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Pressor effect of indolethylamines
EUROPEAN JOURNAL OF PHARMACOLOGY 21 (1973) 242-245. NORTH-HOLLAND PUBLISHING COMPANY
Short communication PRESSOR EFFECT OF |NDOLETHYLAMINES M. G()THERT, P. TUCHINDA and H.G. BAUMGARTEN * Institute of Pharmacology, Department of Neuroanatomy, University of Hamburg, 2000 Hamburg 20, Martinistr. 52, W. Germany
Accepted 9 November 1972
Received 19 October 1972
M. GOTHERT, P. TUCHINDA and H.G. BAUMGARTEN, Pressor effect ofindolethylamines, European J. Pharmacol. 21 (1973) 242-245. 6-Hydroxytryptamine, 7-hydroxytryptamine and 5,7-dihydroxytryptamine increase blood pressure when given intravenously to pithed rats and effect not due to stimulation of 5-hydroxytryptamine receptors. 6-Hydroxytryptamine and 7-hydroxytryptamine interact with c~-adrenoceptors of the vascular bed. An effect of 5,7-dihydroxytryptamine on c~-adrenoceptors was not established. 6-Hydroxytryptamine 7-Hydroxytry ptamine
Blood pressure Pithed rats
I. Introduction Krishnamurty (1971) presented evidence for the existence of specific 5-hydroxytryptamine (5-HT) receptors in the vascular bed of rats, the stimulation of which induced a blood pressure rise in pithed animals (Vanoy, 1965; Haeusler and Finch, 1972). Similarly, the pressor effect of 5,6-dihydroxytryptamine (5,6DHT) - a compound that provokes a selective chemical degeneration of serotonin neurons in brain (Baumgarten et al., 1971) - rests solely on a direct stimulation of 5-HT receptors, despite its uptake and storage in sympathetic nerve terminals and displacement of bound noradrenaline (Baumgarten et al., 1972). It was therefore of interest to evaluate the pressor effects of other indolethylamines - 6-hydroxytryptamine (6-HT), 7-hydroxytryptamine (7-HT) and 5,7dihydroxytryptamine (5,7-DHT) - in pithed rats and to clarify whether or not these tryptamine derivatives interact with 5-HT or adrenoceptors, and whether they might indirectly act on vascular smooth muscle
* Supported by grants from the Deutsche Forschungsgemeinschaft.
5,7-Dihydroxytryptamine
by release of neuronal noradrenaline. 5-HT was included in all experiments as a reference substance.
2. Materials and methods Male Wistar rats (200-220 g body weight) were pithed under light ether anaesthesia by means of a steel probe via the orbit. Injections of drugs were given into the cannulated right jugular vein. Blood pressure was recorded in the right carotid artery by means of a Statham transducer. The drugs were injected at intervals of 10 rain. In each experiment the pressor effects of 4 agonists (5-HT, 6-HT, 7-HT and 5,7-DHT) were measured in the same rat before and after injection of one antagonist or of cocaine. Drugs were injected in a vol. of 0.15 ml and washed with 0.9% saline (total vol. 0.20 ml). The drugs were dissolved in 0.9% saline, in case of (+)-2 [/3-(4-hydroxyphenyl)-ethylaminomethyl]-tetralone 20% ethanol was added. Calculations of drugs refer to the free base. For statistical evaluation of the data, Student's t-test was used.
lkL G6thert et al., Pressor efJect o f indolethylamines Drugs used: 5 - h y d r o x y t r y p t a m i n e c r e a t i n i n e sulfate (5-HT); 6 - h y d r o x y t r y p t a m i n e c r e a t i n i n e sulfate (6-HT); 7 - h y d r o x y t r y p t a m i n e c r e a t i n i n e sulfate (7HT); 5 , 7 - d i h y d r o x y t r y p t a m i n e c r e a t i n i n e sulfate ( 5 , 7 - D H T ) ; m e t h y s e r g i d e bimaleate; p h e n t o l a m i n e m e t h a n e s u l f o n a t e ; (-+)-2 [/3-(4-hydroxyphenyl)-ethyla m i n o m e t h y l ] - t e t r a l o n e h y d r o c h l o r i d e ( H E A T ) ; cocaine h y d r o c h l o r i d e ; reserpine.
