Abstracts
1997 Digestive Disease Week

Endothelin-1 mediates the alcohol-induced reduction of pancreatic capillary blood flow.

T Foitzik, HG Hotz, B Hotz, M Kirchengast,* HJ Buhr. Department of Surgery, Benjamin Franklin Medical Center, Freie Universitat Berlin & *Knoll AG, Ludwigshafen, Germany.

An alcohol-induced reduction of pancreatic blood flow is believed to play an important role in the pathogenesis of alcohol-associated pancreatic injury and pancreatitis. The mechanism by which alcohol reduces pancreatic perfusion is unknown. Increased plasma levels of endothelin-1 (ET-1) found in rats following alcohol administration and increased endothelin receptor expression in the vascular and ductal endothelium of patients with chronic alcoholic pancreatitis have led to the hypothesis that ET-1 may be a possible mediator in alcohol-associated pancreatic injury. To further test this hypothesis, we evaluated the effect of ET-1 and the selective ET-1 receptor antagonist LU135252 on pancreatic capillary blood flow in rats exposed to intravenous alcohol (or saline). Method: After exposure of the pancreas for intravital microscopy, anesthetized rats (n=36) were randomized to six experimental groups (see table). Test solutions were infused over one hour through separate catheters. The following dosages were used: Alcohol (ALC) 2g/kg/h; endothelin (ET-1) 1,25µg/kg/h; endothelin antagonist (LU135252) 50mg/kg/h; saline (SAL) vol.equiv. Pancreatic capillary blood flow (PCBF) was determined at the same location before giving the test solutions (t_0), at the end of the infusion (t_1) and one hour thereafter (t_2). Additional measurements included systemic cardiorespiratory parameters and hematocrit (data not shown). Results (mean ± SEM):

PCBF (nl/min/cap) t_0        PCBF (nl/min/cap) t_2
   SAL + SAL           2.00 ± 0.05                 2.01 ± 0.06
   SAL + ET-1          1.99 ± 0.04                 1.76 ± 0.04^{a,b}
   SAL + LU135252      2.00 ± 0.05                 2.17 ± 0.04^{a,b}
   ALC + SAL           2.00 ± 0.05                 1.77 ± 0.07^{a,b}
   ALC + ET-1          2.01 ± 0.04                 1.49 ± 0.04^{a-c}
   ALC + LU135252      2.00 ± 0.04                 1.99 ± 0.04^c
    a = p<0.05 t_2 vs. t_0; b = p<0.05 vs. SAL+SAL; c = vs. ALC+SAL

Conclusion: The observation (i) that ET-1 and alcohol both reduce PCBF and (ii) that an alcohol-induced reduction of PCBF can be aggravated by ET-1 and prevented by the ET-antagonist LU135252 supports the hypothesis that ET-1 is the mediator of alcohol-associated pancreatic perfusion disturbances.