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Pharmacological Studies of p, N-(3, 4-Methylenedioxy phenyl) Benzoic Acid (RRL-1364) - Part-I Sharadini A Dahanukar, UK ShethDepartment of Pharmacology, Seth G. S. Medical College, Parel, Bombay-400 012, India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 722614
Detailed pharmacological investigations of p-N-(3, 4-methylene dioxy phenyl) benzoic acid revealed marked hypotensive action which was dose dependent and most marked in cats; it was absent in rats. Atropine could block this hypotensive action, thus suggesting cholinomimetic mechanism. Further studies indicated that the hypotension produced was central and possibly medullary in origin.
While screening for PAMBA like activity of a series of substituted anthranilic acid derivatives one of the compounds p, N-(3, 4-methylene dioxyphenyl) benzoic acid (RRL 1364) showed marked hypotensive action in cats. This compound was screened in detail since such activity with this type of compound has never been reported. Pharmacological investigations of the new-p-amino benzoic acid derivative [p, N-(3, 4-methylenedioxy phenyl) Benzoic acid]-RRL 1364 revealed that, it produces a dose dependent hypotension in anaesthetised cats which could be blocked by prior treatment with atropine. Studies in anaesthetised dogs showed similar hypotension, but to a lesser extent; while in anaesthetised rats, B.P. was unaffected. The present paper deals with the detailed investigations of the hypotensive action of RRL-1364 in cats.
Cats of either sex weighing 2.7 to 4 kg. were anesthetised with ether and anesthesia was maintained with chloralose 80 mg/kg i.v. The trachea was cannulated and the animals were maintained on positive pressure artificial ventilation. Carotid arterial blood pressure was recorded by means of a mercury manometer on a kymograph. Drugs were injected through the cannulated femoral vein. The effect of RRL 1364 in doses of 1 mg/kg, 2.5 mg/kg and 5 mg/kg on blood pressure was studied. ECG was recorded before and at various time intervals after the drug administration. The effect of the following blocking agents given i.v. on the hypotensive activity of RRL 1364 was studied. Atropine sulphate 2 mg/kg. Propranolol hydrochloride 400 mg/kg. Chlorpheniramine maleate 5 mg/kg. Responses with standard agonists were recorded before and after the administration of the blocking agent to ensure that complete blockade of the specific receptors had occured. To study the effect of oral administration, the drug RRL 1364 was administered intraduodenally in a dose of 5 mg, kg in 3 cats. Blood pressure studies were done on spinal cats and 3 decerebrate cats prepared by the method described by Burn. [2] In 3 experiments, the effect of RR.I 1364 on centrally mediated reflexes was studied by eliciting pressor responses to carotid occlusion and electrical stimulation of central end of the cut vagus and response to the peripheral end of the cut vagus. Effect of RRL-1364 on responses elicited by epinephrine, norepinephrine isoprenaline, acetyl choline and histamine was also studied. To study the central component of the drug action, RRL 1364 was injected via vertebral artery in 1/10th of the usual i.v. dose by the method described by Gaitonde et al [4] and to study the peripheral component of action, hind quarter perfusion was carried out in 3 cats with sigma motor pump, as described by Beck. [1] Effect of RRL-1364 (1 mg/kg) or superior cervical ganglion was studied by recording the nictitating membrane con. traction induced by electrical stimulation of the pre and post-ganglionic sympathetic nerve by supramaximal rectangular pulses. The effect on responses to injected epinephrine was also recorded. In cats, local administration of RRL-1364 was effected by cannulating the lingual artery. The effect of RRL-1364 was also studied in 3 dogs and 3 rats. The dose was selected on weight and surface area basis as described by Paget and Barnes. [7]
Effect on B.P. and heart rate Intravenous administration of RRL1364 (1, 2.5, 5 mg/kg) lowered the B.P. The onset of action occured within 10-15 minutes and reached its peak gradually at 90 minutes. The B.P. recovered only partially at the end of 240 min. The degree of hypotension was found to be dose dependent [Figure 1]. Heart rate as seen on ECG did not show any significant change except for mild tachycardia at the time of peak fall in B.P. Chlorpheniramine maleate (5 mg/kg) and propranolol hydrochloride 400 mg/kg given i.v. did not alter, in any respect, the fall in B.P., produced by RRL-1364. Atropine sulphate 2 mg/kg completely blocked the depressor response evoked by RRL-1364., given in a dose of 1 mg k [Figure 2]. Detailed study of the cholinomimetic activity of RRL-1364 was carried out as described elsewhere. [3] Intraduodenal administration of 5 mg/ kg of RRL-1364 caused essentially similar effects on blood pressure except for a gradual onset and lesser degree of hypotension. Effect on blood pressure of spinal cats The blood pressure of spinal cats failed to show any change over the pre-drug blood pressure level upto the period of 240 min. after the administration of RRL-1364 (1 mg/kg). Effect on blood pressure of decerebrate cats In decerebrate cats, RRL-1364 in a dose of 1 mg/kg i.v. produced a fall in the B.P. essentially similar in pattern to that seen in anasthetised intact cats. [Figure 3]. Effect on blood pressure responses elicited by carotid occlusion, central and peripheral vagal stimulation, epinephrine, norepinephrine, isoprenaline, acetyl choline and histamine. RRL-1364 in a dose of 1 mg/kg i.v. did not significantly alter the responses elicited by carotid occlusion and stimulation of central end as well as peripheral end of cut vagus. The responses which were elicited by injection of epinephrine, norepinephrine, isoprenaline, acetyl choline and histamine remained unaffected. Effect on blood pressure after intravertehral arterial administration Low doses of RRL-1364 (100 µg/kg) when injected i.v.a. produced an immediate fall in B.P. Within 10-15 min., a maximum fall (50%) was reached. Recovery in blood pressure was partial at the end of 240 minutes. When RRL-1364 was administered in a dose