Therapy of microcirculatory disorders in severe acute pancreatitis: what mediators should we block?

Abstract

To compare the effect of different vasoactive mediator antagonists in the same model of severe acute pancreatitis (AP) and to evaluate whether combinations of the agents exhibit synergistic effects. Prospective experimental study. Microcirculation and pancreas research laboratory at an university hospital. Hundred eighty anesthetized male Sprague-Dawley rats. Six hours after inducing AP by intra-ductal bile salt infusion and i.v. cerulein in 168 rats, these were randomized for therapy with (1) saline, (2) endothelin receptor antagonist (ET-RA), (3) platelet activating factor receptor antagonist (PAF-RA), (4) intercellular adhesion molecule-1 antibody (ICAM-1-AB) or different combinations (5-7). After 24 h the animals underwent a second laparotomy for intra-vital microscopic determination of pancreatic and colonic capillary permeability, blood flow and leukocyte-endothelial interaction. AP induction decreased capillary blood flow and increased permeability and leukocyte rolling. ET-RA, PAF-RA and ICAM-1-AB decreased capillary permeability, increased blood flow and reduced leukocyte rolling. ET-RA was most effective in decreasing capillary permeability in both organs as well as in increasing pancreatic capillary blood flow. Combining vasoactive mediator blockers did not further improve target parameters. This study supports previous observations that ET-RA, PAF-RA and ICAM-1-AB improve microcirculation in AP and that ET-RA is more effective than PAF-RA or ICAM-1-AB, especially in counteracting capillary leakage. Although this may suggest that they act through different mechanisms, antagonist combinations failed to improve microcirculation further. We conclude that ET-RA is the most promising candidate for a clinical trial to reduce capillary leakage in patients with AP.