title: Endothelin-1 mediates the alcohol-induced reduction of pancreatic capillary blood flow.
abstract: Increased plasma endothelin-1 (ET-1) levels in rats after alcohol administration and increased endothelin receptor expression in the pancreas in chronic alcoholic pancreatitis have led to the hypothesis that ET-1 may play a critical role in the pathogenesis of ethanol-induced pancreatic injury through impairment of perfusion. To further test the hypothesis that ET-1 mediates an alcohol-induced reduction of pancreatic perfusion, the present study compares the effect of intravenous alcohol and ET-1 on pancreatic capillary blood flow (PCBF) and investigates whether endothelin receptor blockade prevents the alcohol-induced reduction in PCBF. Anesthetized rats were randomly assigned to receive one of the following: a 1-hour infusion of 2 g/kg alcohol or the volume equivalent of saline solution plus ET-1 (1.25 microgram/kg), a specific endothelin-A receptor antagonist (50 mg/kg), or saline solution (volume equivalent). The pancreas was exposed for intravital microscopy; PCBF was determined at the same location before the test solutions were given, after the infusion, and 1 hour thereafter. Alcohol and ET-1 significantly decreased PCBF from 2.0 nl/min/cap to 1.7 nl/min/cap. The reduction in PCBF was even more pronounced when alcohol and ET-1 were combined (1.5 nl/min/cap), whereas the ET receptor antagonist increased PCBF in saline-treated rats to 2.2 nl/min cap and maintained stable PCBF in alcohol-treated animals. The observation that PCBF is reduced by both alcohol and ET-1 and that the alcohol-induced reduction of PCBF can be aggravated by ET-1 and prevented by a specific endothelin-1 antagonist supports the hypothesis that ET-1 is the mediator of the alcohol-associated reduction of pancreatic perfusion.
authors.affiliation: Department of Surgery, Benjamin Franklin Medical Center, Freie Universität Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Foitzik
authors.forename: H G
authors.initials: HG
authors.lastname: Hotz
authors.forename: B
authors.initials: B
authors.lastname: Hot
authors.forename: M
authors.initials: M
authors.lastname: Kirchengast
authors.forename: H J
authors.initials: HJ
authors.lastname: Buhr
mesh_terms: D000818:Animals; D002196:Capillaries / Q000187:drug effects; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007262:Infusions, Intravenous; D008833:Microcirculation / Q000187:drug effects; D008853:Microscopy; D010179:Pancreas / Q000098:blood supply* / Q000187:drug effects; D010666:Phenylpropionates / Q000494:pharmacology; D010919:Placebos; D011743:Pyrimidines / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000187:drug effects; D012965:Sodium Chloride
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D010919:Placebos; D011743:Pyrimidines; D017466:Receptors, Endothelin; C107831:darusentan; D000431:Ethanol; D012965:Sodium Chloride