title: Therapy for microcirculatory disorders in severe acute pancreatitis: effectiveness of platelet-activating factor receptor blockade vs. endothelin receptor blockade.
abstract: Many of the complications of severe acute pancreatitis are the result of the amplifying effects of microcirculatory disruption. The factors causing microcirculatory disorders in acute pancreatitis involve vasoactive mediators such as platelet-activating factor (PAF) and endothelin-1 (ET) activated during the inflammatory response to pancreatic injury. To further evaluate the potential therapeutic role of specific receptor antagonists (RA) to these mediators, the present study compares the effect of PAF and ET receptor blockade on microcirculation and organ function in a well-established rodent model of severe acute pancreatitis. Six hours after acute pancreatitis induction, rats were randomized to therapy with ET-RA (50 mg/kg LU-135252), PAF-RA (82 microg/kg WEB-2170), or NaCl 0.9% (volume equivalent). After 18 hours of fluid resuscitation, animals were relaparotomized for intravital microscopic determination of capillary blood flow, leukocyte rolling, and capillary permeability in the pancreas and colon. Other measurements included cardiorespiratory parameters, hematocrit, pleural effusions, ascites, urine production, and survival. Compared to saline treatment both ET-RA and PAF-RA significantly improved capillary blood flow in the pancreas and colon, reduced leukocyte rolling, and stabilized capillary permeability. The beneficial effects of receptor antagonist treatment on microcirculation were associated with decreased fluid loss into the third space, improved renal and respiratory function, and survival. Although both receptor antagonists likewise improved capillary blood flow, ET-RA was significantly more effective in counteracting leukocyte rolling and capillary leakage, thereby further reducing 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 severe pancreatitis. Because ET-RA was more effective in stabilizing capillary permeability and avoiding subsequent fluid loss into the third space, we propose that ET-RA should be tested in a clinical trial (either in comparison or in addition to PAF-RA).
authors.affiliation: Department of Surgery, Benjamin Franklin Medical Center, Freie Universität Berlin, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Foitzik
authors.forename: H G
authors.initials: HG
authors.lastname: Hotz
authors.forename: G
authors.initials: G
authors.lastname: Eibl
authors.forename: B
authors.initials: B
authors.lastname: Hotz
authors.forename: M
authors.initials: M
authors.lastname: Kirchengast
authors.forename: H J
authors.initials: HJ
authors.lastname: Buhr
mesh_terms: D000818:Animals; D001201:Ascites / Q000209:etiology; D002196:Capillaries / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D016009:Chi-Square Distribution; D003106:Colon / Q000098:blood supply / Q000187:drug effects; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D005440:Fluid Therapy; D006400:Hematocrit; D007813:Laparotomy; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010179:Pancreas / Q000098:blood supply* / Q000187:drug effects; D019283:Pancreatitis, Acute Necrotizing / Q000188:drug therapy*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D010996:Pleural Effusion / Q000209:etiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012039:Regional Blood Flow / Q000187:drug effects; D015996:Survival Rate; D014556:Urine
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor