) or isocaloric maltose-dextrin (control) for 4 weeks. Subgroups daily received captopril (60 mg/kg/day), losartan (3 mg/kg/day), or no additional agent included in liquid diets. Mean urine alcohol concentrations in all groups fed ethanol were more than 270 mg/dl and not significantly different. Dietary alcohol caused diffuse gland atrophy and interlobular and intralobular fibrosis with mild structural distortion in the pancreas, an effect that was blunted by captopril or losartan treatment. Alcohol also increased the number of alpha-smooth muscle actin-positive cells and transforming growth factor-beta mRNA expression in the pancreas. These increases were blunted significantly by captopril or losartan treatment. These data suggest that angiotensin II contributes to the development of chronic alcohol-induced pancreatic fibrosis through its stimulation of transforming growth factor-beta expression.
Department of Pharmacology and Toxicology, 1307 Research Tower, HSC, University of Louisville School of Medicine, Louisville, KY 40292, USA.
Takehiko
T
Uesugi
Matthias
M
Froh
Erwin
E
Gäbele
Fuyumi
F
Isayama
Blair U
BU
Bradford
Iwao
I
Ikai
Yoshio
Y
Yamaoka
Gavin E
GE
Arteel
D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000633:toxicity* / Q000652:urine; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D000431:Ethanol / Q000633:toxicity* / Q000652:urine; D005355:Fibrosis; D007150:Immunohistochemistry; D019808:Losartan / Q000494:pharmacology; D008297:Male; D010179:Pancreas / Q000201:enzymology / Q000473:pathology; D010182:Pancreatic Diseases / Q000139:chemically induced* / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D012260:Ribonucleases / Q000378:metabolism
D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D002492:Central Nervous System Depressants; D016207:Cytokines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000431:Ethanol; D003094:Collagen; D002216:Captopril; D012260:Ribonucleases; D019808:Losartan