243
3. R e s u l t s
As s h o w n in the
table
1, all i n d o l e t h y l a m i n e s
tested increased b l o o d pressure in p i t h e d rats; 6- and 7-HT were less effective t h a n 5-HT, and the m o n o h y d r o x y t r y p t a m i n e s were m o r e p o t e n t than 5,7-dihyd r o x y t r y p t a m i n e . As e x p e c t e d , m e t h y s e r g i d e prev e n t e d tire pressor e f f e c t o f 5-HT; h o w e v e r it did not b l o c k the pressor e f f e c t o f 5,7-DHT. Surprisingly, the pressor e f f e c t o f 6-HT and 7-HT was e n h a n c e d by
Table 1 Increase in blood pressure (B.P.) after i.v. injection of 5-hydroxytryptamine (5-HT), 6-hydroxytryptamine (6-HT), 7-hydroxytryptamine (7-HT), and 5,7-dihydroxytryptamine (5,7-DHT) in pithed rats (means ± S.E.M.). Influence of methysergide, phentolamine, 2-[/3-(4-hydroxyphenyl)-ethylammomethyl]-tetralone (HEAT), cocaine (i.v. application) on the pressor effect of indolethylamines, and effect of pretreatment with reserpine, 5 mg/kg, i.p., 20 hr belore the experiment. Intervals between the i.v. injections 10 rain. Pressor effects expressed as % of control are given in brackets. 5-HT 20 ~g/kg
6-HT 80 ~g/kg
7-1tT 80 ~g/kg
5,7-DHT 320 ~g/kg
B.P. rise (mm Hg) before methysergide
58 ± 3
24 ± 1
22 +- 0
18-+2
B.P. rise (ram Hg) after methysergide (0.1 mg/kg)
12 ± 1 (-79%) p < 0.001
39 -+ 1 (+62%) p < 0.001
31 -+ 1 (+42%) p < 0.001
18_+2 (±0',~)
B.P. rise 0rim Hg) before phentolamine
53
2l + 1
20 ± 1
18_+1
37 -+ 5 ( - 30%) p < 0.05
10 ± 1 ( -52%) p < 0.001
7±1 ( - 63;/,3 p < 0.001
6+1 (~ 70%) p < 0.001
B.P. rise (mm ltg) before HEAT
61 ± 7
21 ± 1
23 ± 1
17_+1
B.P. rise (mm Hg) after HEAT (2.5 mg/kg)
63 +--7 (+3%) n.s.
8± 1 (62%) p < 0.001
6+ 1 (-74%) p < 0.001
(
B.P. rise (mm Hg) before cocaine
78 -+ 3
22 ± 1
23 ± 1
18-+1
B.P. rise (mm Hg) after cocaine (10 mg/kg)
95 ± 6 (+22%) p < 0.05
20 -+ 2 (-9%1 n.s.
25 • 2 (+9%) n.s.
24+2
B.P. rise (ram Hg) after reserpine pretreatment
51 + 5 (-35%)* p K 0.01
16 _+ 1 (-27%)* p < 0.02 ,
(+4%)* n.s.
n.s.
B.P. rise (ram tlg) after reserpine pretreatment + HEAT (2.5 mg/kg)
57 ±3 (+ 12%) n.s.
10 _+2 ( - 37%) p < 0.05
13 +- 4 (-46%) p < 0.05
( +7',~ ) n.s;
B.P. rise (mm Hg) after phen t olamine (2.5 mg/kg)
:
* Percentage of controls before cocaine.
-+
5
24 + 2
15_+2 12%)
n.s.
(+33%) p < 0.05 14 ±'1 ( 22%)* 15t3
244
M. GiSthert et aL, Pressor effect o f indolethylamines
methysergide pretreatment. Phentolamine strongly attenuated the pressor activity of all indolethylamines analyzed. HEAT did not affect the pressor effects of 5-HT or 5,7-DHT, but markedly reduced those of 6-HT and 7-HT. Cocaine potentiated the pressor action of 5-HT and 5,7-DHT. Reserpine pretreatment (5 mg/kg, 20 hr before testing of the indolethylamines), reduced the pressor responses to 5-HT, 6-HT, and 5,7-DHT (lower than after 5-HT, 6-HT, or 5,7-DHT alone); addition of HEAT to these rats again decreased the effects of 6-HT. In those rats pretreated with reserpine, addition of HEAT also blocked the pressor effect of 7HT.
