Central, cardiovascular and metabolic effects of dexmedetomidine associated with the selective peripheral alpha2-adrenoceptor antagonist MK-467 in dogs

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http://urn.fi/URN:ISBN:978-951-51-1735-9 http://hdl.handle.net/10138/158093
Title: Central, cardiovascular and metabolic effects of dexmedetomidine associated with the selective peripheral alpha2-adrenoceptor antagonist MK-467 in dogs
Author: Restitutti, Flavia
Other contributor: Kästner, Sabine
Vainio, Outi
Raekallio, Marja
Kuusela, Erja
Contributor organization: University of Helsinki, Faculty of Veterinary Medicine, Pharmacology and Toxicology, Department of Equine and Small Animal Medicine
Helsingin yliopisto, eläinlääketieteellinen tiedekunta
Helsingfors universitet, veterinärmedicinska fakulteten
Publisher: Helsingin yliopisto
Date: 2015-12-11
Language: eng
URI: http://urn.fi/URN:ISBN:978-951-51-1735-9
Thesis level: Doctoral dissertation (article-based)
Abstract: This series of investigations aimed to evaluate in dogs the interaction between MK-467, a peripheral α2-adrenoceptor antagonist with poor penetration into the central nervous system, and dexmedetomidine, a selective α2-adrenoceptor agonist commonly employed in small animal clinical practice due its potent sedative effects. The objective of this study was to find an optimal dose-ratio of dexmedetomidine and the antagonist that could attenuate or prevent major cardiovascular changes without any significant effect on the sedation induced by the agonist. The effects on blood flow in abdominal organs and on plasma concentrations of glucose, insulin, non-esterified free fatty acids, lactate and cortisol of this optimal dose were then evaluated. The sedative effects were assessed subjectively by means of a composite sedation score. Simultaneously, hypnosis was evaluated through the bispectral index. Haemodynamic parameters that were evaluated comprised cardiac output, arterial blood pressure, heart rate, central venous pressure and systemic vascular resistance. Time-intensity parameters derived from contrast-enhanced ultrasound imaging were used to assess blood flow in selected abdominal organs. Three doses of MK-467 (250, 500 and 750 µg/kg) were tested against dexmedetomidine alone (10 µg/kg). All treatments were administered IV. Sedation was significantly lower and BIS significantly higher with the medium and highest doses of MK-467 than with dexmedetomidine. However, bioequivalence between dexmedetomidine and the combination was reached with all treatments for the two parameters analysed. Early cardiovascular effects of dexmedetomidine were not completely prevented with the lowest dose of MK-467, and the highest dose reduced mean arterial pressure. The middle dose of MK-467 (500 µg/kg) provided the best cardiovascular stability. Addition of the peripheral antagonist attenuated dexmedetomidine-induced changes in organ blood flow evaluated by the CEUS. An increase in plasma glucose was observed in dexmedetomidine-treated dogs, but not when MK-467 was added. Inversely, plasma insulin concentration was reduced with dexmedetomidine, but not when dexmedetomidine was combined with MK-467. Plasma non-esterified free fatty acids concentration decreased transiently with the combination, while with dexmedetomidine alone the reduction persisted throughout the observation period. Plasma lactate concentration increased with dexmedetomidine, but not with the combination. In conclusion, the addition of MK-467 attenuated or prevented the early cardiovascular effects of dexmedetomidine, not having clinically relevant effects on the sedation induced by the latter. Some metabolic changes induced by dexmedetomidine were halted by MK-467.
Subject: pharmacology
Rights: Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.

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