Therapy for microcirculatory disorders in severe acute pancreatitis: Effectiveness of platelet-activating factor receptor blockade vs. endothelin receptor blockade

Many of the complications of severe acute pancreatitis are the result of th e amplifying effects of microcirculatory disruption. The factors causing mi crocirculatory disorders in acute pancreatitis involve vasoactive mediators such as platelet-activating factor (PAF) and endothelin-l (ET) activated d uring the inflammatory response to pancreatic injury To further evaluate th e potential therapeutic role of specific receptor antagonists (RA) to these mediators, the present study compares the effect of PAF and ET receptor bl ockade on microcirculation and organ function in a well-established rodent model of severe acute pancreatitis. Six hours after acute pancreatitis indu ction, rats were randomized to therapy with ET-RX (50 mg/kg LU-135252), PAF -RA (82 mu g/kg WEB-2170), or NaCl 0.9% (volume equivalent). After 18 hours of fluid resuscitation, animals were relaparotomized for intravital micros copic determination of capillary blood flow, leukocyte rolling, and capilla ry permeability in the pancreas and colon. Other measurements included card iorespiratory parameters, hematocrit, pleural effusions, ascites, urine pro duction, and survival. Compared to saline treatment both ET-RA and PAF-RA. significantly improved capillary blood flow in the pancreas and colon, redu ced leukocyte rolling, and stabilized capillary permeability. The beneficia l effects of receptor antagonist treatment on microcirculation were associa ted with decreased fluid loss into the third space, improved renal and resp iratory function, and survival. Although both receptor antagonists likewise improved capillary blood flow; ET-RA was significantly more effective in c ounteracting leukocyte rolling and capillary leakage, thereby further reduc ing fluid sequestration. The present study confirms the beneficial effects of PAF and ET receptor blockade on microcirculation inside and outside the pancreas, organ function, and survival when given at the early stage of sev ere pancreatitis. Because ET-RA was more effective in stabilizing capillary permeability and avoiding subsequent fluid loss into the third space, we p ropose that ET-RA should be tested in a clinical trial(either in comparison or in addition to PAF-RA).