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Modification of the central hypotensive effect of α-methyldopa by reserpine, imipramine and tranylcypromine
EUROPEAN JOURNAL OF PttARMACOLOGY 9 (1970}120 123. NORTII-HOLLANDPUBLIStflN(;('OMP..AMSTI'RI)AM
MODIFICATION OF THE CENTRAL HYPOTENSIVE EFFECT OF c~-METHYLDOPA BY RESERPINE, IMIPRAMINE AND TRANYLCYPROMINE A.K. KALE and R.S. SATOSKAR Department o./ Pharmacolog 3 . L.T.Ji. Medical ('~:lw.g~. Ston Bomt)ay-22 Italia
~ccepted ~ Dccc;nbt~ 19(,~
Received 24 November 1969
A.K. KALF, and R.S. SATOSKAR Modification o f the central hypolensi~ e e f]k,ct oj o~-methyhtopa I~v reserpine, imipramine and tranylcypromine. European J. Pharmacol. 9 (1970) 120 123. In chlorolase anae~;ihetised cats, O~-methyldopa infused into the vertebral artery produces a ILypotensive cffe~t ill doses tbat are ineffective peripherally. Pretreatment of cuts with reserpine or imiprami~Je blocks this eflect where~l, prctreatment with tranylcypromine greatly augments it. Translcypromine doe~ not shox~, l[liS t2t'tect {i/ Lmilnals pretreated with reserpine or imipramine. ~-Methyldopa Franylcypromine
Reserpine ('entral hypotensive effect
l. INTRODUCTION The hypotensive drug, c~-methyldopa when infused int~avertebrally in chloralose-anaesthetJzed cats, produces a delayed but sustained fall in blood pressure with dose'~ that are ineffective intravepously (Henning and Zwieten, 1967, 1 9 6 8 ) However, both intra,,ertebral and intravenous infiisions of the drug decrease in brain dopamine and noradrenaline levels arrd produce equivalent increases hr the concentration of a-methyldopamine in the brain. It was, therefore, decided to study the effect of drugs affecting the uptake/release/metabo!ism of catecholamines on the central hypotensive effect of ~-methyldopa.
2. METHODS AND MATERIAL Cats e f either sex weighing 2.5 to at kg and anaesthetized with ether followed by chloralose (50 70 mg/kg i.v.) were used. The right vertebral artery was employed for infusion (Reis and Zwieten, 1967). This procedure does no'~ require tl,.oracotomy. The duration of infusion varied from 45 min 1o 1 hr.
lmiprammc
Respiration was maintained artificially tt,,rot@l a tracheal cannula and blood pressure was recorded from the right femoral artery b~ a me~cmy map.ometer. All the drugs were dissolved m normal saline. Animals of Group I (control: n = 51 received c~-methyidopa (20 mg/kg; 10 mg/ml) intravertebrally Group I1 (n = 10) received reserpine (1.25 mg/kg i p.: Serpasil. Ciba) 24 hr before irmavertebrai a-methyldepa. Group 1II (n = 10) received imipraInine (3 mg/kg i.p.: 10 mg/ml) 30 mm before the il;travertebral infusion of 0~-metbyldopa and Group IV (~, = 10) were treated with tranylcypromine {10,ng/kg i.p.: 20 mg/ml) followed 30 rain later by intravertebral ~-methyldopa. In additiot~. (it 2 cats pretreated with tranyl-cypron'ine were given c~-tnethyidopa infusion intravenously aF,d (ii) 2 cats pretreated with reserpine or imiprine received tranylcypromme i p. followed by intravertebral oe-methyldopa.
3. RESULTS 3.1. O : n t r o l
The initial average blood pressure of the cats in
CENTRAL HYPOTENSIVE EFFECT OF ct-METttYLDOPA this group was 140 mm Hg (S.E. -+ 7.8). Tire central hypotensive effect of a-methyldopa was confirmed (Henning and Zwieten, 1967, 1968). The fall in blood pressure during infusion was negligible (0 5 mm Hg). The mean fall within the first hour following infusion was 15 mm Hg (S.E. +- 2.5). The average fall within the 2nd and the 3rd hr was 26 mm Hg (S.E. +- 4.3) and 36 mm ttg (S.E. -+ 6.6) respectively. There was no appreciable fall after this period.
