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Research ArticleCARDIOVASCULAR

Donitriptan Selectively Decreases Jugular Venous Oxygen Saturation in the Anesthetized Pig: Further Insights into Its Mechanism of Action Relevant to Headache Relief

Robert Létienne, Yvan Verscheure, Michel Perez, Bruno Le Grand, Francis C. Colpaert and Gareth W. John
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 749-754; DOI: https://doi.org/10.1124/jpet.102.047225
Robert Létienne
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Yvan Verscheure
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Michel Perez
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Bruno Le Grand
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Francis C. Colpaert
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Gareth W. John
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Abstract

The effects of donitriptan on systemic arterial-jugular venous oxygen saturation difference were evaluated in pentobarbitone-anesthetized pigs. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (40% polyethyleneglycol in saline, n = 9) or donitriptan (0.01, 0.04, 0.16, 0.63, 2.5, 10, and 40 μg/kg, n= 7) were cumulatively infused over 15 min/dose. The involvement of 5-hydroxytryptamine1B (5-HT1B) receptors was assessed in the presence of the 5-HT1B/1D receptor antagonist, GR 127935. Donitriptan decreased markedly and dose dependently jugular venous oxygen saturation [ED50 0.5 (0.3–1.1) μg/kg], in parallel with increases in carotid vascular resistance [ED50 0.9 (0.7–1.1) μg/kg]. Since arterial oxygen saturation and partial pressure remained unchanged, donitriptan significantly increased arteriovenous oxygen saturation difference from 0.63 μg/kg (maximal variation: 57 ± 18%, P< 0.05 compared with vehicle). Unexpectedly, donitriptan from 2.5 μg/kg induced marked and significant increases in carbon dioxide partial pressure (pVCO2) in venous blood (maximal increase 18.8 ± 5.7%; P < 0.05 compared with vehicle). Pretreatment with GR 127935 (0.63 mg/kg,n = 5) abolished the fall in venous oxygen saturation and the increase in carotid vascular resistance and reduced the increases in pVCO2 induced by donitriptan. The results demonstrate that donitriptan, via 5-HT1B receptor activation, decreases the oxygen saturation of venous blood draining the head, concomitantly with cranial vasoconstriction. Since donitriptan also increased pVCO2, an effect upon cerebral oxygen consumption and metabolism is suggested in addition to cranial vasoconstriction, which may be relevant to its headache-relieving effects.

Footnotes

  • DOI: 10.1124/jpet.102.047225

  • Abbreviations:
    5-HT
    5-hydroxytryptamine
    AVA
    arteriovenous anastomosis
    AVOSD
    arterial-jugular venous oxygen saturation difference
    LVP
    left ventricular pressure
    TCBF
    total carotid blood flow
    ABF
    aortic blood flow
    LAD
    left anterior descending
    LADVR
    LAD vascular resistance
    AOS
    oxygen saturation in systemic arterial blood
    VOS
    venous oxygen saturation
    GR 127935
    N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2[-methyl-4(5-methyl-1,2,4)-oxadiazol-3-yl]-(1,1 biphenyl)-4-carboxamide dihydrochloride
    ANOVA
    analysis of variance
    HR
    heart rate
    • Received November 21, 2002.
    • Accepted January 22, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Research ArticleCARDIOVASCULAR

Donitriptan Selectively Decreases Jugular Venous Oxygen Saturation in the Anesthetized Pig: Further Insights into Its Mechanism of Action Relevant to Headache Relief

Robert Létienne, Yvan Verscheure, Michel Perez, Bruno Le Grand, Francis C. Colpaert and Gareth W. John
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 749-754; DOI: https://doi.org/10.1124/jpet.102.047225

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Research ArticleCARDIOVASCULAR

Donitriptan Selectively Decreases Jugular Venous Oxygen Saturation in the Anesthetized Pig: Further Insights into Its Mechanism of Action Relevant to Headache Relief

Robert Létienne, Yvan Verscheure, Michel Perez, Bruno Le Grand, Francis C. Colpaert and Gareth W. John
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 749-754; DOI: https://doi.org/10.1124/jpet.102.047225
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