Endothelin receptor blockade in severe acute pancreatitis leads to systemic enhancement of microcirculation, stabilization of capillary permeability,and improved survival rates

Background. We previously demonstrated that therapy with a new endothelin A receptor antagonist (ET-RA) significantly reduced mortality rates in sever e acute pancreatitis (AP) in the rat without attenuating local signs of dis ease severity (intrapancreatic protease activation, acinar cell necrosis). This raised the question as to why ET-RA was so effective. The purpose of t his study was to assess the effect of ET-RA on microcirculation (particular ly capillary permeability) within and outside of the pancreas on intravascu lar fluid loss and extravascular fluid sequestration and on distant organ f unction. Methods. Severe AP was induced in rats by standardized intraductal bib acid infusion and cerulein hyperstimulation. Starting 6 hours (n = 24 rats) and 12 hours (n = 30 rats) after the onset of AP: animals randomly received ei ther the ET-RA (LU-135252) or saline solution with fluid resuscitation (6 m L/kg/h Ringer's lactate). At 24 hours, animals were relaparotomized for int ravital microscopic determination of capillary blood flow, leukocyte rollin g, and capillary permeability in the pancreas and colon. Further monitoring included cardiorespiratory and renal parameters, hematocrit levels and qua ntification of ascites and pleural effusions, and acinar cell necrosis at a utopsy. Groups of sham-operated healthy animals (n = 6 animals each) that h ad been treated according to the same protocol served as control animals. Results. ET-RA treatment that was started 6 hours after AP-induction signif icantly decreased hematocrit levels (38% +/- 1% vs 45% +/- 2% with saline s olution treatment), reduced ascites and pleural effusions (6.7 +/- 1.3 mt v s 11.9 +/- 1.3 mi), and improved urine production (4.8 +/- 0.5 mi vs 2.9 +/ - 0.6 mi) and respiratory parameters. Moreover; all microcirculatory parame ters were improved; in particular, capillary permeability was stabilized (1 58% +/- 9% vs 248% +/- 8% in the colon). These beneficial effects were also seen when therapy was delayed until 12 hours after AP induction. Pancreati c necrosis was not significantly reduced. The overall mortality rate was 12 % in ET-RA-treated animals and 42% in saline solution-treated control anima ls (P < .05). In healthy animals ET-RA did not significantly alter the targ et parameters, except for a reduction of capillary permeability in the panc reas. Conclusions. Improved microcirculation and stabilized capillary permeabilit y in ET-RA-treated animals together with reduced intravascular fluid loss a nd extravascular fluid sequestration and improved renal and pulmonary funct ion (1) may explain improved survival in this model, (2) support the hypoth esis that systemic disease sequelae significantly contribute to outcome in AP, and (3) suggest that ET-RA may be a promising therapeutic tool in AP be cause it counteracts microcirculatory disorders that contribute to pancreat itis-associated organ dysfunction even when therapy is delayed to a point a t which pancreatic injury may no longer be influenced.