ETA and ETB receptor function in pancreatitis-associated microcirculatory failure, inflammation, and parenchymal injury.
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.
Plusczyk
T
T
Dept. of General Surgery, University of Saarland, 66421 Homburg/Saar, Germany. chtplu@uniklinik-saarland.de
Witzel
B
B
Menger
M D
MD
Schilling
M
M
D000818:Animals; D001783:Blood Flow Velocity; D002196:Capillaries / Q000473:pathology / Q000502:physiology; D002756:Cholagogues and Choleretics; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D008297:Male; D010179:Pancreas / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism; D019283:Pancreatitis, Acute Necrotizing / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*; D013656:Taurocholic Acid; D013777:Tetrazoles / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D002756:Cholagogues and Choleretics; D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013777:Tetrazoles; D014665:Vasodilator Agents; D013656:Taurocholic Acid; C120582:tezosentan