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

M Rasmussen, P H Poulsen, A Treiber, S Delahaye, A Tankisi, G E Cold, K Therkelsen, A Gjedde, J Astrup

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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 cm3/min. Administration of bosentan i.v. did not change CBF significantly. Indomethacin decreased CBF to 41 +/- 5 ml/100 cm3/min (P < 0.002). In group 2, baseline CBF was 54 +/- 10 ml/100 cm3/min. Placebo did not change CBF while indomethacin decreased CBF significantly to 41 +/- 5 ml/100 cm3/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 microg/ml, respectively. The corresponding values for the pharmacologically active metabolite Ro 48-5033 were 1.2 and 0.4 microg/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.

OriginalsprogEngelsk
BogserieActa Anaesthesiologica Scandinavica
Vol/bind47
Udgave nummer2
Sider (fra-til)200-7
Antal sider8
ISSN0001-5172
DOI
StatusUdgivet - feb. 2003

Fingeraftryk

Indomethacin
Placebos
Endothelin Receptors
Vasoconstriction
Pancuronium
Midazolam
Nitrous Oxide
Ketamine
Fentanyl
Intravenous Injections
Pharmacokinetics
Maintenance

Citer dette

Rasmussen, M ; Poulsen, P H ; Treiber, A ; Delahaye, S ; Tankisi, A ; Cold, G E ; Therkelsen, K ; Gjedde, A ; Astrup, J. / No influence of the endothelin receptor antagonist bosentan on basal and indomethacin-induced reduction of cerebral blood flow in pigs. I: Acta Anaesthesiologica Scandinavica. 2003 ; Bind 47, Nr. 2. s. 200-7.
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title = "No influence of the endothelin receptor antagonist bosentan on basal and indomethacin-induced reduction of cerebral blood flow in pigs",
abstract = "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 cm3/min. Administration of bosentan i.v. did not change CBF significantly. Indomethacin decreased CBF to 41 +/- 5 ml/100 cm3/min (P < 0.002). In group 2, baseline CBF was 54 +/- 10 ml/100 cm3/min. Placebo did not change CBF while indomethacin decreased CBF significantly to 41 +/- 5 ml/100 cm3/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 microg/ml, respectively. The corresponding values for the pharmacologically active metabolite Ro 48-5033 were 1.2 and 0.4 microg/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.",
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author = "M Rasmussen and Poulsen, {P H} and A Treiber and S Delahaye and A Tankisi and Cold, {G E} and K Therkelsen and A Gjedde and J Astrup",
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No influence of the endothelin receptor antagonist bosentan on basal and indomethacin-induced reduction of cerebral blood flow in pigs. / Rasmussen, M; Poulsen, P H; Treiber, A; Delahaye, S; Tankisi, A; Cold, G E; Therkelsen, K; Gjedde, A; Astrup, J.

I: Acta Anaesthesiologica Scandinavica, Bind 47, Nr. 2, 02.2003, s. 200-7.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - No influence of the endothelin receptor antagonist bosentan on basal and indomethacin-induced reduction of cerebral blood flow in pigs

AU - Rasmussen, M

AU - Poulsen, P H

AU - Treiber, A

AU - Delahaye, S

AU - Tankisi, A

AU - Cold, G E

AU - Therkelsen, K

AU - Gjedde, A

AU - Astrup, J

N1 - Copyright Acta Anaesthesiologica Scandinavica 47 (2003)

PY - 2003/2

Y1 - 2003/2

N2 - 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 cm3/min. Administration of bosentan i.v. did not change CBF significantly. Indomethacin decreased CBF to 41 +/- 5 ml/100 cm3/min (P < 0.002). In group 2, baseline CBF was 54 +/- 10 ml/100 cm3/min. Placebo did not change CBF while indomethacin decreased CBF significantly to 41 +/- 5 ml/100 cm3/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 microg/ml, respectively. The corresponding values for the pharmacologically active metabolite Ro 48-5033 were 1.2 and 0.4 microg/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.

AB - 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 cm3/min. Administration of bosentan i.v. did not change CBF significantly. Indomethacin decreased CBF to 41 +/- 5 ml/100 cm3/min (P < 0.002). In group 2, baseline CBF was 54 +/- 10 ml/100 cm3/min. Placebo did not change CBF while indomethacin decreased CBF significantly to 41 +/- 5 ml/100 cm3/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 microg/ml, respectively. The corresponding values for the pharmacologically active metabolite Ro 48-5033 were 1.2 and 0.4 microg/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.

KW - Anesthesia

KW - Animals

KW - Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics

KW - Antihypertensive Agents/pharmacokinetics

KW - Bosentan

KW - Brain/diagnostic imaging

KW - Brain Chemistry/drug effects

KW - Cerebrovascular Circulation/drug effects

KW - Drug Interactions

KW - Endothelin Receptor Antagonists

KW - Female

KW - Indomethacin/pharmacokinetics

KW - Oxygen Consumption/drug effects

KW - Sulfonamides/pharmacokinetics

KW - Swine

KW - Tomography, Emission-Computed

U2 - 10.1034/j.1399-6576.2003.00019.x

DO - 10.1034/j.1399-6576.2003.00019.x

M3 - Journal article

VL - 47

SP - 200

EP - 207

JO - Acta Anaesthesiologica Scandinavica. Supplementum

JF - Acta Anaesthesiologica Scandinavica. Supplementum

SN - 0515-2720

IS - 2

ER -