Journal of Postgraduate Medicine
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ARTICLE
 
 
Year : 1978  |  Volume : 24  |  Issue : 3  |  Page : 177-181  

Pharmacological Studies of p, N-(3, 4-Methylenedioxy Phenyl) Benzoic Acid (RRL-1364) - part-II

Sharadini A Dahanukar, UK Sheth 
 Department of Pharmacology, Seth G.S.Medical College, Parel, Bombay 400012, India

Correspondence Address:
Sharadini A Dahanukar
Department of Pharmacology, Seth G.S.Medical College, Parel, Bombay 400012
India

Abstract

Cholinomimetic activity of p, N- (3, 4-methylene dioxy phenyl) benzoic acid was revealed while studying its hypotensive activity in cats. Further evaluation of this activity showed that this com­pound had both muscarinic and nicotinic components. The cholino­mimetic activity was not similar to anticholinesterase like activity. Species variation was present; in rats it failed to show any activity and no activity was exhibited in vitro suggesting some metabolic transformation.



How to cite this article:
Dahanukar SA, Sheth U K. Pharmacological Studies of p, N-(3, 4-Methylenedioxy Phenyl) Benzoic Acid (RRL-1364) - part-II.J Postgrad Med 1978;24:177-181


How to cite this URL:
Dahanukar SA, Sheth U K. Pharmacological Studies of p, N-(3, 4-Methylenedioxy Phenyl) Benzoic Acid (RRL-1364) - part-II. J Postgrad Med [serial online] 1978 [cited 2019 Sep 18 ];24:177-181
Available from: http://www.jpgmonline.com/text.asp?1978/24/3/177/42665


Full Text

 Introduction



Pharmacological investigations of the new PABA derivative [p, N- (3, 4-Methy­lenedioxy phenyl) benzoic acid-RRL­1364] revealed dose dependent hypoten­sive action in anaesthetised cats. This action could be blocked by atropinization of cats. Detailed evaluation of the cholinomimetic activity of RRL-1364 was carried out in cats, which is discuss­ed in the present paper.

 Material and Methods



Effect on smooth muscle: In 3 cats, the effect on smooth muscle of the intestines was studied in vivo by the method de­scribed by Jackson. [2]

In three guinea pigs, the effect of RRL-1364 was studied on smooth muscle of the bronchial tree using Konzett Rossler method. [3] Response to RRL-1364 alone and its effect on acetyl choline action was studied.

The effect of RRL-1364 was observed on smooth mscles in vitro by using various isolated tissues like guinea pig ileum, rat uterus, guinea pig tracheal chain (Sheth et al [4] ).

The responses of RRL-1364 in graded doses and its effect on the action of vari­ous agonists like acetyl choline, histamine, 5 hydroxytryptamine was noted.

For this purpose, since RRL-1364 was insoluble in water, propylene glycol was used as a solvent and for each experiment control responses with the solvent alone were recorded.

Effect on secretions: The effect of RRL 1364 was noted on the salivary secretions according to the method described by Jackson . [2]

Evaluation of the nicotinic component: Blood pressure was recorded in 3 cats anaesthetised with ether chioralose. Atropine sulphate 2 mg/kg was injected slowly i.v. and complete blockade of de­pressor response to acetyl choline (3-5 µg/kg) was confirmed. RRL-1364 was ­then injected in a large dose (10 mg/kg) i.v. and the response noted.

Effect on superior cervical ganglion: The contractions of the nictitating mem­brane of cats were elicited in four cats by pre-ganglionic and post-ganglionic stimu­lation by rectangular pulses. The effect on responses to injected epinephrine (3.5 .g/kg) was also recorded.

When RRL-1364 was given, i.v. a fall in B.P. was produced and therefore, for better interpretation of results of effect on SCG, RRL-1364 was given in small dose (100 µg) in the local circulation of ipsilateral SCG by cannulating lingual artery' , and the effect observed on the contractions of the nictitating membrane.

Effect on neuromuscular junction: Action of RRL-1364 on the neuro­muscular junction was studied in situ on tibialis anterior muscle nerve preparation in 3 anaesthetised cats. RRL-1364­-200 µg. was injected intra-arterially.

Effect of neostigmine (200 µg. i.a.) on RRL induced contraction was also observ­ed. In addition, effect of the direct muscle stimulation was noted.

Effect on neuromuscular junction was studied on rat phrenic nerve diaphragm preparation as described by Sheth et al. [4] Contractions produced by nerve stimula­tion were recorded on E and M physio­graph using myograph type B. RRL­1364 was added to the bath solution in a concentration ranging from 10-40 µg/ml and was allowed to act for five minutes and the effect of the compound in dif­ferent doses on muscle contractions elicit­ed by nerve stimulation was studied.

The isolated frog-rectus abdominis muscle was also used to study the effect of RRL-1364 on the skeletal muscle.

 Results



Effect on intestinal movements: In­testinal movements in cats under the in­fluence of RRL-1364 (1 mg/kg) were seen to be augmented. The effect started in 15 minutes, was maximum at 90 minutes and continued with increased intensity till the end of four hours [Figure 1].

Konzett Rossler preparation: The compound did not produce any effect perse and it did not affect the effect of acetyl choline on the bronchial resistance.

Effect on isolated smooth muscle pre­parations: RRL-1364 in doses of 10-40 µg/ml of the bath solution did not pro­duce any effect on the guinea pig ileum, rat uterus and guinea pig tracheal chain.

In addition, the compound in above men­tioned doses had no effect on acetyl choline, histamine and barium chloride induced contractions of the guinea pig ileum, 5 Hydroxytryptamine induced contractions of the rat uterus and his­tamine and acetyl choline induced con­tractions of the guinea pig tracheal chain.