3.2. Reserphw pretreatment The cats pretreated with reserpine were sedated and required smaller amounts of chloralose (50 mg/kg i.v.). Their initial average blood pressure was 96.5 mm Hg (S.E. -+ 7.2). Following intravertebral infusion of a-methyldopa, the mean fall in blood pressure within 3 hr following infusion was only 10 mm Hg (S.E. -+ 5.3). These results are highly significant when compared to control values (p < 0 . 0 0 5 ) .
121
within the first and the second hours after it,. ,.:ompletion in controls and treated animals are highly significant (p < 0.0005). lntravertebral infusion of normal saline at a pH of 6.8 (same as tkat of tranylcypromine solution) or intravenous infusion of a-methyldopa in animals pretreated with tranylcypromine lowered the blood pressure gradually by an average of 15 mm Hg (S.E. +- 5.5) within 3 hr. Pretreatment of animals with reserpine or imipramine completely blocked the central hypotensive effect of a combination of tranylcypromine and a-methyldgpa.
180 /
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3.3. lmipramine pretreatment Pretreatment with imipramine produced a fall in blood pressure of 25 mm Hg (S.E. + 7.2) and blood pressure stabilized at this level within 30 rain (average 113.5 -+ 7.9 ram). The mean fall in blood pressure within 3 hr following a-methyldopa infusion was 9.5 mm Hg (S.E. -+ 8.6). These values are significantly different from those of the control group (p < 0.005 ).
.O j , ~ . ! 2 3 4 TIME IN HOURS = : 4 - M E T H Y l DOPA "°--°-RESERPINE PRETREATMENT : : IMIPRAMINE PRETREATMENT . . . . TRANYI.CYPROMINE PRETREATMENT 4. DISCUSSION
3.4. Tranylcypromine pretreatment The average blood pressure in this group was 145 m m Hg (S.E. -+- 11.2). Pretreatment with tranylcypromine produced a moderate rise in blood pressure followed by a fall, the mean fall being 15 mm Hg (S.E. + 4.5); blood pressure stabilized at this level within 30 min. These cats developed a marked hypotension with intravertebral infusion of a-methyldopa. The fall started within 5 rain of infusion and by lhe end of i hr when the infusion was over, the average fall was 50 mm Hg (S.E. ± 13.1). The mean fall during the first hour after infusion was 100 mm Hg (S.E. + 16.4) and that in the second hour was 135 mm Hg (S.E. -+ 8.8). In 4 of the 10 cats, the blood pressure had reached zero within 2 hr and in the remainder it fell to zero during the third hour, The differences between falls in blood pressure during infusion and
a-Methyldopa inhibits the aromatic amino acid decarboxylases in vivo and in vitro and thereby reduces the noradrenaline and serotonin concentrations in the central and peripheral nervous systems (Westermann et ai., 1950; Lindmar and Muscholt, 1965). Only the/-isomer of the drug exhibits pharmacological activity (Hess et al., 1961). Muscholl and Maitre (1963) demonstrated that in rabbits pretreated with a-methyldopa, a-methylnoradrenaline is released from the perfused heart on stimulation of its sympathetic supply. Conversion of a-methyldopa to c~-methyldopamine has been demonstrated in brain by other workers (Carlsson and Lindqvist, 1962; Carlsson et al., 1968). Day and Rand ( 1 9 6 3 a ) h a v e proposed that a-methylnoradrenaline synthesized in the adrenergic neurones from a-methyldopa displaces noradrenaline from the sympathetic nerves and acts as a false neurohumoral transmitter. Both a-methyl-
\ t~ \
\
122
A.K.KALE and R.S.SATOSKAR
