Therapy for microcirculatory disorders in severe acute pancreatitis: Comparison of delayed therapy with ICAM-1 antibodies and a specific endothelin Areceptor antagonist

Many of the complications in severe acute pancreatitis result from the ampl ifying effects of microcirculatory disruption. The pathogenesis of these mi crocirculatory disorders is multifactorial and involves various vasoactive mediators. Thus questions arise as to which vasoactive mediators are most i mportant and how long after the onset of disease vasoactive mediator blocka de may be effective. The present study compares the effect of delayed thera py with two vasoactive mediator antagonists, previously tested with promisi ng results in other studies in a well-established rodent model of severe ac ute 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/k g LU 135252), or saline solution (volume equivalent). After 12 hours of flu id resuscitation, animals underwent repeat laparotomy for intravital micros copic de termination of capillary blood flow, leukocyte rolling, and capill ary permeability in the pancreas and colon. Other measurements included car diorespiratory parameters, hematocrit, pleural effusions, ascites, urine pr oduction, and survival. Compared to saline treatment, both ICAM antibody an d ET-RA significantly enhanced capillary blood flow in the pancreas and col on, reduced leukocyte rolling, and stabilized capillary permeability. These beneficial effects on microcirculation were associated with decreased flui d loss into the third space and improved renal function and survival. Altho ugh both antagonists likewise enhanced capillary blood flow and reduced leu kocyte rolling, ET-RA was significantly more effective than ICAM antibody i n counteracting capillary leakage, thereby further reducing fluid sequestra tion. The present study confirms the beneficial effects of endothelin and I CAM antagonists in severe acute pancreatitis, even with delayed therapy, su ggesting that both compounds are candidates for further clinical testing. S elective endothelin A receptor blockade appears to be especially am-active for clinical use not only because it was superior to ICAM antibody in the p resent study but also because of its favorable pharmacologic properties and (preliminary) positive results in clinical phase 2 studies currently under way for other diseases.