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Effects of the peripherally acting α2-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated by intramuscular administration of medetomidine and ketamine and reversed by intramuscular administration of atipamezole

Magdy Adam DVM1,2, Marja R. Raekallio DVM, PhD3, Kati M. Salla DVM, PhD4, Juhana M. Honkavaara DVM, PhD5,6, Sofia Männikkö MSc7, Mika Scheinin MD, PhD8,9, Marena Kajula MSc10, Sari H. Mölsä DVM, PhD11, and Outi M. Vainio DVM, PhD12
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  • 1 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, 00100 Helsinki, Finland.
  • | 2 Pharmacology Department, Faculty of Veterinary Medicine, Beni-Suef University, 62511 Beni-Suef, Egypt.
  • | 3 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, 00100 Helsinki, Finland.
  • | 4 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, 00100 Helsinki, Finland.
  • | 5 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, 00100 Helsinki, Finland.
  • | 6 William Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 7 Department of Statistics, 4Pharma Ltd, Tykistökatu 4D, 20520 Turku, Finland.
  • | 8 Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland.
  • | 9 Unit of Clinical Pharmacology, Turku University Hospital, FI-20520 Turku, Finland.
  • | 10 Admescope Ltd, Typpitie 1, 90620 Oulu, Finland.
  • | 11 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, 00100 Helsinki, Finland.
  • | 12 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, 00100 Helsinki, Finland.

Abstract

OBJECTIVE To evaluate effects of the peripherally acting α2-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated with medetomidine and ketamine.

ANIMALS 9 healthy adult female sheep.

PROCEDURES Each animal received an IM injection of a combination of medetomidine (30 μg/kg) and ketamine (1 mg/kg; Med-Ket) alone and Med-Ket and 3 doses of MK-467 (150, 300, and 600 μg/kg) in a randomized blinded 4-way crossover study. Atipamezole (150 μg/kg, IM) was administered 60 minutes later to reverse sedation. Cardiopulmonary variables and sedation scores were recorded, and drug concentrations in plasma were analyzed. Data were analyzed with a repeated-measures ANCOVA and 1-way ANOVA. Reference limits for the equivalence of sedation scores were set at 0.8 and 1.25.

RESULTS Heart rate, cardiac output, and Pao2 decreased and mean arterial blood pressure, central venous pressure, and systemic vascular resistance increased after Med-Ket alone. Administration of MK-467 significantly alleviated these effects, except for the decrease in cardiac output. After sedation was reversed with atipamezole, no significant differences were detected in cardiopulmonary variables among the treatments. Administration of MK-467 did not significantly alter plasma concentrations of medetomidine, ketamine, norketamine, or atipamezole. Sedation as determined on the basis of overall sedation scores was similar among treatments.

CONCLUSIONS AND CLINICAL RELEVANCE Concurrent administration of MK-467 alleviated cardiopulmonary effects in sheep sedated with Med-Ket without affecting sedation or reversal with atipamezole.

Abstract

OBJECTIVE To evaluate effects of the peripherally acting α2-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated with medetomidine and ketamine.

ANIMALS 9 healthy adult female sheep.

PROCEDURES Each animal received an IM injection of a combination of medetomidine (30 μg/kg) and ketamine (1 mg/kg; Med-Ket) alone and Med-Ket and 3 doses of MK-467 (150, 300, and 600 μg/kg) in a randomized blinded 4-way crossover study. Atipamezole (150 μg/kg, IM) was administered 60 minutes later to reverse sedation. Cardiopulmonary variables and sedation scores were recorded, and drug concentrations in plasma were analyzed. Data were analyzed with a repeated-measures ANCOVA and 1-way ANOVA. Reference limits for the equivalence of sedation scores were set at 0.8 and 1.25.

RESULTS Heart rate, cardiac output, and Pao2 decreased and mean arterial blood pressure, central venous pressure, and systemic vascular resistance increased after Med-Ket alone. Administration of MK-467 significantly alleviated these effects, except for the decrease in cardiac output. After sedation was reversed with atipamezole, no significant differences were detected in cardiopulmonary variables among the treatments. Administration of MK-467 did not significantly alter plasma concentrations of medetomidine, ketamine, norketamine, or atipamezole. Sedation as determined on the basis of overall sedation scores was similar among treatments.

CONCLUSIONS AND CLINICAL RELEVANCE Concurrent administration of MK-467 alleviated cardiopulmonary effects in sheep sedated with Med-Ket without affecting sedation or reversal with atipamezole.

Contributor Notes

Address correspondence to Dr. Adam (magdy.adam@helsinki.fi).