ETA and ETB receptor function in pancreatitis-associated microcirculatory failure, inflammation, and parenchymal...

The role of endothelin (ET)A and ETB 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 ETA receptor function or combined ETA and ETB receptor blockade affects the development of pancreatitis-associated microcirculatory failure, inflammation, and parenchymal injury. Pretreatment with 10 mg/kg body wt of a combined ETA/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 ETA/B receptor antagonist (4 mg/kg body wt), which predominantly inhibits the ETA receptor, revealed an improvement of some microcirculatory disorders and a significant attenuation of leukocyte recruitment and tissue injury. Furthermore, pretreatment with a selective ETA receptor antagonist (1 microg/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 ETA 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 ETA receptor, which therefore may represent a promising target for novel strategies in the treatment of pancreatitis.