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1 The selectivity of a number of agonists for peripheral alpha 1- and alpha 2- adrenoreceptors was determined and related to their cardiovascular effects in pentobarbitone-anaesthetized rats. 2 In isolated tissues, presynaptic alpha 2- and postsynaptic alpha 1-adrenoreceptor activity was determined on the rat vas deferens and anococcygeus muscle respectively. Xylazine, guanabenz, guanoxabenz and guanfacin were more selective, whilst lofexidine, tiamenidine, naphazoline, oxymetazoline and St 91 were less selective than clonidine for presynaptic alpha 2-adrenoreceptors. 3 The anococcygeus muscle of the pithed rat was used to determine the alpha-adrenoreceptor selectivity of the compounds in vivo. The selectivities were similar to those obtained in vitro. 4 Following intravenous administration to pentobarbitone-anaesthetized rats guanabenz and guanfacin caused small transient pressor responses and a prolonged secondary hypotension. In contrast oxymetazoline and St 91 produced marked initial pressor responses and the secondary reduction in blood pressure was absent. Clonidine and tiamenidine produced marked initial pressor responses followed by secondary hypotensive effects. All compounds reduced heart rate. 5 Intracerebroventricular (i.c.v.) administration of clonidine, guanabenz and guanfacin elicited falls in blood pressure and heart rate. In contrast blood pressure was either unaffected or elevated following i.c.v. administration of St 91, oxymetazoline and tiamenidine. 6 It is concluded that in the normotensive rat, central alpha 2-adrenoreceptors play a major role in the hypotensive effects of clonidine and related compounds.

The effects of alpha-adrenoceptor agonists and antagonists and of antidepressant drugs were studied on pre- and postsynaptic alpha-adrenoceptors. The rat vas deferens, stimulated at low frequency (0.1 Hz) was used for presynaptic studies. The rat anococcygeus muscle was used in postsynaptic studies. In the agonist studies clonidine and guanfacine were selective for presynaptic alpha-adrenoceptors, methoxamine and phenylephrine were selective for postsynaptic alpha-adrenoceptors and noradrenaline and alpha-methylnoradrenaline were equipotent at pre- and post-synaptic alpha-adrenoceptors. In the antagonist studies piperoxane and yohimbine were selective for presynaptic alpha-adrenoceptors, phentolamine was equipotent at pre- and postsynaptic alpha-adrenoceptors and prazosin was a selective postsynaptic alpha-adrenoceptor antagonist. In the series of antidepressants studied, mianserin was the most potent antagonist at presynaptic alpha-adrenoceptors, followed by trazodone, amitriptyline and nortriptyline in descending order of potency. Mianserin was approximately two hundred times less potent than piperoxane as a presynaptic alpha-adrenoceptor antagonist. Viloxazine and desipramine were inactive. With the exception of viloxazine all of the antidepressants examined possessed postsynaptic alpha-adrenoceptor antagonist properties.

The ability of a series of alpha adrenoceptor agonists to induce a sleep-like state (as measured by the time interval between the loss and regaining of the righting reflex) has been assessed in 2-day-old chicks in order to understand their pharmacological profile better. Guanabenz, guanoxabenz, UK-14,304, guanfacine and xylazine produced dose-related increases in sleeping time, the highest dose of these agonists causing the chicks to sleep for over 120 min. In contrast, the dose-response curves to tiamenidine and clonidine were flatter and bell-shaped with maxima of 30 and 60 min, respectively. The effects of all these compounds were antagonized by idazoxan (RX781094) and yohimbine (two selective alpha-2 adrenoceptor antagonists) but were moderately enhanced or unaffected by prazosin (a selective alpha-1 adrenoceptor antagonist) confirming that the state of arousal in chicks can be depressed by stimulation of alpha-2 adrenoceptors. In particular, idazoxan displaced significantly the guanoxabenz dose-response curve to the right without affecting its slope and apparent maximum and blocked the sleep induced by clonidine. However, idazoxan failed to affect the sleep evoked by ethanol, etorphine or pentobarbital. Naloxone antagonized the effects of etorphine but not those of guanoxabenz, ethanol or pentobarbital. The relatively selective alpha-1 adrenoceptor agonist, cirazoline, given in doses up to 20 mg/kg i.m., produced in chicks behavioral manifestations suggestive of enhanced arousal.(ABSTRACT TRUNCATED AT 250 WORDS)

In the pithed rat electrically induced contractions of the anococcygeus muscle were inhibited by clonidine (0.1--3.0 microgram/kg, i.v.), mecamylamine (1 mg/kg, i.v.) and guanethidine (1 mg/kg, i.v.). Only the inhibition produced by clonidine was antagonised by yohimbine (0.3 mg/kg, i.v.). At higher concentrations (10 microgram/kg, i.v.) clonidine increased the resting tension of the tissue; this effect was antagonised by phentolamine (1 mg/kg, i.v.). The anococcygeus muscle of the pithed rat was used to simultaneously assess pre- and postsynaptic alpha-adrenoceptor agonist activity. Guanfacin was more selective and tiamenidine less selective than clonidine for presynaptic alpha-adrenoceptors. Naphazoline and oxymetazoline were selective postsynaptic alpha-adrenoceptor agonists.