Differential effects of ET-1, ET-2, and ET-3 on pancreatic microcirculation, tissue integrity, and inflammation.
The differential effects of endothelin-1, -2, and -3 (ET-1, ET-2, and ET-3) on pancreatic microcirculation, pancreatic tissue integrity, and an initial inflammatory response, which are three distinct characteristics of acute necrotizing pancreatitis, were investigated in a dose-dependent manner in rats using in vivo microscopy. Red blood cell (RBC) velocity and functional capillary density (FCD) were estimated after topical superfusion of the pancreas with ET-1, ET-2, and ET-3 (100, 10, 1 pmol), revealing that ET-1 (100, 10, 1 pmol) or high ET-2 (100 pmol) and ET-3 (100 pmol) cause a dose-related deterioration of exocrine nutritive pancreatic blood flow. Analysis of pancreatic exocrine tissue damage employing the Spormann score displayed that the ET-mediated microcirculatory impairment was paralleled by dose-dependent tissue damage, which was significant compared to the control group (topical superfusion with 1 ml, saline solution 0.9%). Estimation of pancreatic postcapillary leukocyte accumulation by histomorphologically counting choracetate esterase (CAE) stained leukocytes in 50 high-power fields per animal demonstrated a significant increase in postcapillary accumulation of white blood cells, after topical administration of ET-1, ET-2, and ET-3 compared to controls. In contrast to ET-caused effects on microcirculation and tissue impairment, quantitative analysis of postcapillary leukocyte accumulation revealed the most pronounced effect after ET-2 administration but not after ET-1 administration. This demonstrates that ET-1, ET-2, and ET-3 are all able to mediate microcirculatory impairment, tissue damage, and inflammation. However, ET-3-induced damaging effects are less pronounced, while ET-1 most severely alters microcirculation and ET-2 preferentially induces leukocyte-dependent inflammation.
Plusczyk
T
T
Department of General Surgery, University of Saarland, Homburg/Saar, Germany.
Bersal
B
B
Menger
M D
MD
Feifel
G
G
D000818:Animals; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D019333:Endothelin-2 / Q000494:pharmacology / Q000502:physiology*; D019334:Endothelin-3 / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010179:Pancreas / Q000098:blood supply* / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000209:etiology / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew
D019332:Endothelin-1; D019333:Endothelin-2; D019334:Endothelin-3