Effect on salivary Secretion: RRL­ 1364 in a dose of 1 mg/kg i.v. did not produce any significant effect on the salivary secretions collected from the submaxillary gland.

Nicotinic effect on blood pressure: RRL-1364 when given in a higher dose (10 mg/kg) after prior atropinization, sufficient to completely block the depres­sor response of acetyl choline (1.3 µg/ kg)-produced a sharp rise in blood pres­sure (about 40%) and recovered to the basal pre-drug level by ten minutes [Figure 2].

Effect on superior cervical ganglion and nictitating membrane of cat: Though the contractions of the nictitating mem­brane were diminished after i.v. adminis­tration of RRL-1364, locally administer­ed compound did not alter the responses of the nictitating membrane to the stimu­lation of pre-ganglionic and post-gan­glionic nerves.

Rat phrenic nerve diaphragm prepara­tion: RRL-1364 in doses of 10-40 µg/ ml of the bath solution did not produce any effect on contractions of the rat hemidia­phragm elicited by the phrenic nerve stimulation.

Effect on Neuro-muscular junction: Cat tibialis anterior muscle-nerve prepara­tion: RRL-1364 injected in a cumulative dose of 200 µg. through the femoral artery, produced initial transient fascicul­ations of the contractions of tibialis elicit­ed by nerve stimulation. This was follow­ed by a decrease in the height of contrac­tions in about three minutes and marked blockade was observed within 7 to 10 minutes.

This blockade continued without any recovery till the end of four hours. The blockade was unaffected by neostigmine 200 µg. given intra-arterially. The res­ponses to direct muscle stimulation, how­ever, were unaltered [Figure 3].

RRL-1364 did not produce any effect per se nor did it have any effect on con­tractions induced by acetyl choline, in frog rectus abdominis muscle and rat phrenic nerve diaphragm preparation.

 Discussion



During evaluation of RRL-1364-a derivative of para-amino-benzoic acid­for hypotensive activity, it was seen that its hypotensive action could be complete­ly blocked by pre-treatment with atro­pine. When further studies were carried out for its cholinomimetic activity, it was observed that it has got some action on the muscarinic receptors of the smooth muscles of intestines as recorded by Jack­son's enterograph. But there was no sig­nificant augmentation of the salivary secretions from the sub-maxillary salivary glands collected from Wharton's duct. There was no effect on bronchial smooth muscles.

RRL-1364 exhibited nicotinic action on the blood pressure through stimulation of the sympathetic ganglia and adrenal medulla. But it had no effect on the supe­rior cervical ganglion when it was given in the local circulation.

The diminution in contractions of the nictitating membrane on systemic admi­nistration of RRL-1364, could be due to an accompanied fall in the blood pressure and this hypotensive effect is excluded when the compound is given locally, in a small dose.

On the neuromuscular junction the compound had action resembling that of membrane depolarisers, producing initial fasciculations and later blockade which could not be reversed by the use of anti­cholinesterase.

Thus the compound RRL-1364 appear­ed to have complex cholinomimetic ac­tions, having both muscarinic as well as nicotinic components. Like acetyl choline, it produced a fall in blood pressure block­ed by atropine, it stimulated the intesti­nal movements and it produced membrane depolarization at the site of the neuro­muscular junction. Its nicotinic action on blood pressure could also be demonstrat­ed but unlike acetyl choline, it had long duration of action; it was absorbed when given intraduodenally [1] and there was no effect on the salivary secretions.

The cholinomimetic activity of the com­pound does not appear to be due to anti­cholinesterase activity as the depressor effect of acetyl choline on blood pressure was unaffected.

Another feature of this compound was its inability to show any muscarinic acti­vity on the isolated smooth muscle of guinea pig ileum, guinea pig tracheal chain and isolated rat uterus. Similarly, it failed to show any effect on the isolated rat phrenic nerve diaphragm preparation and frog rectus abdominis muscle. This could be explained on the basis of species variation because it was seen in our ear­lier work that the compound had marked and prolonged hypotensive activity in cats, less pronounced and shorter lasting hypotensive activity in dogs and no acti­vity in rats.

Another possibility which could be sug­gested is that the compound as such may not be effective in vitro and it is active only in vivo. Thus the results of the pre­sent study reveal cholinomimetic activity of complex nature, and it is premature to conjecture whether this compound will find a place in the treatment of hyperten­sion. Much is yet to be known about it, for example its effect on hypertensive animals, effects on peripheral biogenic amines, etc. before its therapeutic poten­tial can be considered.

 Acknowledgements



We sincerely thank Dr. P. B. Sattur, Re­gional Research Laboratories, Hyderabad, for his assistance in synthesizing and supplying the compound.[5]

References

1Dahanukar, Sharadini A. and Sheth, U. K.: Pharmacological studies of p, N-(3, 4­methylene dioxy phenyl) benzoic acid (RRL-1364) Part I., J. Postgrad Med., 24:, 1978.
2Jackson, D. E.: "Experimental Pharma­cology and Materia Medica". 2nd Edition, C. V. Mosby and Co., Saint Louis, 1939, pp. 83-91 and 523.
3Konzett, H. and Rossler, R.: Versuch­sanordnung zu untersuchungen an der Bronchialmuskulatur. Arch. f. exper. Path. u. Pharmakol ., 195: 71-74, 1940.
4Sheth, U. K., Dadkar, N. K. and Kamat, Usha G.: "Selected Topics in Experi­mental Pharmacology". Kothari Book Depot, Bombay, 1972, pp. 82, 163.
5Trendelenberg, U.: Non-nicotinic ganglion­stimulating substances (From The Sym­posium on Autonomic Pharmacology), Fed. Proc. , 18: 1001-1005, 1959.

 
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