4. Discussion Despite their similarity in chemical structure and pressor activity, the hydroxyderivatives of tryptamine investigated differed in their mechanisms of action. Since 5,6-DHT had earlier been found to exclusively act on 5-HT receptors of the vascular bed (Baumgarten et al., 1972) it was assumed that 6- and 7-HT and 5,7-DHT might also interact with these receptors. The failure of methysergide, a specific 5-HT antagonist, to prevent the pressor effects of these indolamines, argues against this assumption. Unexpectedly, the pressor effects of 6- and 7-HT were increased by methysergide, a finding which is difficult to explain. One possibility is that methysergide interferes with the inactivation of both serotonin isomers, thereby potentiating their effects on blood pressure. Phentolamine prevented the pressor action of the indolethylamines tested. This is not surprising since phentolamine blocks both 5-HT and a-adrenoceptors. Since HEAT, a specific a-adrenoceptor blocking drug (Benthe et al., 1972), inhibited the pressor effect of 7-HT in both the untreated and reserpine-pretreated rat, it may be concluded that it acts directly upon a-adrenoceptors of the vascular bed. A significant indirect sympathomimetic component does not seem to be involved since neither reserpine nor cocaine modified the action of 7-HT on blood pressure. Similarly, HEAT considerably weakened the pressor effect of 6-HT suggesting a direct interaction with c~-adrenoceptors. 6-HT, however, apparently possesses weak indirect sympathomimetic properties since its pressor
action was attenuated after reserpine pretreatment. Neither methysergide nor HEAT influenced the rise in blood pressure caused by 5,7-DHT; therefore, its effect is not mediated by either 5-HT or a-adrenoceptors. Potentiation of its pressor effect after blockade of the amine uptake mechanism at adrenergic nerves by cocaine is compatible with the idea that it is inactivated by uptake into adrenergic neurons, like 5-HT (Thoa et al., 1967; Eccleston et al., 1968; Pluchino, 1972). When injected into the lateral ventricles of rat brain, 5,7-DHT causes toxic damage to serotonin and - to a lesser extent - to catecholamine containing neurons (Baumgarten and Lachenmayer, 1972). Despite this similarity in mechanism of action on monoamine neurons, 5,6-DHT and 5,7-DHT thus strinkingly differ in their effect on vascular smooth muscle.
Acknowledgements We thank Hoffman-La Roche (England) for a gift of 6-HT, and Beiersdorf (Hamburg) for a gift of HEAT. The generous supply of 7-HT and 5,7-DHT by Dr. A. Manian, N.I.M.H., Bethesda, Maryland, is gratefully acknowledged.
References Baumgarten, H.G. and L. Lachenmayer, 1972, 5,7-Dihydroxytryptamine: Improvement in chemical lesioning of indoleamine neurons in the mammalian brain, Z. Zellforsch., in press. Baumgarten, H.G., A. Bj6rklund, L. Lachenmayer, A. Nobin and U. Stenevi, 1971, Long lasting selective depletion of brain serotonin by 5,6-dihydroxytryptamine, Acta Physiol. Scand., Suppl. 373. Baumgarten, H.G., M. GiSthert, H.G. Schlossberger and P. Tuchinda, 1972, Mechanism of pressor effect of 5,6dihydroxytryptamine in pthed rats, Naunyn-Schmiedeb. Arch. Pharmakol. 274, 375. Benthe, H.F., M. G~Sthert and P. Tuchinda, 1972, Noradrenalin-antagonistische Wirkung verschiedener Phenylaethylamin- und Phenoxyaethylamin-Derivate, Arzneimittel Forsch. 22, 1468. Eccleston, D., N.B. Thoa and J. Axeirod, 1968, Inhibition by drugs of the accumulation in vitro of 5-hydroxytryptamine in guinea-pig vas deferens, Nature (London) 217, 846. Haeusler, G. and L. Finch, 1972, Vascular reactivity to 5hydroxytryptamine and hypertension in the rat, NaunynSchmiedeb. Arch. Pharmakol. 272, 101.
M. GOthert et aL, Pressor effect of indolethylamines Krishnamurty, V.S.R., 1971, Receptors for sympathomimetic amines and 5-hydroxytryptarnine in the rat aorta, Arch. Int. Pharmacodyn. 189, 90. Pluchino, S., 1972, Direct and indirect effects of 5-hydroxytryptamine and tyramine on cat smooth muscle, NaunynSchmiedeb. Arch. Pharmakol. 272, 189.
245
Thoa, N.B., J. Axelrod and D. Eccleston, 1967, Uptake and release of 14C-serotonin in the noradrenergic neurons of the guinea-pig vas deferens, Pharmacologist 9, 251. Vanov, S., 1965, Response of the rat urinary bladder in situ to drugs and to nerve stimulation, Brit. J. Pharmacol. 24, 591.
