No influence of the endothelin receptor antagonist bosentan on basal and indomethacin-induced reduction of cerebral blood flow in pigs

Background: The mechanism behind indomethacin-induced cerebral vasoconstriction is incompletely understood. We tested the hypothesis that the mixed endothelin-1 receptor antagonist bosentan would modify or prevent indomethacin-induced reduction of CBF in the anaesthetized pig. Furthermore, we investigated the effect of bosentan on resting CBF and CMRO2. Methods: Twelve pigs were randomized in two groups of six, and received either bosentan and indomethacin (group 1), or placebo and indomethacin (group 2). Anaesthesia was induced with ketamine and midazolam and maintained with fentanyl, nitrous oxide and pancuronium. Baseline measurements of CBF and CMRO2 were performed before intravenous bolus injection of bosentan (10 mg/kg) or placebo (0.9% NaCl). The second CBF and CMRO2 measurement was performed 30 min after administration of bosentan/placebo. A 40-min infusion of indomethacin (0.05 mg/kg/min) was administered and the third CBF and CMRO2 measurement was performed 80 min after administration of bosentan/placebo. Independently, pharmacokinetic data of bosentan were generated in four pigs. Results: In group 1, baseline CBF was 55 +/- 7 ml/100 cm(3) /min. Administration of bosentan i.v. did not change CBF significantly. Indomethacin decreased CBF to 41 +/- 5 ml/100 cm(3)/min (P < 0.002). In group 2, baseline CBF was 54 +/- 10 ml/100 cm(3) /min. Placebo did not change CBF while indomethacin decreased CBF significantly to 41 +/- 5 ml/100 cm(3)/min (P < 0.002). No significant changes in CMRO2 were observed. In group 2, a significant increase in MABP was observed after administration of indomethacin. No change in MABP was observed in the bosentan-treated animals. Total plasma concentrations of bosentan at the time of the first and the second PET measurement were 3.9 and 1.4 mug/ml, respectively. The corresponding values for the pharmacologically active metabolite Ro 48-5033 were 1.2 and 0.4 mug/ml. Conclusion: These findings indicate that endothelin receptor stimulation is not involved in indomethacin-induced cerebral vasoconstriction or maintenance of cerebrovascular tone in the anaesthetized pig. However, our results suggest that the increase in MABP is mediated through endothelin receptors.