Marta Weinstock

Blockade of 5-hydroxytryptamine receptors in the central nervous system by β-adrenoceptor antagonists

Abstract (±)-propranolol, oxprenolol and pindolol in doses ranging from 0.5 to 5 mg/kg antagonised the head twitch produced in mice by 5HTP. These doses had no effect on the pinna reflex. (+) propranolol was inactive. These β-adrenoceptor antagonists also prevented the induction of sleep in 5-day old chicks by 5HT. Their activities in the two tests were similar to their 5HT receptor blocking potencies in the rat fundus preparation. It is suggested that these β-adrenoceptor antagonists may block some 5HT receptors in the central nervous system.

Role of adrenergic neurone blockade in the hypotensive action of propranolol

1 Propranolol, in doses of 25–100 μg/kg, blocks contractions of the nictitating membrane to nerve stimulation but not to injected noradrenaline. 2 This adrenergic neurone blocking action of propranolol is antagonized by amphetamine. 3 It is also reversed by raising the dose of propranolol to amounts exceeding 0·5 mg/kg. 4 Still larger amounts potentiate the responses of the nictitating membrane to both submaximal stimulation of the cervical sympathetic nerve and to injected noradrenaline. 5 The (+) isomer of propranolol produced adrenergic nerve blockade and some degree of hypotension without blocking cardiac β‐adrenoceptors. 6 The relevance of adrenergic neurone blockade to the hypotensive effect of propranolol is discussed.

The effect of dl-propranolol, d-propranolol and practolol on the hyperactivity induced in rats by prolonged isolation

Exploratory behaviour in an open field situation was found to be greatly increased in rats, isolated for 6–8 weeks, when compared with grouphoused controls. Propanolol, dl- and d- and practolol, 0.2–0.5 mg/kg reduced hypermotility, sniffing and rearing in isolated rats without affecting behaviour of group-housed rats. 20 mg/kg dl-propanolol was needed to reduce exploratory behaviour of group housed rats. Chlorpromazine reduced activity of isolated rats at a dose of 0.1 mg/kg, and group housed rats at 0.5–1 mg/kg. The action of propranolol does not appear to result from central receptor blockade because of the almost equal activity of d- and dl-propranolol. Since practolol was also active in this test, the effect of these drugs also does not appear to result from general C.N.S. depression. It is suggested that these compounds may reduce hyperactivity by diminishing an excessive release of central catecholamines.

β-Adrenoceptor blocking agents and responses to adrenaline and 5-hydroxytryptamine in rat isolated stomach and uterus

1 Four β‐adrenoceptor blocking agents, (±)‐ and (+)‐propranolol, practolol and oxprenolol, were found to antagonize, apparently competitively, the responses of both the rat isolated stomach and uterus to 5‐hydroxytryptamine (5‐HT). 2 The pA2 values for each of these agents as antagonists of the contractile action of 5‐HT on the rat stomach were found to be: (±)‐propranolol, 6.08; (+)‐propranolol, 4.94; practolol, 3.43; and oxprenolol, 5.99. These values were very similar to the corresponding figures for antagonism of 5‐HT‐induced contractions of the uterus. 3 pA2 values for antagonism of adrenaline‐induced relaxations by the four blocking agents on the rat stomach and uterus did not differ from the values for 5‐HT blockade. 4 To antagonize contractile responses to acetylcholine of the rat stomach it was necessary to give 100 times more (±)‐propranolol than was needed to antagonize responses to 5‐HT.

A new probe for heterogeneity in muscarinic receptors: 2-methyl-spiro-(1, 3-dioxolane-4, 3')-quinuclidine.

The title compound (MSDQ) is a new muscarinic agonist related to 3-acetoxyquinuclidine (3-AcQ) but also of a highly rigid structure. In view of this, it may constitute a probe for the detection of heterogeneity among muscarinic receptors. Indeed, equipotent molar ratios (EPMR) for ACh, 3-AcQ and MSDQ were as follows: guinea pig ileum, 1 : 14 : 240; vasodepressor effect in the cat, 1 : 6 : 188. But EPMR for 3-AcQ and MSDQ as stimulants of the superior cervical ganglion in the cat were 1 : 1 and for the induction of tremors in mice, 9 : 5. No such subtle differences in receptor specificity were detected when the probe used was the 2, 2-diphenyl analogue (DiPSDQ) of MSDQ which was a powerful competitive antagonist in all systems, more potent than atropine, but with a CNS/PNS activity of 1.1 compared to 26 for atropine. In view of this, the use of potent antagonists as probes for muscarinic receptor heterogeneity is questionable.