Short communication PRESSOR EFFECT OF |NDOLETHYLAMINES M. G()THERT, P. TUCHINDA and H.G. BAUMGARTEN * Institute of Pharmacology, Department of Neuroanatomy, University of Hamburg, 2000 Hamburg 20, Martinistr. 52, W. Germany
Accepted 9 November 1972
Received 19 October 1972
M. GOTHERT, P. TUCHINDA and H.G. BAUMGARTEN, Pressor effect ofindolethylamines, European J. Pharmacol. 21 (1973) 242-245. 6-Hydroxytryptamine, 7-hydroxytryptamine and 5,7-dihydroxytryptamine increase blood pressure when given intravenously to pithed rats and effect not due to stimulation of 5-hydroxytryptamine receptors. 6-Hydroxytryptamine and 7-hydroxytryptamine interact with c~-adrenoceptors of the vascular bed. An effect of 5,7-dihydroxytryptamine on c~-adrenoceptors was not established. 6-Hydroxytryptamine 7-Hydroxytry ptamine
Blood pressure Pithed rats
I. Introduction Krishnamurty (1971) presented evidence for the existence of specific 5-hydroxytryptamine (5-HT) receptors in the vascular bed of rats, the stimulation of which induced a blood pressure rise in pithed animals (Vanoy, 1965; Haeusler and Finch, 1972). Similarly, the pressor effect of 5,6-dihydroxytryptamine (5,6DHT) - a compound that provokes a selective chemical degeneration of serotonin neurons in brain (Baumgarten et al., 1971) - rests solely on a direct stimulation of 5-HT receptors, despite its uptake and storage in sympathetic nerve terminals and displacement of bound noradrenaline (Baumgarten et al., 1972). It was therefore of interest to evaluate the pressor effects of other indolethylamines - 6-hydroxytryptamine (6-HT), 7-hydroxytryptamine (7-HT) and 5,7dihydroxytryptamine (5,7-DHT) - in pithed rats and to clarify whether or not these tryptamine derivatives interact with 5-HT or adrenoceptors, and whether they might indirectly act on vascular smooth muscle
* Supported by grants from the Deutsche Forschungsgemeinschaft.
5,7-Dihydroxytryptamine
by release of neuronal noradrenaline. 5-HT was included in all experiments as a reference substance.
2. Materials and methods Male Wistar rats (200-220 g body weight) were pithed under light ether anaesthesia by means of a steel probe via the orbit. Injections of drugs were given into the cannulated right jugular vein. Blood pressure was recorded in the right carotid artery by means of a Statham transducer. The drugs were injected at intervals of 10 rain. In each experiment the pressor effects of 4 agonists (5-HT, 6-HT, 7-HT and 5,7-DHT) were measured in the same rat before and after injection of one antagonist or of cocaine. Drugs were injected in a vol. of 0.15 ml and washed with 0.9% saline (total vol. 0.20 ml). The drugs were dissolved in 0.9% saline, in case of (+)-2 [/3-(4-hydroxyphenyl)-ethylaminomethyl]-tetralone 20% ethanol was added. Calculations of drugs refer to the free base. For statistical evaluation of the data, Student's t-test was used.
lkL G6thert et al., Pressor efJect o f indolethylamines Drugs used: 5 - h y d r o x y t r y p t a m i n e c r e a t i n i n e sulfate (5-HT); 6 - h y d r o x y t r y p t a m i n e c r e a t i n i n e sulfate (6-HT); 7 - h y d r o x y t r y p t a m i n e c r e a t i n i n e sulfate (7HT); 5 , 7 - d i h y d r o x y t r y p t a m i n e c r e a t i n i n e sulfate ( 5 , 7 - D H T ) ; m e t h y s e r g i d e bimaleate; p h e n t o l a m i n e m e t h a n e s u l f o n a t e ; (-+)-2 [/3-(4-hydroxyphenyl)-ethyla m i n o m e t h y l ] - t e t r a l o n e h y d r o c h l o r i d e ( H E A T ) ; cocaine h y d r o c h l o r i d e ; reserpine.
