Haemodynamic effects of MK-467 in combination with medetomidine and selected sedative and anaesthetic agents in dogs

Medetomidine (MED), an 2-adrenergic agonist, is widely used in veterinary practice as a sedative and premedication agent, as it provides reliable sedation. However, the marked haemodynamic changes limit its use to only healthy patients. MK-467, a peripheral 2 -adrenoceptor antagonist, has been demonstrated to attenuate the early haemodynamic disturbances induced by MED with intravenous co-administration in dogs. The main aim of this series of investigations was to evaluate the haemodynamic effects of MK-467 when it is combined with MED and selected sedative or anaesthetic agents that are commonly used in veterinary practice in dogs. More specifically, the concomitant administration of MK-467, MED and butorphanol via intravenous or intramuscular routes was studied and compared with sedation induced with MED-butorphanol. The haemodynamic effects after the various doses of MK-467 in relation to the standard dose of MED were evaluated prior to and during isoflurane anaesthesia. In addition, the haemodynamic effect of the administration of MK-467 as a constant rate infusion was assessed during MED-alfaxalone total intravenous anaesthesia. As a comparison, the haemodynamic effects of the co-administration of MK-467 and MED as a premedication regimen in relation to acepromazine-butorphanol or glycopyrrolate-medetomidine prior to and during isoflurane anaesthesia were assessed. Finally, the influence of MK-467 on plasma dexmedetomidine and alfaxalone concentrations was determined. After intravenous administration of MK-467 and MED with or without butorphanol heart rate, cardiac output and oxygen delivery were well maintained, and the increase in systemic vascular resistance and blood pressures was prevented. The profitable effects of MK-467 appeared more slowly after intramuscular than after intravenous administration. The initial MED-induced haemodynamic effects were dose-dependently attenuated by MK-467 during the premedication period but not during isoflurane anaesthesia with these studied doses of MK-467 in relation to a standard dose of MED as a premedication regimen. The addition of MK-467 to MED and alfaxalone produced a stable haemodynamic outcome when they were administered as constant rate infusions. Cardiac output and oxygen delivery were well maintained during both inhalation and total intravenous anaesthetic regimens when MK-467 was involved. The haemodynamic effects after the co-administration of MED-MK-467 or acepromazine-butorphanol mimicked each other prior to and during isoflurane anaesthesia. Pre-treatment with subcutaneous glycopyrrolate failed to improve the MED-induced reduction in cardiac output by means of increasing heart rate prior to or during isoflurane anaesthesia. Peripheral 2- adrenergic receptor blockade by MK-467 resulted in a reduction in plasma dexmedetomidine and alfaxalone concentrations, presumably by altering the haemodynamic function. In conclusion, the addition of MK-467 in a MED-contained sedation or anaesthetic regimen attenuates the rather dramatic MED-induced haemodynamic changes by blocking peripheral 2-adrenergic receptors and by decreasing the plasma concentrations of dexmedetomidine. The overall haemodynamic stability is well maintained during either an isoflurane anaesthesia or an alfaxalone constant rate infusion. The combination of MK-467 with MED may offer an alternative premedication regimen to the combination of acepromazine and butorphanol in healthy dogs.