dopamine and c~-rnethylnoradrenaline are resistant to the action of MAO (Carlsson and Lindqvist, 1962). The false neurohumoral transmitter hypothesis can explain the various instances of reserpine, c~-methyldopa antagonism (Day and Rand, 1963b: De Vos et al., 1968). Reserpine does not interfere with the uptake of a-metbylnoradrenaline at the neuronal level IHamberger and Masuoka, 1965). Similarly brain c~-methylnoradrenaline formed b y pretreatment with u-methyldopa is not depleted by subsequent reserpine administration (Carlsson et al., 1965). However 3H a-methylnoradrenaline disappears more rapidly from the tissues of reserpinized mice as compared to controls, showing failure of binding of c~-methylnoradrenaline in the granules (Carlsson et al., 1968). The uptake of labelled noradrenaline by the particulate fraction is also reduced by reserpine pretreatment (Lundborg, 1969). The conversion of dopamine to noradrenaline has been shown to occur in the granules and is blocked by reserpine (Stjarne, 1966). It is, therefore, likely that reserpine blocks the hypotensive effect of a-methyldopa by preventing the conversion of c~-methyldopamine to a-methylnoradrenaline within the granules or by blocking the granular uptake of these sub~trates. Imipramine and the related anti-depressants prevent the uptake of noradrenaline in both the central and peripheral nervous systems (Axelrod et al.. 1962: lversen. 1965). These drugs enhance the pressor response to exogenous noradrenatine (Osborne and Sigg, 1960; Sigg and Hill, 1967). However, they also exhibit a central antiadrenergic activity in doses that enhance the pressor response to exogenous noradrenaline (Schmitt, 1967). The blockade of the central hypotensive effect of c~-methyldopa by imipramine is, therefore, probably due to inhibition of uptake of a-methyldopa by imipramine or desmethyl imipramine at the central neuronal level, lmipramine may also act by preventing the displacement of noradrenaline by c~-methylnoradrenaline (Carlsson eI al., 1969). Tranylcypromine, apart from being a MAO inhibitor, bears a marked structural similarity to amphetamine. Administered intraventricularly in cats, it produces a pronounced rise in the blood pressure, heart rate and respiratory rate (Feldberg and Lotti, 1967). It also depletes the myocardiac catecholamii~es in the same species (Goldberg and Shidenran, 1962) and can release 3H-metaraminol from mice hearts (Carlsson
and Waldeck, 1966). Amphetamine has been shown to release dopamine and noradrenaline from the extragranular pool within the adrenergic neurones (Carlsson et al., 1966). It, therefore, appears likely that tranylcypromine may enhance the hypotensive effect of a-methyldopa by depletion of extragranular noradrenaline within the central neurons.
ACKNOWLEDGEM ENTS The generous supply of methyldopa by Merck, Sharp and Dohme (India). imipramine by Surhid Geigy Ltd. (India) and tranylcypromine by Smith, Kline and French (India) is gratefully acknowledged. The authors are indebted to Mr. A.R. Ghate, Mr. P.R. Menkurkar and Miss M.R. Rele for the technical assistance rendered.
REFERENCES Axelrod, J., G. Hertting and L. Porter, 1962, Effect of drugs on the uptake and release of 3H-norepinephrine, Nature 194, 29% Carlsson, A. and M. Liudqvist, 1962, In vivo decarboxylation of methyldopa and a-methyl metatyrosine, Acta Physiol. Scand. 54, 87. Carlsson, A., A. Dahlstrom, K. Fuxe and N.A. Hillarp, 1965, Failure of reserpine to deplete noradrenaline neurons of O~-methylnoradrenaline formed from a-methyldopa, Acta Pharmacol. Toxicol. 22,270. Carlsson, A., K. Fuxe, B. Hamberger and M. Lindqvist, 1966, Biochemical and histochemical studies on the effects of imipramine-like drugs and (+) amphetamine on central and peripheral autonomic neurones, Acta Physiol. Scand. 67, 48 I. Carlsson, A. and B. Waldeck, 1966, Release of 3H-metaraminol by different mechanisms, Acta Physiol. Scand. 67, 471. Carlsson, A., J.J. Meisch and B. Waldeck, 1968, On the 13-hydroxylation of (+) a-methyldopamine in vivo European J. Pharmacol. 5, 85. Carlsson, A., K. Fuxe, K. Fuxe and T. Hokfelt, 1969, Effects of some antidepressant drugs on the depletion of introneuronal brain catecholamine stores caused by 4, ct-dimethyl metatyramine, European J. Pharmacol. 5,367. Day, M.D. and M.J. Rand, 1963a, A hypothesis for the mode of action of a-methyldopa in relieving hypertension, J. Pharm. Pharmacol. 15,221. Day, M.D. and M.J. Rand, 1963b, Awakening from reserpine sedation by a-methyldopa, J. Pharm. Pharmacol. 15,631. De Vos, C.J., H. Grijsen and 1.L. Bonta, 1968, Prevention by a-methyldopa of the reserpine induced prolongation of