Antagonism by propranolol of the ganglion stimulant action of 5-hydroxytryptamine.

The effects of racemic propranolol and its constituent isomers were studied on ganglionic stimulation produced in situ by close arterial injection of 5-HT and DMPP to the superior cervical ganglion. Ganglion stimulation was recorded in terms of the resultant contraction of the nictitating membrane. d,l-Propranolol caused a biphasic antagonism of the ganglion stimulant effect of 5-HT. At low doses, 0.5-10 mug, the antagonism was surmountable by increasing the amount of 5-HT. The l-isomer (0.2-4 mug) but not d-propranolol also caused antagonism. At higher doses, 0.1-5 mg, both d,l- and d-propranolol caused a second type of blockade of 5-HT which was not surmountable and resembled that seen with procaine. The ganglion stimulant effects of DMPP and acetylcholine were only antagonised by the higher doses of d- and d,l-propranolol. d,l-Propranolol did not reduce the direct stimulation by 5-HT on the muscle of the nictitating membrane.

Reduction by propranolol of raised urinary output of MHPG in hyperactive rats

Prolonged isolation of rats resulted in hyperactivity in the open field and a significant increase in 24 hr urinary excretion of MHPG (3-methoxy-4-hydroxyphenylglycol). Exploratory activity of group-housed rats in open field was not associated with raised MHPG excretion, compared with that of rats remaining in home cages. Exposure of group-housed rats to 4 degrees C for 2 hr also increased urinary excretion of MHPG. Pretreatment of isolated rats with dl-, d-propranolol or practolol abolished hyperactivity of isolated rats and reduced MHPG output in these rats and in rats exposed to cold. dl-Propranolol did not reduce activity of group-housed rats in open field or their urinary excretion of MHPG. It is suggested that propranolol may have a selective inhibitory effect on stress-induced increases in noradrenaline turnover.

Modification by propranolol and related compounds of motor activity and stereotype behaviour induced in the rat by amphetamine

Abstract Pretreatment of rats with 4 β-adrenoceptor antagonists, d,1- and d-propanol, oxprenolol and practolol, resulted in a decrease in hypermoyility produced by d,1-amphetamine, 2 mg/kg. This effect occured with similar amounts of all 4 agents over a narrow dose range, 0.4 = 1 mg/kg; higher doses were generally ineffective. Injection of d,1-propranolol and oxprenolol after amphetamine caused an increase in hypermotility, while d-propranolol and practolol did not. Non of these agents had any effect on amphetamine-induced stereotype behaviour in amounts ranging from 0.2 to 10 mg/kg. The results are compatible with the suggestion that all the above drugs may reduced hepermotility by diminishing central noradrenaline release. Increased motor activity induced by d,1-propranolol and oxprenolol may result from a blockade of the inhibitory effects of noradrenaline via β-receptors.

The role of supersensitivity to acetylcholine in the production of tolerance to morphine in stimulated guinea-pig ileum

1 Morphine caused a dose‐dependent reduction in both the height of contraction and acetylcholine release from coaxially stimulated strips of guinea‐pig ileum. 2 Exposure of the tissue to morphine for 90 min produced acute tolerance to the effect of subsequent doses of morphine on contraction height. 3 There was no change in the ability of morphine to suppress acetylcholine release. 4 The responses of morphine‐tolerant ileum to exogenous acetylcholine were enhanced 3 to 10‐fold. 5 If the ileum did not show tolerance to morphine it did not become more sensitive to acetylcholine. 6 The results presented suggest that tolerance to morphine could result from a form of disuse supersensitivity.

Tricyclic antidepressant drugs as antagonists of muscarinic receptors in sympathetic ganglia

Close arterial injection of McN-A-343 into the superior cervical ganglion of the cat resulted in contractions of the nictitating membrane. The ganglionic effects of McN-A-343 but not those of DMPP were antagonized in a dose-related manner by 2-10 mug of desipramine, imipramine, chlorimpramine, iprindole and viloxazine. No correlation was found between the dose of each drug which blocked the effects of McN-A-343 and that required to potentiate the responses of the nictitating membrane to intra-arterial administration of noradrenaline. It is concluded that clinically effective antidepressant agents can block muscarinic receptors in neural tissue, even if they do not do so in smooth muscle and gland cells.