of 100 µg/kg by the same route (i.e. i.v.a.) after the administration of atropine sulphate (200µg i.v.a.) the fall in blood pressure was not elicited. Effect on hindquarters perfusion Intra-arterial injection of RRL-1364 in doses of 50-200 µg. caused a transient fall in the mean perfusion pressure to the lower extremities of the cat without any accompanying change in the systemic blood pressure A dose response relationship was observed over a small dose range only. This fall in the mean perfusion pressure was partially blocked by atropine (200 µg.) which was sufficient to block the response to acetyl choline (0.05 µg) given by the same route. Effect on the superior cervical ganglion The contraction of nictitating membrane elicited by stimulation of preganglionic and post-ganglionic sympathetic nerves was diminished after the injection of RRL-1364 1 mg/kg i.v. and this effect was accompanied by a fall in B.P. However, administration of the compound in local circulation of the ganglion (i.e. lingual artery) did not alter the responses of the nictitating membrane to the stimulation of preganglionic and postganglionic nerves. Hypotensive activity in dogs and rats RRL-1364 in a dose of 0.7 mg/kg it dogs produced a fall in blood pressure essentially similar in time of onset and peak but it was significantly less as compared to that in cats and recovered to original pre-drug level at the end of observation period (four hours). 2.3 mg/kg dose of RRL 1364 in rats did not produce any significant fall in blood pressure. [Figure 4].
RRL-1364 produced a dose dependent hypotension in anaesthetised normotensive cats. The hypotension was accompained by mild tachycardia. There was no evidence of myocardial depression. The hypotensive action of RRL-1364 was completely blocked in atropinised cats which led to a series of experiments evaluating cholinomimetic activity of RRL-1364, as described elsewhere. [3] The blockade of the hypotensive effect was specific to atropine, because the hypotensive effect persisted even after pretreatment with β adronergic blocking agent (propranolol) and an antihistaminic (chlorpheniramine). These findings excluded stimulation of β adrenergic receptors or involvement of histamine release in the mechanism of drug induced hypotension. During the hypotension by RRL1364, the pressor responses to carotid occlusion, central and peripheral vagal stimulation and responses to injected epinephrine, norepinephrine, isoprenaline (3.5 mg/kg) remained unaltered. This ruled out the possibility that the hypotensive activity of the compound was mediated via an afferent of the parasympathetic nervous system or through carotid sinus. The possibility of the hypotensive activity being due to ganglioplegic action appears unlikely because response to the stimulation of peripheral end of cut vagus was unaltered. Since the responses to the injected norepinephrine and epinephrine were neither potentiated nor blocked, hypotension due to adrenergic neurone blockade and receptor blockade could also be ruled out. Failure of the drug to have an effect on the superior cervical ganglion and the nictitating membrane preparation on local administration substantiates this view. Inhibition of contractions of the nictitating membrane which was observed on systemic administration could be due to a fall in the blood pressure produced by RRL-1364. The absence of a hypotensive response in spinal transected animals (at C2 level) after the administration of this compound indicated its site of action in the CNS rostral to transection. Decerebration at the midcollicular plane, thus excluding hypothalanic influence did not affect the hypotensive response. This localised its site of action to the vasomotor centre (VMC) lying between the midcollicular and the second cervical spinal segments. The immediate profound fall caused by small dose of RRL-1364 via intravertebral artery supported the view that the compound has its action on VMC because the vertebral artery in cats is the principal vascular supply of the brain stem where VMC is located. [6] Though RRL-1364 did exhibit a direct depression of the smooth muscle of the vasculature as revealed by a fall in the perfusion pressure, during the perfusion of cat hind limbs, this cannot account for the prolonged hypotension induced by the compound. The hypotensive activity of RRL-1364 appears to be central in origin and localised to the region of VMC in the medulla on the basis of results obtained. Injection of atropine sulphate 200 µg i.v.a could block the effect of RRL-1364 which was given i.v.a. (100 µg/kg.) This finding suggested that the central hypotensive activity of the compound could be cholinomimetic in nature. The blockade of the hypotensive response cannot be due to blockade of peripheral receptors by atropine sulphate, since it was given in a small dose which was insufficient to cause blockade when given intravenously. Secondly the depressor response to acetyl choline injected peripherally could still be elicited and this confirmed that the peripheral leakage or spill over of atropine sulphate had not occurred, on i.v.a. administration. The hypotensive effect was immediate without any lag period which was observed on peripheral administration. This lag period on peripheral administration could be due to inability of the compound to cross the blood brain barrier easily. From these observations it may be hypothesized that RRL-1364 possibly acts on the cholinoceptive cells of chemosensitive zone situated on the ventral surface of the medulla. [5] These cells could act as relay stations in the central vasomotor pathway or they could be the origin of tonic influence on the sympathetic discharge on the blood vessels. RRL-1364 is only one of the many drugs which produced vaso-depression due to a decrease in the sympathetic vaso-motor tone; vaso-depression is obtained by pentobarbitone sodium carbachol, physostigmine, glycine, gamaamino-butyric acid and clonidine.
We sincerely thank Dr. P. B. Sattur, Regional Research Laboratories, Hyderabad, for his assistance in synthesizing and supplying the compound.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
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