Objective: To evaluate the effect of a new Endothelin A receptor antagonist (ET-RA) on pancreatic microcirculation in a pig transplant model. Background: Impaired microcirculation is a major determinant of graft pancreatitis post transplant in humans. In animal models Endothelin 1 has been shown to reduce local blood flow in the pancreas and to aggravate pancreatitis.
Methods: Heterotopic pancreas transplantation was performed in Göttinger minipigs (n = 16 donors, n=16 recipients, female 20-25 kg). The grafts were stored for 6 hours in University of Wisconsin solution at 4C. Cyclosporine A and Prednisolon were administered for immunosuppression. The animals were randomized to a control (n = 8) and treatment group (n = 8) that received 10 mg/kg of the selective endothelin A receptor antagonist (BSF 208075) i.v. during reperfusion and after 6 h. Target parameter measured before and after reperfusion included quantification of the morphological damage by a score, tissue oxygenation, laser doppler flowmetry, serum amylase, serum lipase, and trypsinogen-activation peptide (TAP).
Results: A rapid onset of morphological alterations immediately after reperfusion was noted. The tissue damage score was significant lower in the treatment group (p<0,05). 60 min after reperfusion pO2 values were significant better in the treatment group (83.1% ± 9.7% of basal values vs. control group: 45.4% ± 12.1%; p< 0.05). Laser doppler-flowmetry showed also a significant improvement of erythrocyte flux in the treatment group (78.4% ± 8.2% of basal values vs. control: 47.1% ± 13.3%; p< 0.05). 60 min after reperfusion serum amylase (treatment 22.6 ± 5.3 µmol/l vs control: 81,0 ± 20,1 µmol/l) but not lipase and 6 hours after reperfusion serum lipase (treatment: 4.7 ± 1.0 µmol/l vs control: 9.8 ± 1.2 µmol/l), but not amylase values were significant lower in therapy group (p<0.05). TAP values measured at its maximum 45 min after reperfusion revealed no significant differences.
Conclusion: There is a marked impairment of pancreatic microcirculation after reperfusion. A selective endothelin A receptor antagonist counteracts this impairment and has a protective effect on ischemia/reperfusion injury after pancreas transplantation.