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.

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The effect of cimetidine on human microsomal drug metabolism was studied. In five of six healthy volunteers therapeutic doses of cimetidine prolonged the half-life of antipyrine (range 12-37%; p < 0.05). Its clearance was decreased in five subjects (range 2-18%) and was increased in one subject (15%), the changes not being statistically significant. The volume of distribution increased on average by about 14% (range 9--19%; p < 0.001). Cimetidine in vitro inhibited the hydroxylation of benzo(a)pyrene and coumarin, as well as the O-deethylation of 7-ethoxycoumarin, by homogenised liver biopsies. The in vitro studies suggest that the effect of cimetidine on antipyrine elimination is due to inhibition of microsomal drug metabolism, which may prove an important drug interaction.

The action of ethanol on peptic activity in the stomach was evaluated by studying ethanol-induced changes in pepsinogen secretion in the rat in vivo and the effects of ethanol on pepsinogen and pepsin in vitro. Irrigation of the stomach with 3% ethanol in 100 mM HCl plus 50 mM NaCl had no effect on pepsinogen secretion, whereas 10 and 20% ethanol gave maximal increases of about 40 and 65%, respectively. 10% ethanol in 150 mM NaCl (pH 5.0) stimulated pepsinogen secretion maximally by about 60%. 10% ethanol in distilled water had no effect on spontaneous secretion of pepsinogen, but enhanced pepsinogen secretion induced by irrigation of the stomach with 100 mM HCl, 100 mM NaCl, 150 mM sucrose, or by an intravenous injection of carbachol. Ethanol inhibited the activation of pepsinogen to pepsin in vitro in a pH-dependent manner. The activity of pepsin was inhibited by ethanol with an IC50 value of about 10%. The results indicate that the effects of ethanol on pepsinogen secretion and the enzymes, pepsinogen and pepsin, are opposite in the rat. It is thus difficult to conclude what are the net effects of various concentrations of ethanol on the peptic activity of the gastric content, but at least higher concentrations can be expected to reduce this activity.

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