CENTRAL HYPOTENSIVE EFFECT OF o~-METHYLDOPA hippocampal after discharges, European J. Pharmacol. 4, 476. Feldberg, W. and V.J. Lotti, 1967, Body temperature responses in cats and rabbits to the monoamine oxidase inhibitor tranylcypromine, J. Physiol. (London), 190, 203. Goldberg, N.D. and F.E. Shideman, 1962, Species differences in the cardiac effects of a monoamine oxidase inhibitor, J. Pharmacol. Exptl. Therap. 136, 142. Hamberger, B. and D. Masuoka, 1965, Localization of catecholamine uptake in rat brain slices, Acta Pharmacol. Toxicol. 22,270. Henning, M. and P.A.Van Zwieten, 1967, Centr',d hypotensive effect of a-methyldopa, J. Pharm. Pharmacol. 19, 403. Henning, M. and P.A. Van Zwieten, 1968, Central hypothensive effect of a-methyldopa, J. Pharm. Pharmacol. 20, 409. Hess, S.M., R.M. Connamacher, M. Ozaki and S. Udenfriend, 1961, The effects of a-methyldopa and a-methyl metatyrosine on the metabolism of norepinephrine and serotonin in vivo, J. Pharmacol. Exptl. Therap. 134, 129. lversen, L.L., 1965, Inhibition of noradrenaline uptake by drugs, J. Pharm. Pharmacol. 17, 62. Lindmar, R. and Z. Muscholl, 1965, Aufnahme und Friesetzung von a-Methylnoradrenaline, Arch. Exptl. Pathol. Pharmakol. 249, 529.
123
Lundborg, P., 1969, Effects of reserpine on the cellulax distribution of 3H-a-methylnoradrenaline in the mouse heart, Brit. 1. Pharmacol. 36,386. Muscholl, E. and L. Maitre, 1963, Release by sympathetic stimulation of a-methyinoradrenaline stores in the heart after administration of a-methyldopa, Experientia, 19, 658. Osborne, M. and Z. Sigg, 1960, Effects of imipramine on the peripheral autonomic system, Arch. intern. Pharmacodyn. 129,273. Reis, H.E. and P.A. Van Zwieten, 1967, ttypotensive effect of hydralazine injected into the vertebral artery of the cat, Arch. Intern. Pharmacodyn. 169,494. Schmitt, N., 1967, Selective action of antidepressant drugs on some rhinencephalic and related structures, in: Antidepressant drugs, eds. S. Garattini and M.N. Dukes (Excerpta Medica, Amsterdam) pp. 104-115. Sigg, E.B. and R.T. Hill, 1967, The effect of imipramine on central adrenergic mechanisms, in: Neuropsychopharmacology, ed. H. Brill (Excerpta Medica, Amsterdam) pp. 367-372. Stjarne, L., 1966, Studies on noradrenaline biosynthesis in nerve tissue, Acta Physiol. Scand. 67,441. Westerman, E., H. Balzer and J. Knell, 1958, Hemmung der Serotonin Bildung durch a-metbyldopa, Arch. Exptl. Pathol. Pharmakol. 234, 194.
MODIFICATION OF THE CENTRAL HYPOTENSIVE EFFECT OF c~-METHYLDOPA BY RESERPINE, IMIPRAMINE AND TRANYLCYPROMINE A.K. KALE and R.S. SATOSKAR Department o./ Pharmacolog 3 . L.T.Ji. Medical ('~:lw.g~. Ston Bomt)ay-22 Italia
~ccepted ~ Dccc;nbt~ 19(,~
Received 24 November 1969
A.K. KALF, and R.S. SATOSKAR Modification o f the central hypolensi~ e e f]k,ct oj o~-methyhtopa I~v reserpine, imipramine and tranylcypromine. European J. Pharmacol. 9 (1970) 120 123. In chlorolase anae~;ihetised cats, O~-methyldopa infused into the vertebral artery produces a ILypotensive cffe~t ill doses tbat are ineffective peripherally. Pretreatment of cuts with reserpine or imiprami~Je blocks this eflect where~l, prctreatment with tranylcypromine greatly augments it. Translcypromine doe~ not shox~, l[liS t2t'tect {i/ Lmilnals pretreated with reserpine or imipramine. ~-Methyldopa Franylcypromine
Reserpine ('entral hypotensive effect
l. INTRODUCTION The hypotensive drug, c~-methyldopa when infused int~avertebrally in chloralose-anaesthetJzed cats, produces a delayed but sustained fall in blood pressure with dose'~ that are ineffective intravepously (Henning and Zwieten, 1967, 1 9 6 8 ) However, both intra,,ertebral and intravenous infiisions of the drug decrease in brain dopamine and noradrenaline levels arrd produce equivalent increases hr the concentration of a-methyldopamine in the brain. It was, therefore, decided to study the effect of drugs affecting the uptake/release/metabo!ism of catecholamines on the central hypotensive effect of ~-methyldopa.
