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Home , Spiramide

BLOCKADE OF DEPRESSOR RESPONSE OF

K.M. DHASMANA, K.S. DIXIT, K.N. DHAWAN AND G.P. GUPTA Department of Pharmacology and Therapeutics, King George's Medical College, Lucknow-3, India Received for publication August 15, 1968

Dopamine, a precursor of noradrenaline, is found in high concentrations in mammalian tissues (1). It has got many pharmacological actions similar to, but much weaker than adrenaline and noradrenaline. It produces a vasopressor response in dog and cat in doses 20 to 50 times higher than those of adrenaline (2, 3). Like adrenaline, the pressor response of dopamine is blocked by alpha adrenergic blocking agents and is con verted into a depressor response (4), but, unlike adrenaline and isoprenaline, the depressor response of dop amine is not blocked by conventional beta adrenergic blocking agents (4, 5). This response is also not blocked by antihistaminic, anticholinergic and ganglion blocking agents (4). Van Rossum (6), however, recently reported that spiramide and block the dopamine depressor response. Haloperidol is structurally related to pethidine (7). The present study was, therefore, undertaken to investigate the blocking effect of pethidine and allied drugs, on the depressor response of dopamine. In addition, , which have a profile of action similar to that of haloperidol, have also been included in the study. Cats of either sex weighing from 2 to 4 kg were used. The animals were anaesthetized with pentobar bitone sodium (35 mg/kg intraperitoneally), bilaterally vagotomized and maintained on positive pressure artificial respiration. The blood pressure was recorded from a common carotid artery by means of a mercury manometer on a smoked paper. Femoral vein of one side was cannulated by a polythene tube for intravenous administration of drugs. Adrenergic a-blockers (dibenzyline 10 mg/kg or hydrochloride 1 mg/kg) were used to obtain the depressor response of dopamine (50-100 leg/kg i.v.). Phenothiazines ( hydrochloride and hydrochloride) and pethidine hydrochloride and related drugs (morphine

FIG. 1-A. Cat blood pressure, pentobarbitone (30 mg/kg i.v.) anaesthesia : The effect of morphine (15 mg/kg i.v.) on the depressor response of dopamine (D) on dibenzyline (10 mg/kg i.v.) treated cat blood pressure. The subsequent administration of nalorphine (10 mg/kg) abolishes the effect of morphine. B. Shows the effect of codeine on the dopamine depressor response. Note that nalor phine antagonizes the action of codeine. (D=Dopamine 100 ug/kg i.v.). sulphate, codeine sulphate, dihydrocodeinone bitartrate and hydrochloride) were investigated for their effect on the dopamine depressor response. In one series of experiments (21 cats) pethidine (50 mg/kg), morphine (15-20 mg/kg), codeine (20 mg/ kg), dihydrocodeinone (10-15 mg/kg) and apomorphine (5-10 mg/kg), were studied for their effect on the dopamine depressor response. It was observed that among these agents morphine and codeine converted the dopamine depressor response into a pressor one (see Fig. 1) while pethidine, apomorphine and dihydro codeinone had no action. The effect of morphine and codeine appeared within 15 minutes of administra tion and persisted for 2 % to 3 hours. In the experiments where morphine or codeine had blocked the depressor response of dopamine, admini stration of nalorphine (5-10 mg/kg) promptly antagonized the blocking effect of these drugs and the depressor response of dopamine reappeared. Chlorpromazine (5-10 mg/kg) and fluphenazine (2-5 mg/kg) were administered in three cats each. They failed to antagonize the depressor response of dopamine. Dopamine, similar to adrenaline, exerts a biphasic effect on blood pressure. The pressor response of both these agents is due to an effect on a-adrenergic receptors which is blocked by a-adrenergic blocking agents. The depressor component, however, in contrast to adrenaline, is not blocked by beta adrenergic blocking agents (5). The depressor response is also not blocked by antihistaminic, anticholinergic and gan glion blocking agents (4). Van Rossum (6), on the other hand, reported blockade of depressor response of dopamine by haloperidol and spiramide. In the present study the depressor response of dopamine has been shown to be blocked by morphine and codeine. Therefore, it seems that the receptors (j3-adrenergic receptors) producing the depressor response of dopamine are different in nature from adrenaline receptors and may be specific for dopamine. Eble (5) attributed this depressor response to a vasodilator action of dopamine on renal and mesenteric blood vessels. Studies on the isolated mesenteric and renal blood vessels, may further reveal the nature of these receptors for dopamine. Alternatively, the blockade of the depressor response of dopamine by morphine and codeine could be due to antagonism of dibenzyline or yohimbine by these drugs, which by displacing the alpha blockers from their site of action may be restoring the pressor action of dopamine. However, this does not seem probable. Firstly, the a-blockade by dibenzyline is irreversible (8) and it is difficult to assume that morphine and codeine would reverse this block. Secondly, the present findings show that nalorphine antagonizes the action of mor phine and codeine and the depressor response of dopamine reappears which indicates that the a-blockade is still persisting. This study, therefore, suggests the presence of some atypical j3-adrenergic receptors specific for dopamine in the blood vessels.

Acknowledgement: The authors are grateful to the Indian Council of Medical Research, New Delhi for financial assistance.

REFERENCES

1) HAGEN, P.: Pharmac. Rev. 11, 361 (1959) ; 2) GOLDBERG,L.I. ANDSJOERDSMA, A.: J. Pharmac. exp. Ther. 127, 212 (1959) ; 3) BURN,J.H. ANDRAND, M.J.: Br. J. Pharmac. Chemother.13, 471 (1958) ; 4) MCDONALD, R.H. ANDGOLDBERG, L.I.: J. Pharmac. exp. Ther. 140, 60 (1963) ; 5) EBLE, J.N.: J. Pharmac. exp. Ther. 145, 64 (1964); 6) VAN RossuM, J.M.: Archs int. Pharmacodyn. The'r. 160, 492 (1966); 7) JAFFE, J.H.: The Phar macologicalBasis of Therapeutics, Edited by GOODMAN,L.S. ANDGILMAN, A., 3rd ED., p. 249, The Macmillan Co., New York (1965) ; 8) NICKERSON,M.: Pharmac. Rev. 9, 246 (1957)