Therapy for microcirculatory disorders in severe acute pancreatitis: comparison of delayed therapy with ICAM-1 antibodies and a specific endothelin A receptor antagonist.
Many of the complications in severe acute pancreatitis result from the amplifying effects of microcirculatory disruption. The pathogenesis of these microcirculatory disorders is multifactorial and involves various vasoactive mediators. Thus questions arise as to which vasoactive mediators are most important and how long after the onset of disease vasoactive mediator blockade may be effective. The present study compares the effect of delayed therapy with two vasoactive mediator antagonists, previously tested with promising results in other studies in a well-established rodent model of severe acute pancreatitis. Twelve hours after induction of acute pancreatitis, rats were randomized to therapy with intracellular adhesion molecule-1 (ICAM-1) antibody (2 mg/kg IA-29), endothelin A receptor antagonist (ET-RA) (40 mg/kg LU 135252), or saline solution (volume equivalent). After 12 hours of fluid resuscitation, animals underwent repeat laparotomy 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 ICAM antibody and ET-RA significantly enhanced capillary blood flow in the pancreas and colon, reduced leukocyte rolling, and stabilized capillary permeability. These beneficial effects on microcirculation were associated with decreased fluid loss into the third space and improved renal function and survival. Although both antagonists likewise enhanced capillary blood flow and reduced leukocyte rolling, ET-RA was significantly more effective than ICAM antibody in counteracting capillary leakage, thereby further reducing fluid sequestration. The present study confirms the beneficial effects of endothelin and ICAM antagonists in severe acute pancreatitis, even with delayed therapy, suggesting that both compounds are candidates for further clinical testing. Selective endothelin A receptor blockade appears to be especially attractive for clinical use not only because it was superior to ICAM antibody in the present study but also because of its favorable pharmacologic properties and (preliminary) positive results in clinical phase 2 studies currently underway for other diseases.
Foitzik
T
T
Department of Surgery, Benjamin Franklin Medical Center, Freie Universität Berlin, Germany. foitzik@ukbf.fu-berlin.de
Eibl
G
G
Buhr
H J
HJ
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D065128:Endothelin Receptor Antagonists; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D008833:Microcirculation / Q000187:drug effects; D010179:Pancreas / Q000098:blood supply*; D010195:Pancreatitis / Q000145:classification / Q000628:therapy*; D010666:Phenylpropionates / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D016019:Survival Analysis
D000911:Antibodies, Monoclonal; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D018799:Intercellular Adhesion Molecule-1; C107831:darusentan