Effects of dexmedetomidine and MK-467 on plasma glucose, insulin and glucagon in a glibenclamide-induced canine hypoglycaemia model

I.J Kallio-Kujala,R.C Bennett,M.R Raekallio,E Yatkin,A Meierjohann,E Savontaus,M Scheinin,T Spillmann,O.M Vainio

doi:10.1016/j.tvjl.2018.09.012

Abstract

The commonly used sedative α2-adrenoceptor agonist dexmedetomidine has adverse cardiovascular effects in dogs that can be prevented by concomitant administration of the peripherally acting α2-adrenoceptor antagonist MK-467. An ancillary effect of dexmedetomidine is to decrease insulin release from the pancreas, whereas MK-467 stimulates insulin release. This study assessed the effects of co-administered dexmedetomidine and MK-467 in a canine glibenclamide-induced hypoglycaemia model. In a randomised, cross-over experiment, eight beagle dogs received five intravenous treatments, comprising two administrations of saline, with dexmedetomidine or dexmedetomidine and MK-467, and three administrations of glibenclamide, with saline, dexmedetomidine or dexmedetomidine and MK-467. Plasma concentrations of glucose, lactate, insulin, glucagon and the test drugs were monitored. Administration of glibenclamide significantly increased insulin secretion and decreased blood glucose concentrations. Dexmedetomidine counteracted glibenclamide-evoked hypoglycaemia. This was opposed by the α2-adrenoceptor antagonist MK-467, but the glibenclamide-evoked hypoglycaemia was not potentiated by co-administration of dexmedetomidine and MK-467. None of the dogs developed uncontrolled hypoglycaemia. Thus, the combination of dexmedetomidine and MK-467 appeared to be safe in this canine hypoglycaemia model. Nevertheless, when MK-467 is used to alleviate the undesired cardiovascular effects of α2-adrenoceptor agonists in dogs, it should be used with caution in animals at risk for hypoglycaemia because of its insulin-releasing and hypoglycaemic effects.

Highlights

Dexmedetomidine is a selective agonist of α2-adrenoceptors, an important class of receptors for noradrenaline and adrenaline
The aim of the present study was to determine the effects of the combination of dexmedetomidine and MK-467 in a canine glibenclamide-induced hypoglycaemia model to predict its safety in hypoglycaemic dogs undergoing sedation
Whilst coadministration of MK-467 blocked this anti-hypoglycaemic effect of dexmedetomidine, glucose responses were not different after glibenclamide as the sole drug (GLIB) and glibenclamide followed by the sedative combination (GLIB-dexmedetomidine and MK-467 (DEX-MK))

Summary

Introduction

Dexmedetomidine is a selective agonist of α2-adrenoceptors, an important class of receptors for noradrenaline and adrenaline. In addition to their sedative effects, all drugs in this class depress the cardiovascular system by evoking vasoconstriction, followed by marked baroreflex-mediated bradycardia (Bloor et al, 1992; Flacke et al, 1993; Pypendop and Verstegen, 1998). Dexmedetomidine decreases insulin release from the pancreas (Burton et al, 1997) and increases plasma glucose concentrations in dogs (Benson et al, 2000; Ambrisko and Hikasa, 2002; Restitutti et al, 2012). Co-administration of MK-467 prevents dexmedetomidine-induced changes in plasma insulin, glucose and lactate concentrations in healthy dogs (Restitutti et al, 2012)

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