Investigation of the spasmogenic effect of manganese on the guineapig isolated ileum preparation.

1. The mechanism of the manganese-induced spasm of the guinea-pig ileum was investigated using agents known to modify nerve function. The spasm was reduced by cooling, tetrodotoxin, procaine, Botulinus toxin (Type A), hyoscine and pempidine. It was potentiated by mipafox.2. In the presence of manganese, the release of acetylcholine from the ileum was greatly increased.3. Tetrodotoxin prevented the manganese-induced increase in acetylcholine output from the ileum but had no significant effect on the spontaneous acetylcholine output.4. It is suggested that the manganese-induced spasm of the ileum results from an action on intramural cholinergic nerves.

Spasmolytic effects of cadmium and zinc ions upon the guinea-pig isolated ileum preparation.

1. An investigation has been made of the effects of cadmium and zinc ions upon the contractile response of the guinea-pig isolated ileum to methacholine, histamine, potassium ion and a.c. field stimulation. The metal ions depress the response to all of these agents.2. Radioisotope studies showed that cadmium and zinc ions have very much larger apparent volumes of distribution than sorbitol, both within whole ileum and within strips of the longitudinal smooth muscle layer. The results of these studies were indicative of surface binding and/or intracellular accumulation of these ions.3. It is suggested that cadmium and zinc ions directly depress smooth muscle contractility in a non-specific manner. This action may result from their binding to or accumulation within the muscle cells.

Olfactory bulb ablation in the rat: behavioural changes and their reversal by antidepressant drugs.

1. The effects of bilateral olfactory bulbectomy, sham-operation and inducement of peripheral anosmia were studied on locomotor activity, passive avoidance acquisition and irritability. 2. Bulbectomized rats were hyperactive, deficient at learning a step-down passive avoidance response and hyperirritable. Peripheral anosmia, induced by intranasal infusion of ZnSO4 solution resulted in no behavioural changes. 3. Chronic pretreatment with amitriptyline (3 and 10 mg/kg) and a tetracyclic antidepressant mianserin (Org GB 94, 5 and 15 mg/kg) reversed the hyperactivity and reduced the learning deficit of bulbectomized rats. These drugs had no significant effects on sham-operated animals. 4. Neither amitriptyline nor mianserin reduced the exaggerated responses of bulbectomized rats to external stimuli. 5. (+)-Amphetamine (1 and 3 mg/kg) accelerated the acquisition of the passive avoidance response, greatly enhanced the locomotor activity and slightly increased the irritability score of both sham-operated and bulbectomized rats. 6. Chlorpromazine (1 and 3 mg/kg) and chlordiazepoxide (10 mg/kg) significantly reduced the acquisition, locomotor activity and irritability of experimental and control rats. 7. Lithium sulphate (1 and 3 mg/kg) had no effect on activity or irritability but produced a small impairment in acquistion of bulbectomized rats. 8. It is concluded that the reversal by antidepressant drugs of the behavioural syndrome seen after olfactory bulb ablation could constitute a new model for the detection of this group of centrally acting compounds.

A comparison between amantadine and bromocriptine using the stereotyped behaviour response test (SBR) in the rat.

Amantadine (100 mg/kg), apomorphine (2.5-10 mg/kg) and bromocriptine (10-50 mg/kg) all produced stereotyped behaviour in the rat. Apomorphine was rapid in onset and of short duration, amantadine was slower to reach a maximum and bromocriptine had a delayed onset of 50 min and a prolonged action. Amantadine and bromocriptine were antagonised by pimozide (1 mg/kg for 30 min) suggesting an action on dopamine receptors, and by D,L-alpha-methyl-p-tyrosine (150 mg/kg for 3 h) suggesting an indirect action. Amantadine, though not bromocriptine, antagonised apomorphine and amantadine also reversed the SBR due to bromocriptine. Pretreatment of rats with p-chlorophenylalanine (100 mg/kg twice daily for 2 days) had no effect on bromocriptine. The significance of these results is discussed with reference to the proposed mechanism of action of bromocriptine and to the use of multiple drug therapy in Parkinsonism.