2. METHODS AND MATERIAL Cats e f either sex weighing 2.5 to at kg and anaesthetized with ether followed by chloralose (50 70 mg/kg i.v.) were used. The right vertebral artery was employed for infusion (Reis and Zwieten, 1967). This procedure does no'~ require tl,.oracotomy. The duration of infusion varied from 45 min 1o 1 hr.
lmiprammc
Respiration was maintained artificially tt,,rot@l a tracheal cannula and blood pressure was recorded from the right femoral artery b~ a me~cmy map.ometer. All the drugs were dissolved m normal saline. Animals of Group I (control: n = 51 received c~-methyidopa (20 mg/kg; 10 mg/ml) intravertebrally Group I1 (n = 10) received reserpine (1.25 mg/kg i p.: Serpasil. Ciba) 24 hr before irmavertebrai a-methyldepa. Group 1II (n = 10) received imipraInine (3 mg/kg i.p.: 10 mg/ml) 30 mm before the il;travertebral infusion of 0~-metbyldopa and Group IV (~, = 10) were treated with tranylcypromine {10,ng/kg i.p.: 20 mg/ml) followed 30 rain later by intravertebral ~-methyldopa. In additiot~. (it 2 cats pretreated with tranyl-cypron'ine were given c~-tnethyidopa infusion intravenously aF,d (ii) 2 cats pretreated with reserpine or imiprine received tranylcypromme i p. followed by intravertebral oe-methyldopa.
3. RESULTS 3.1. O : n t r o l
The initial average blood pressure of the cats in
CENTRAL HYPOTENSIVE EFFECT OF ct-METttYLDOPA this group was 140 mm Hg (S.E. -+ 7.8). Tire central hypotensive effect of a-methyldopa was confirmed (Henning and Zwieten, 1967, 1968). The fall in blood pressure during infusion was negligible (0 5 mm Hg). The mean fall within the first hour following infusion was 15 mm Hg (S.E. +- 2.5). The average fall within the 2nd and the 3rd hr was 26 mm Hg (S.E. +- 4.3) and 36 mm ttg (S.E. -+ 6.6) respectively. There was no appreciable fall after this period.
3.2. Reserphw pretreatment The cats pretreated with reserpine were sedated and required smaller amounts of chloralose (50 mg/kg i.v.). Their initial average blood pressure was 96.5 mm Hg (S.E. -+ 7.2). Following intravertebral infusion of a-methyldopa, the mean fall in blood pressure within 3 hr following infusion was only 10 mm Hg (S.E. -+ 5.3). These results are highly significant when compared to control values (p < 0 . 0 0 5 ) .
121
within the first and the second hours after it,. ,.:ompletion in controls and treated animals are highly significant (p < 0.0005). lntravertebral infusion of normal saline at a pH of 6.8 (same as tkat of tranylcypromine solution) or intravenous infusion of a-methyldopa in animals pretreated with tranylcypromine lowered the blood pressure gradually by an average of 15 mm Hg (S.E. +- 5.5) within 3 hr. Pretreatment of animals with reserpine or imipramine completely blocked the central hypotensive effect of a combination of tranylcypromine and a-methyldgpa.
180 /
~O
\
"~ 80t
"\\\\\
40~
\\
3.3. lmipramine pretreatment Pretreatment with imipramine produced a fall in blood pressure of 25 mm Hg (S.E. + 7.2) and blood pressure stabilized at this level within 30 rain (average 113.5 -+ 7.9 ram). The mean fall in blood pressure within 3 hr following a-methyldopa infusion was 9.5 mm Hg (S.E. -+ 8.6). These values are significantly different from those of the control group (p < 0.005 ).