243
3. R e s u l t s
As s h o w n in the
table
1, all i n d o l e t h y l a m i n e s
tested increased b l o o d pressure in p i t h e d rats; 6- and 7-HT were less effective t h a n 5-HT, and the m o n o h y d r o x y t r y p t a m i n e s were m o r e p o t e n t than 5,7-dihyd r o x y t r y p t a m i n e . As e x p e c t e d , m e t h y s e r g i d e prev e n t e d tire pressor e f f e c t o f 5-HT; h o w e v e r it did not b l o c k the pressor e f f e c t o f 5,7-DHT. Surprisingly, the pressor e f f e c t o f 6-HT and 7-HT was e n h a n c e d by
Table 1 Increase in blood pressure (B.P.) after i.v. injection of 5-hydroxytryptamine (5-HT), 6-hydroxytryptamine (6-HT), 7-hydroxytryptamine (7-HT), and 5,7-dihydroxytryptamine (5,7-DHT) in pithed rats (means ± S.E.M.). Influence of methysergide, phentolamine, 2-[/3-(4-hydroxyphenyl)-ethylammomethyl]-tetralone (HEAT), cocaine (i.v. application) on the pressor effect of indolethylamines, and effect of pretreatment with reserpine, 5 mg/kg, i.p., 20 hr belore the experiment. Intervals between the i.v. injections 10 rain. Pressor effects expressed as % of control are given in brackets. 5-HT 20 ~g/kg
6-HT 80 ~g/kg
7-1tT 80 ~g/kg
5,7-DHT 320 ~g/kg
B.P. rise (mm Hg) before methysergide
58 ± 3
24 ± 1
22 +- 0
18-+2
B.P. rise (ram Hg) after methysergide (0.1 mg/kg)
12 ± 1 (-79%) p < 0.001
39 -+ 1 (+62%) p < 0.001
31 -+ 1 (+42%) p < 0.001
18_+2 (±0',~)
B.P. rise 0rim Hg) before phentolamine
53
2l + 1
20 ± 1
18_+1
37 -+ 5 ( - 30%) p < 0.05
10 ± 1 ( -52%) p < 0.001
7±1 ( - 63;/,3 p < 0.001
6+1 (~ 70%) p < 0.001
B.P. rise (mm ltg) before HEAT
61 ± 7
21 ± 1
23 ± 1
17_+1
B.P. rise (mm Hg) after HEAT (2.5 mg/kg)
63 +--7 (+3%) n.s.
8± 1 (62%) p < 0.001
6+ 1 (-74%) p < 0.001
(
B.P. rise (mm Hg) before cocaine
78 -+ 3
22 ± 1
23 ± 1
18-+1
B.P. rise (mm Hg) after cocaine (10 mg/kg)
95 ± 6 (+22%) p < 0.05
20 -+ 2 (-9%1 n.s.
25 • 2 (+9%) n.s.
24+2
B.P. rise (ram Hg) after reserpine pretreatment
51 + 5 (-35%)* p K 0.01
16 _+ 1 (-27%)* p < 0.02 ,
(+4%)* n.s.
n.s.
B.P. rise (ram tlg) after reserpine pretreatment + HEAT (2.5 mg/kg)
57 ±3 (+ 12%) n.s.
10 _+2 ( - 37%) p < 0.05
13 +- 4 (-46%) p < 0.05
( +7',~ ) n.s;
B.P. rise (mm Hg) after phen t olamine (2.5 mg/kg)
:
* Percentage of controls before cocaine.
-+
5
24 + 2
15_+2 12%)
n.s.
(+33%) p < 0.05 14 ±'1 ( 22%)* 15t3
244
M. GiSthert et aL, Pressor effect o f indolethylamines
methysergide pretreatment. Phentolamine strongly attenuated the pressor activity of all indolethylamines analyzed. HEAT did not affect the pressor effects of 5-HT or 5,7-DHT, but markedly reduced those of 6-HT and 7-HT. Cocaine potentiated the pressor action of 5-HT and 5,7-DHT. Reserpine pretreatment (5 mg/kg, 20 hr before testing of the indolethylamines), reduced the pressor responses to 5-HT, 6-HT, and 5,7-DHT (lower than after 5-HT, 6-HT, or 5,7-DHT alone); addition of HEAT to these rats again decreased the effects of 6-HT. In those rats pretreated with reserpine, addition of HEAT also blocked the pressor effect of 7HT.
