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 initia l inflammatory response, which are three distinct characteristics of acute necrotizing pancreatitis, were investigated in a dose-dependent manner in r ats using in vivo microscopy. Fled blood cell (RBC) velocity and functional capillary density (FCD) were estimated after topical superfusion of the pa ncreas with ET-1, ET-2, and ET-3 (100, 10, 1 pmol), revealing that ET-1 (10 0, 10, 1 pmol) or high ET-2 (100 pmol) and ET-3 (100 pmol) cause a dose-rel ated deterioration of exocrine nutritive pancreatic blood flow. Analysis of pancreatic exocrine tissue damage employing the Spormann score displayed t hat the ET-mediated microcirculatory impairment was paralleled by dose-depe ndent tissue damage, which was significant compared to the control group (t opical superfusion with 1 ml, saline solution 0.9%). Estimation of pancreat ic postcapillary leukocyte accumulation by histomorphologically counting ch oracetate esterase (CAE) stained leukocytes in 50 high-power fields per ani mal demonstrated a significant increase in postcapillary accumulation of wh ite blood cells, after topical administration of ET-1, ET-2, and ET-3 compa red to controls. In contrast to ET-caused effects on microcirculation and t issue impairment, quantitative analysis of postcapillary leukocyte accumula tion 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 inflam mation. However, ET-3-induced damaging effects are less pronounced, while E T-1 most severely alters microcirculation and ET-2 preferentially induces l eukocyte-dependent inflammation.