.O j , ~ . ! 2 3 4 TIME IN HOURS = : 4 - M E T H Y l DOPA "°--°-RESERPINE PRETREATMENT : : IMIPRAMINE PRETREATMENT . . . . TRANYI.CYPROMINE PRETREATMENT 4. DISCUSSION
3.4. Tranylcypromine pretreatment The average blood pressure in this group was 145 m m Hg (S.E. -+- 11.2). Pretreatment with tranylcypromine produced a moderate rise in blood pressure followed by a fall, the mean fall being 15 mm Hg (S.E. + 4.5); blood pressure stabilized at this level within 30 min. These cats developed a marked hypotension with intravertebral infusion of a-methyldopa. The fall started within 5 rain of infusion and by lhe end of i hr when the infusion was over, the average fall was 50 mm Hg (S.E. ± 13.1). The mean fall during the first hour after infusion was 100 mm Hg (S.E. + 16.4) and that in the second hour was 135 mm Hg (S.E. -+ 8.8). In 4 of the 10 cats, the blood pressure had reached zero within 2 hr and in the remainder it fell to zero during the third hour, The differences between falls in blood pressure during infusion and
a-Methyldopa inhibits the aromatic amino acid decarboxylases in vivo and in vitro and thereby reduces the noradrenaline and serotonin concentrations in the central and peripheral nervous systems (Westermann et ai., 1950; Lindmar and Muscholt, 1965). Only the/-isomer of the drug exhibits pharmacological activity (Hess et al., 1961). Muscholl and Maitre (1963) demonstrated that in rabbits pretreated with a-methyldopa, a-methylnoradrenaline is released from the perfused heart on stimulation of its sympathetic supply. Conversion of a-methyldopa to c~-methyldopamine has been demonstrated in brain by other workers (Carlsson and Lindqvist, 1962; Carlsson et al., 1968). Day and Rand ( 1 9 6 3 a ) h a v e proposed that a-methylnoradrenaline synthesized in the adrenergic neurones from a-methyldopa displaces noradrenaline from the sympathetic nerves and acts as a false neurohumoral transmitter. Both a-methyl-
\ t~ \
\
122
A.K.KALE and R.S.SATOSKAR
dopamine and c~-rnethylnoradrenaline are resistant to the action of MAO (Carlsson and Lindqvist, 1962). The false neurohumoral transmitter hypothesis can explain the various instances of reserpine, c~-methyldopa antagonism (Day and Rand, 1963b: De Vos et al., 1968). Reserpine does not interfere with the uptake of a-metbylnoradrenaline at the neuronal level IHamberger and Masuoka, 1965). Similarly brain c~-methylnoradrenaline formed b y pretreatment with u-methyldopa is not depleted by subsequent reserpine administration (Carlsson et al., 1965). However 3H a-methylnoradrenaline disappears more rapidly from the tissues of reserpinized mice as compared to controls, showing failure of binding of c~-methylnoradrenaline in the granules (Carlsson et al., 1968). The uptake of labelled noradrenaline by the particulate fraction is also reduced by reserpine pretreatment (Lundborg, 1969). The conversion of dopamine to noradrenaline has been shown to occur in the granules and is blocked by reserpine (Stjarne, 1966). It is, therefore, likely that reserpine blocks the hypotensive effect of a-methyldopa by preventing the conversion of c~-methyldopamine to a-methylnoradrenaline within the granules or by blocking the granular uptake of these sub~trates. Imipramine and the related anti-depressants prevent the uptake of noradrenaline in both the central and peripheral nervous systems (Axelrod et al.. 1962: lversen. 1965). These drugs enhance the pressor response to exogenous noradrenatine (Osborne and Sigg, 1960; Sigg and Hill, 1967). However, they also exhibit a central antiadrenergic activity in doses that enhance the pressor response to exogenous noradrenaline (Schmitt, 1967). The blockade of the central hypotensive effect of c~-methyldopa by imipramine is, therefore, probably due to inhibition of uptake of a-methyldopa by imipramine or desmethyl imipramine at the central neuronal level, lmipramine may also act by preventing the displacement of noradrenaline by c~-methylnoradrenaline (Carlsson eI al., 1969). Tranylcypromine, apart from being a MAO inhibitor, bears a marked structural similarity to amphetamine. Administered intraventricularly in cats, it produces a pronounced rise in the blood pressure, heart rate and respiratory rate (Feldberg and Lotti, 1967). It also depletes the myocardiac catecholamii~es in the same species (Goldberg and Shidenran, 1962) and can release 3H-metaraminol from mice hearts (Carlsson
and Waldeck, 1966). Amphetamine has been shown to release dopamine and noradrenaline from the extragranular pool within the adrenergic neurones (Carlsson et al., 1966). It, therefore, appears likely that tranylcypromine may enhance the hypotensive effect of a-methyldopa by depletion of extragranular noradrenaline within the central neurons.