A comparison between a melanocyte-stimulating hormone inhibitory factor (MIF-I) and substances known to activate central dopamine receptors.

The tripeptide, prolyl-leucyl glycine amide, a melanocyte-stimulating hormone inhibitory factor (MIF-I), which has been reported to be effective in improving symptoms of Parkinson's disease, has been compared with drugs known to activate dopamine receptors in rat and mouse brain. Unlike apomorphine, amphetamine and amantadine it was incapable of producing sterotyped behaviour in the rat and unlike 1-dopa it was also ineffective in rats pretreated with the monoamineoxidase inhibitor mebanazine. Neither did it potentiate apomorphine nor amphetamine in this test. MIF-I did not antagonise chlorpromazine-induced loss of locomotor activity in mice, an effect which was antagonised by apomorphine, amphetamine and amantadine. Chlorpromazine hypothermia in the mouse was antagonised by 1-dopa but not by MIF-I; similar findings were obtained in reserpine-pretreated mice. These results suggest that the reported beneficial effect of MIF-I in Parkinson's disease is unlikely to be due to an interaction with dopamine systems in the brain.

Neuromuscular blocking activity in an extract from the East African wild sisal Sansevieria ehrenbergii.

S. ehrenbergii and A. sisalana extracts (equivalent to 50-250 mg leaf/ml) cause potentiation (ca. 40%) of indirectly elicited contractions of the chick biventer nerve-muscle preparation. The subsequent blockade to direct and indirect stimulation and the sustained but reversible change in baseline tension resemble actions of the depolarizing suxamethonium rather than the nondepolarizing gallamine.

The economics of mild hypertension programmes.

The recently reported results from several controlled randomised trials of the drug treatment of mild hypertension suggest that such treatment may be expected to exert a small effect toward the primary prevention of stroke disease. In order that the economic implications of these results might be examined, two hypothetical programmes of anticipatory care are considered according to the principles of cost-effectiveness analysis. Each notional 5 year programme is set in a defined population, residents of Stockport, Greater Manchester, aged between 35 and 64 years, and each is addressed toward the detection and treatment of mild hypertension in the community. The programmes differ with respect to their detection processes: one programme is based upon the screening method conducted under the aegis of health visitor staff employed by a District Health Authority, the other upon opportunistic case finding conducted by general practitioners. It is likely that the screening programme would prevent about 13 strokes over a 5 year period; if set in leisure time total programme costs are estimated to be 309,500 pounds at 1986 prices. Discounting future costs and future prevented strokes provides for the development of a present value total cost per prevented stroke of 25,000 pounds. Alternately, the 5 year opportunistic programme, costing 252,650 pounds, would be expected to prevent about 15 strokes at a present value of 17,050 pounds per prevented stroke. The prevention of stroke disease attributable to these programmes can only be achieved in the presence of group compliance to drug treatment. This clearly depends upon the perception of the value of treating hypertension according to each individual subject. The respective merits of the two programmes are examined with particular reference to their sensitivity to this issue, as well as to their likely feasibility and practicability.

Characterization of receptors on postganglionic cholinergic neurons in the guinea-pig isolated ileum.

Dopamine, apomorphine, noradrenaline and isoprenaline reduced the response of the isolated guinea-pig ileum to exogenous acetylcholine by a maximum of 40%. Propranolol reversed this inhibition whilst phentolamine and pimozide were ineffective, suggesting that the drugs were acting on a post-synaptic beta-adrenoceptor. The same agonists were more effective as inhibitors of the response to transmural electrical stimulation of the ileum, lower doses producing almost complete inhibition. This inhibition was partially antagonized by phentolamine, pimozide and propranolol. Clonidine proved to be the most potent inhibitor of the response to transmural electrical stimulation, whilst phenylephrine was ineffective. pA2 determinations showed that phentolamine was a potent antagonist of clonidine but a weak antagonist of apomorphine whilst for pimozide the opposite was true. The results suggest that there are two populations of prejunctional receptors on the cholinergic nerves innervating the smooth muscle of the guinea-pig ileum. One receptor is similar to a classical prejunctional alpha-adrenoceptor and the other resembles a central dopamine receptor.