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A study of the cardiovascular and respiratory pharmacology of amitraz

Cullen, Leonard Keith (1986) A study of the cardiovascular and respiratory pharmacology of amitraz. PhD thesis, Murdoch University.

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Abstract

The formarnidine, amitraz, is used as an acaricide wash for dogs and side effects, although rare, have been reported. These include CNS depression, ataxia, vomiting and, in more severe cases, hypothermia, bradycardia, hyperventilation and tachycardia.

The unexplained side effects, particularly the unusual biphasic heart rate responses, prompted this pharmacological study of the actions of amitraz on the cardiovascular and respiratory systems. Methods for reversal of the toxic effects of amitraz may emerge from these studies.

Studies were made using mongrel dogs anaesthetised with thiopentone and methoxyflurane. Initial investigations showed that IV amitraz (1, 2 and 5 mg kg-1) increased mean arterial pressure, lowered heart rate and depressed tidal volume. Respiratory rate, tidal volume and respiratory minute volume were all markedly depressed immediately after injection but respiratory rate then showed a dose-related increase and minute volume showed little change from the control. Bradycardia was less after higher doses.

Cumulative doses of IV arnitraz were given after cardiovascular antagonists. Phentolamine antagonised the amitraz-induced hypertension, the effects of atropine and hexamethonium suggested that initial bradycardia was a reflex response and propranolol had no obvious effect on arnitraz responses. The rise in blood pressure elicited by amitraz appeared to follow peripheral a-adrenoceptor stimulation. A peripheral vascular effect was supported by the concurrent dose-related rise in total peripheral resistance and blood pressure. Cardiac output remained unchanged 5 minutes after injection following an immediate transient fall.

Blood pressure responses to tyrarnine were increased by amitraz but a possible indirect sympathomirnetic effect is unlikely since desipramine failed to alter amitraz responses. The effects of acetylcholine and DMPP on mean arterial pressure were depressed by amitraz; the reduced DMPP response was attributed to α2 -adrenoceptor stimulation. Responses to noradrenaline, isoprenaline and histamine remained unchanged.

Blood pressure and heart rate responses to bilateral carotid artery occlusion -1 were depressed by amitraz (threshold doses 2 μg kg-1 intracisternally [ICM] and 60 μg kg-1 IV), an effect antagonised by ICM yohimbine but not ICM prazosin. The baroreceptor-heart rate reflex was enhanced by 75 and 275 μg kg-1 of amitraz IV but inhibited by 0.5, 2 and 5 mg kg-1, effects attributed to α2- and α1-adrenoceptor stimulation, respectively.

Blood pressure and heart rate were lowered by 0.5 μg kg-1 of amitraz ICM and between 40 and 60 μg kg-1 IV. ICM yohimbine antagonised the hypotensive effects while ICM yohimbine and ICM prazosin, in separate experiments, each partly inhibited the bradycardia. Amitraz stimulated both α1- and α2-adrenoceptors in the peripheral vasculature.

The a2-adrenoceptor agonist action of amitraz was confirmed using rat isolated vas deferens preparations.

Amitraz has been shown to be an α2-adrenoceptor agonist with some action at the α1-subtype. Its central effects are hypotension, bradycardia and interference with cardiovascular reflexes while its peripheral actions increase blood pressure and produce a transient reflex bradycardia.

Publication Type: Thesis (PhD)
Murdoch Affiliation: School of Veterinary Studies
Supervisor: Reynoldson, Jim
URI: http://researchrepository.murdoch.edu.au/id/eprint/42185
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