Abstracts
1997 Digestive Disease Week

Is the pancreas especially susceptible to endothelin?

HG Hotz, T Foitzik, N Runkel, M Kirchengast*, HA Reber**, HJ Buhr. Departments of Surgery, Benjamin Franklin Medical Center, Freie Universitat Berlin, Germany and **UCLA School of Medicine, Los Angeles, CA, and *Knoll AG, Ludwigshafen, Germany.

Capillary blood flow impairment is believed to play an important role in both the progression of acinar cell injury as well-as in the development of gut failure and multiorgan dysfunction in severe acute pancreatitis (AP). The factors causing these microcirculatory disorders are still unknown but most likely involve vasoactive mediators. Recent research has identified endothelin-1 (ET-1) as possible mediator of vascular sequelae in various diseases associated with ischemia, low flow states and systemic inflammatory response syndrome. In AP, ET-1 is thought to mediate disease progression by disrupting pancreatic blood flow. The present study investigates whether ET-1 primarily targets the pancreas or whether it also effects other vascular beds e.g. the colon. Methods: Severe AP was induced in rats by a standardized intraductal infusion of bile salt followed by i.v. cerulein over 6 hrs. Animals were randomized to three experimental groups (Table). The test solutions were given in the following doses: ET-1 30µg/(kg·24h); ET-1 antagonist (LU 135252) 120mg/(kg·24h); saline vol.equiv. Healthy rats given the same test solutions served as controls. Capillary blood flow of the pancreas (PCBF) and the colonic mucosa (CCBF) was determined in all animals after 24 hrs. by intravital microscopy.

Results (mean ± SEM):

                      PCBF [nl/(min·cap)]      CCBF [nl/(min·cap)]   n
 Control + Saline        1.98 ± 0.04              2.28 ± 0.03        6
 Control + ET-1          1.78 ± 0.06*             1.95 ± 0.05*       6
 Control + LU135252      2.14 ± 0.03*             2.22 ± 0.03        6
 AP + Saline             1.30 ± 0.04              1.59 ± 0.04        6
 AP + ET-1               1.27 ± 0.04              1.49 ± 0.04        6
 AP + LU135252           1.98 ± 0.03^{#}          1.69 ± 0.03        6
      * = p<0.05 vs. Control + Saline; ^{#} = p<0.01 vs. AP + Saline

Conclusions: The results confirm that PCBF and CCBF are significantly reduced in AP. Endothelin superimposed on AP does not further decrease PCBF and CCBF, suggesting that ET-1 receptors are activated by endogenous ET-1. ET-1 receptor blockade significantly improves PCBF in the normal pancreas as well as in AP, while CCBF is not affected, suggesting that the pancreas is especially susceptible to endothelin.