Studies on the hypotensive and other pharmacological activities of an extract from Anthocleista Nobilis

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The pharmacological effects of the aqueous extract and the alcohol-insoluble fraction of the aqueous extract of the dried powdered root bark of Antiocleis ta nobilis have been studied with the object of finding the possible mechanism of action of the hypoterisive principle(s) present in the extract. Cardiovascular studies were carried out on the arterial blood pressure of the anaesthetised cat and on the isolated perfused rabbit heart. A dose-dependent depressor effect, which is as slightly antagonised by atropine, was observed in both models. Bilateral vagotomy had no effect on the hypotensive effect of the extract. Phentolamine and propranolol had no effect on the extract- induced transient hypotension, indicating that the lowering of the blood pressure was not due to either a direct or an indirect anrenergic effect. The extract is not likely to have any stimulant effect on the vagus, since bilateral vagotomy had no effect on its hypotensive action. The hypotensive action was also thought to be partially due to a direct muscarinic effect because bilateral vagotomy did not affect the atropine-sensitive portion of the depressor effect. The extract also antagonised the pressor phase (nicotinic Effect) of a large dose (150 μg) of acetyicholine. This action could be due to a ganglion-blocking effect, as investigations in later experiments revealed. The crystalline compound of the extract (alcohol-insoluble fraction) had a slightly less hypotensive effect on the anaesthetised cat. This hypotensive effect was completely antagonised by atropine, indicating that the hypotensive action of the crystalline compound could be due only to a muscarinic effect. Thus this action might account for the muscarinic action of the whole extract deserved on the anaesthetised cat. Bilateral vagotony also had effect on the hypotensive effect of the crystalline compound. This further supports the suggestion that the muscarinic portion of the hypotensive effect of the extract is a direct effect and not mediated through vagal stimulation. Phentolainine and propranolol also had no effect on the blood-pressure lowering action of the crystalline compound. These also suggest that the crystals, like the extract, had no adrenergic action, either directly or indirectly. The isolated perfused rabbit heart also showed negative inotropic and chronotropic effects in the presence of the extract. This was attributed to a direct effect of the extract on heart nuscle. Similar results were obtained with the crystals but, unlike the extract, the d.epresssor effect of the crystals could be antagonised by atropine. High doses of the crystalline compound, 30 mg, also slightly increased the rate and force of the heart beats in the presence of atropine. The tachycardia was antagonised by hexamethonium, 20 μg, and propranolol. High doses of the extract above 30 mg were therefore thought to have an effect on the intrinsic sympathetic ganglia on the heart. The contractions of the nictitating membrane obtained through stimulation of the superior cervical pre-ganglionic nerve trunk were antagonised by 1.0 ml of the extract, thus confirming a ganglion blocking effect of the extract. The extract relaxed the rabbit duodenum. The relaxation could not be antagonised by either phentolamine or propranolol. On the guinea-pig ileum the extract antagonised contractions induced by nicotine, histamine and potassium chloride, in that order of decreasing susceptibility. The antagonism of nicotine-induced contractions was far greater than that for histamine or potassium chloride. Other smooth muscle preparations like the isolated guinea- pig tracheal chain were also relaxed and neither propranolol nor mepyramine had any effect on the relaxations. It was concluded from these observations that the extract did not induce its spasmolytic effect through interaction with adrenergic receptors through’ a local release of sympathomimetic amines. Though the extract showed a greater activity at the nicotinic site (ganglion) it also acted non-specifically on smooth muscles to relax them. The crystalline compound of the extract contracted the isolated guinea-pig-il.eum. The crystal-induced contractions were antagonised by only atropine i.e. mepyrarnine and hexamethonium had no effect on these contractions. This further confirmed that the crystals had muscarinic actions. The actions of the extract on skeletal muscle preparations were also studied. The twitches of the directly stimulated muscle were considerably depressed in the presence of the extract. The extract was, therefore, thought to have a direct muscle relaxant action. The contraction of the isolated rat phrenic nerve-hemidiaphragm preparation produced by stimulation of the phrenic nerve ire also depressed. It was thought that the extract could also have a neuromuscular blocking action even though the observation could be attributed to the direct muscle relaxant actions. Results from the guinea-pig intradermal wheal and the corneal reflex experiments indicate a weak local anaesthetic action for the extract. Since local anaesthetics interfere with conduction of impulses along nerve and muscle fibres, it was thought that part of the hypotensive effect could be attributed to this action. The LD50 for the extract administered intraperitoneally to rats was 4.01 ± 0.22 ml/kg body at 95% confidence limits. The acute toxicity studies on rats revealed that the extract had neither central nervous depressant nor stimulant effects. There were, however, indications of alterations in the autonomic nervous system manifested by purgation and urination at dose levels above i.0 ml per kg body weight. The hind limbs were also paralysed at doses above 5.0 ml per kilogram body weight. From these results it was concluded that the extract had a very wide spectrum of pharmacological activity and that the hypotensive principle(s) acted mainly through blocking autonomic ng1ia and also by a non-specific depressant action on both smooth and skeletal muscles. The resultant lowered tone of the muscles can cause a drop in the blood pressure. The direct cardiac depressant effect of the extract can also partially account for the fall in the blood pressure on administering the extract, since this effect reduces the cardiac output. It is also concluded that the crystalline compound from the extract is probably the muscarinic portion of the extract. Considering the widespread nature of the activity of the extract, with particular reference to actions like the ganglion-blocking actions, together with the observed drop in the arterial blood pressure of the anaesthetised cat caused by the crystals, it was concluded that this fraction only partially accounts for the hypotensive effects of the extract from the dried powdered root of Anthocleita nobilis
A thesis submitted to the Board of Postgraduate Studies, Kwame Nkrumah University of Science and Technology, Kumasi, in partial fulfilment of the requirements for the award of the Degree of Master of Science in Pharmacology, 1983