EVIDENCE FOR MEDETOMIDINE AS A SELECTIVE AND POTENT AGONIST α₂‐ADRENORECEPTORS

Abstract

The activity on alpha-adrenoreceptors of medetomidine ((+/-)-4-(alpha,2,3-trimethylbenzyl)imidazole), an alpha-methyl derivative of detomidine, has been characterized in vivo and in vitro using detomidine, MPV 207, MPV 295, azepexole, clonidine and xylazine for reference purposes. Medetomidine (1-100 micrograms/kg i.v.) was a hypotensive and bradycardic compound in anaesthetized rats. Furthermore, it induced vasopressor (PD50 1.7 microgram/kg) and sympatho-inhibitory (ID50 1.6 microgram/kg) actions in pithed rats, the effects being antagonized by idazoxan (0.3 mg/kg i.v.) but not by prazosin (0.1 mg/kg i.v.). Medetomidine (30-300 micrograms/kg i.m.) had an alpha 2-adrenoreceptor mediated sedative effect on chicks. Medetomidine was, overall, more potent than detomidine, MPV 207, clonidine, xylazine, MPV 295 or azepexole in central (sedation in the chick) and peripheral (cardiac presynaptic in the pithed rat) actions on alpha 2-adrenoreceptors. Clonidine had, however, about an equal potency to medetomidine in the vascular smooth muscle of the pithed rat. Like detomidine and MPV 295, medetomidine had no agonistic activity in the rat aortic ring, but high concentrations antagonized methoxamine-induced contractions, giving a pA2 value of 5.68 for alpha 1-adrenoreceptor antagonism. The overall lipophilicity (log P') of medetomidine in the octanol/buffer (pH 7.4, 24-26 degrees C, HPLC technique) was 2.80. In summary, the experimental data suggest that medetomidine is a lipophilic compound with selective alpha 2-adrenoreceptor-stimulating properties and high potency. It may, therefore, prove to be a suitable pharmacologic tool for interventions in alpha 2-adrenoreceptor mediated effects in the autonomic nervous system.

The effect of medetomidine, an α2‐adrenoceptor agonist, on plasma atrial natriuretic peptide levels, haemodynamics and renal excretory function in spontaneously hypertensive and Wistar‐Kyoto rats

“…Although decreasing similarly heart rate in both strains, the effect of medetomidine on blood pressure differed in WKY and SHR rats, causing a decrease in mean arterial pressure in SHR, while in normotensive WKY it increased blood pressure. In anesthetized rats, medetomidine had a blood pressure action resembling that of clonidine, with an initial transient rise in blood pressure followed by a gradual decrease (Savola et al, 1986). In pithed rats, its vasoconstrictor effect has been found to be antagonized by a2-adrenoceptor, but not a1-adrenoceptor blocking drugs (Savola et al, 1986).…”

“…In anesthetized rats, medetomidine had a blood pressure action resembling that of clonidine, with an initial transient rise in blood pressure followed by a gradual decrease (Savola et al, 1986). In pithed rats, its vasoconstrictor effect has been found to be antagonized by a2-adrenoceptor, but not a1-adrenoceptor blocking drugs (Savola et al, 1986). …”

“…The present study was thus undertaken to examine the effects of an Ox2-agonist, medetomidine, on plasma levels of immunoreactive ANP (IR-ANP), haemodynamics (mean arterial pressure, heart rate, right atrial pressure) and renal excretory function simultaneously in genetically hypertensive and agematched normotensive control rats. Medetomidine has been shown to be a potent, selective and specific a2-adrenoceptor agonist both in experimental animals and in man (Savola et al, 1986;Scheinin et al, 1986;1987;Virtanen et al, 1988). Binding studies carried out in rat brain membranes showed a relative a2/ja selectivity ratio of 1620 for medetomidine (compared to 220 for clonidine, 300 for UK 14304) and negligible binding to, or effects at, fiadrenoceptors and opiate, adenosine, dopamine, histamine or 5-hydroxytryptamine receptors (Virtanen et al, 1988).…”

“…Biochemical experiments in rats have indicated that the compound reduces the release and metabolism of noradrenaline in the central nervous system (Scheinin et al, 1986). In anaesthetized rats, medetomidine reduced blood pressure and heart rate, and in the pithed rat it caused peripheral vasoconstriction and inhibition of tachycardia induced by preganglionic sympathetic nerve stimulation (Savola et al, 1986). Idazoxan and other a2-adrenoceptor antagonists, but not prazosin, antagonized these effects (Savola et al, 1986;Scheinin et al, 1986).…”

Characterization of pigment aggregating α2‐adrenoceptors of fish melanophores by use of different agonists after partial irreversible receptor inactivation

“…Thus, a non-linear relationship of the double reciprocal plot indicates more than one binding site. The novel imidazole compound medetomidine, which has been shown to possess a very high x2-adrenoceptor selectivity and potency (Savola et al, 1986), possibly interacts with two, kinetically different binding sites in the melanophores. The nonlinear relationship of the double reciprocal plot of equieffective concentrations of medetomidine, before and after receptor inactivation with benextramine, probably reflects different sensitivities of the binding sites to benextramine.…”