4. Discussion Despite their similarity in chemical structure and pressor activity, the hydroxyderivatives of tryptamine investigated differed in their mechanisms of action. Since 5,6-DHT had earlier been found to exclusively act on 5-HT receptors of the vascular bed (Baumgarten et al., 1972) it was assumed that 6- and 7-HT and 5,7-DHT might also interact with these receptors. The failure of methysergide, a specific 5-HT antagonist, to prevent the pressor effects of these indolamines, argues against this assumption. Unexpectedly, the pressor effects of 6- and 7-HT were increased by methysergide, a finding which is difficult to explain. One possibility is that methysergide interferes with the inactivation of both serotonin isomers, thereby potentiating their effects on blood pressure. Phentolamine prevented the pressor action of the indolethylamines tested. This is not surprising since phentolamine blocks both 5-HT and a-adrenoceptors. Since HEAT, a specific a-adrenoceptor blocking drug (Benthe et al., 1972), inhibited the pressor effect of 7-HT in both the untreated and reserpine-pretreated rat, it may be concluded that it acts directly upon a-adrenoceptors of the vascular bed. A significant indirect sympathomimetic component does not seem to be involved since neither reserpine nor cocaine modified the action of 7-HT on blood pressure. Similarly, HEAT considerably weakened the pressor effect of 6-HT suggesting a direct interaction with c~-adrenoceptors. 6-HT, however, apparently possesses weak indirect sympathomimetic properties since its pressor
action was attenuated after reserpine pretreatment. Neither methysergide nor HEAT influenced the rise in blood pressure caused by 5,7-DHT; therefore, its effect is not mediated by either 5-HT or a-adrenoceptors. Potentiation of its pressor effect after blockade of the amine uptake mechanism at adrenergic nerves by cocaine is compatible with the idea that it is inactivated by uptake into adrenergic neurons, like 5-HT (Thoa et al., 1967; Eccleston et al., 1968; Pluchino, 1972). When injected into the lateral ventricles of rat brain, 5,7-DHT causes toxic damage to serotonin and - to a lesser extent - to catecholamine containing neurons (Baumgarten and Lachenmayer, 1972). Despite this similarity in mechanism of action on monoamine neurons, 5,6-DHT and 5,7-DHT thus strinkingly differ in their effect on vascular smooth muscle.
Acknowledgements We thank Hoffman-La Roche (England) for a gift of 6-HT, and Beiersdorf (Hamburg) for a gift of HEAT. The generous supply of 7-HT and 5,7-DHT by Dr. A. Manian, N.I.M.H., Bethesda, Maryland, is gratefully acknowledged.
References Baumgarten, H.G. and L. Lachenmayer, 1972, 5,7-Dihydroxytryptamine: Improvement in chemical lesioning of indoleamine neurons in the mammalian brain, Z. Zellforsch., in press. Baumgarten, H.G., A. Bj6rklund, L. Lachenmayer, A. Nobin and U. Stenevi, 1971, Long lasting selective depletion of brain serotonin by 5,6-dihydroxytryptamine, Acta Physiol. Scand., Suppl. 373. Baumgarten, H.G., M. GiSthert, H.G. Schlossberger and P. Tuchinda, 1972, Mechanism of pressor effect of 5,6dihydroxytryptamine in pthed rats, Naunyn-Schmiedeb. Arch. Pharmakol. 274, 375. Benthe, H.F., M. G~Sthert and P. Tuchinda, 1972, Noradrenalin-antagonistische Wirkung verschiedener Phenylaethylamin- und Phenoxyaethylamin-Derivate, Arzneimittel Forsch. 22, 1468. Eccleston, D., N.B. Thoa and J. Axeirod, 1968, Inhibition by drugs of the accumulation in vitro of 5-hydroxytryptamine in guinea-pig vas deferens, Nature (London) 217, 846. Haeusler, G. and L. Finch, 1972, Vascular reactivity to 5hydroxytryptamine and hypertension in the rat, NaunynSchmiedeb. Arch. Pharmakol. 272, 101.
M. GOthert et aL, Pressor effect of indolethylamines Krishnamurty, V.S.R., 1971, Receptors for sympathomimetic amines and 5-hydroxytryptarnine in the rat aorta, Arch. Int. Pharmacodyn. 189, 90. Pluchino, S., 1972, Direct and indirect effects of 5-hydroxytryptamine and tyramine on cat smooth muscle, NaunynSchmiedeb. Arch. Pharmakol. 272, 189.
245
Thoa, N.B., J. Axelrod and D. Eccleston, 1967, Uptake and release of 14C-serotonin in the noradrenergic neurons of the guinea-pig vas deferens, Pharmacologist 9, 251. Vanov, S., 1965, Response of the rat urinary bladder in situ to drugs and to nerve stimulation, Brit. J. Pharmacol. 24, 591.