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LIVER AND BILIARY TRACT

ET_A and ET_B receptor function in pancreatitis-associated microcirculatory failure, inflammation, and parenchymal injury

¹Department of General Surgery and ²Institute for Clinical and Experimental Surgery, University of Saarland, 66421 Homburg/Saar, Germany

Submitted 14 May 2002 ; accepted in final form 24 February 2003

The role of endothelin (ET)_A and ET_B receptor function in experimental pancreatitis is still not fully understood. Using a rat model of sodium taurocholate-induced pancreatitis and intravital microscopy, we therefore studied whether selective inhibition of ET_A receptor function or combined ET_A and ET_B receptor blockade affects the development of pancreatitis-associated microcirculatory failure, inflammation, and parenchymal injury. Pretreatment with 10 mg/kg body wt of a combined ET_A/B receptor antagonist, which is thought to mediate a simultaneous inhibition of both receptors, did not attenuate the pancreatitis-induced microcirculatory failure, inflammatory response, and parenchymal tissue injury. In contrast, pretreatment with a low concentration of the combined ET_A/B receptor antagonist (4 mg/kg body wt), which predominantly inhibits the ET_A receptor, revealed an improvement of some microcirculatory disorders and a significant attenuation of leukocyte recruitment and tissue injury. Furthermore, pretreatment with a selective ET_A receptor antagonist (1 µg/kg body wt) almost abolished pancreatitis-associated capillary constriction, restored functional capillary density, and, consequently, improved overall nutritive perfusion. Importantly, the maintenance of an appropriate microcirculation by selective ET_A receptor inhibition was accompanied by a significant attenuation of the inflammation-associated leukocytic response and by a marked reduction of parenchymal injury. Thus our study indicates that pancreatitis-associated development of microcirculatory failure, inflammation, and parenchymal injury is caused by ETs coupling onto the ET_A receptor, which therefore may represent a promising target for novel strategies in the treatment of pancreatitis.

experimental pancreatitis; intravital microscopy; endothelin

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