ACKNOWLEDGEM ENTS The generous supply of methyldopa by Merck, Sharp and Dohme (India). imipramine by Surhid Geigy Ltd. (India) and tranylcypromine by Smith, Kline and French (India) is gratefully acknowledged. The authors are indebted to Mr. A.R. Ghate, Mr. P.R. Menkurkar and Miss M.R. Rele for the technical assistance rendered.
REFERENCES Axelrod, J., G. Hertting and L. Porter, 1962, Effect of drugs on the uptake and release of 3H-norepinephrine, Nature 194, 29% Carlsson, A. and M. Liudqvist, 1962, In vivo decarboxylation of methyldopa and a-methyl metatyrosine, Acta Physiol. Scand. 54, 87. Carlsson, A., A. Dahlstrom, K. Fuxe and N.A. Hillarp, 1965, Failure of reserpine to deplete noradrenaline neurons of O~-methylnoradrenaline formed from a-methyldopa, Acta Pharmacol. Toxicol. 22,270. Carlsson, A., K. Fuxe, B. Hamberger and M. Lindqvist, 1966, Biochemical and histochemical studies on the effects of imipramine-like drugs and (+) amphetamine on central and peripheral autonomic neurones, Acta Physiol. Scand. 67, 48 I. Carlsson, A. and B. Waldeck, 1966, Release of 3H-metaraminol by different mechanisms, Acta Physiol. Scand. 67, 471. Carlsson, A., J.J. Meisch and B. Waldeck, 1968, On the 13-hydroxylation of (+) a-methyldopamine in vivo European J. Pharmacol. 5, 85. Carlsson, A., K. Fuxe, K. Fuxe and T. Hokfelt, 1969, Effects of some antidepressant drugs on the depletion of introneuronal brain catecholamine stores caused by 4, ct-dimethyl metatyramine, European J. Pharmacol. 5,367. Day, M.D. and M.J. Rand, 1963a, A hypothesis for the mode of action of a-methyldopa in relieving hypertension, J. Pharm. Pharmacol. 15,221. Day, M.D. and M.J. Rand, 1963b, Awakening from reserpine sedation by a-methyldopa, J. Pharm. Pharmacol. 15,631. De Vos, C.J., H. Grijsen and 1.L. Bonta, 1968, Prevention by a-methyldopa of the reserpine induced prolongation of
CENTRAL HYPOTENSIVE EFFECT OF o~-METHYLDOPA hippocampal after discharges, European J. Pharmacol. 4, 476. Feldberg, W. and V.J. Lotti, 1967, Body temperature responses in cats and rabbits to the monoamine oxidase inhibitor tranylcypromine, J. Physiol. (London), 190, 203. Goldberg, N.D. and F.E. Shideman, 1962, Species differences in the cardiac effects of a monoamine oxidase inhibitor, J. Pharmacol. Exptl. Therap. 136, 142. Hamberger, B. and D. Masuoka, 1965, Localization of catecholamine uptake in rat brain slices, Acta Pharmacol. Toxicol. 22,270. Henning, M. and P.A.Van Zwieten, 1967, Centr',d hypotensive effect of a-methyldopa, J. Pharm. Pharmacol. 19, 403. Henning, M. and P.A. Van Zwieten, 1968, Central hypothensive effect of a-methyldopa, J. Pharm. Pharmacol. 20, 409. Hess, S.M., R.M. Connamacher, M. Ozaki and S. Udenfriend, 1961, The effects of a-methyldopa and a-methyl metatyrosine on the metabolism of norepinephrine and serotonin in vivo, J. Pharmacol. Exptl. Therap. 134, 129. lversen, L.L., 1965, Inhibition of noradrenaline uptake by drugs, J. Pharm. Pharmacol. 17, 62. Lindmar, R. and Z. Muscholl, 1965, Aufnahme und Friesetzung von a-Methylnoradrenaline, Arch. Exptl. Pathol. Pharmakol. 249, 529.
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