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Hypertension and tachycardia produced by inhibition of reuptake of 5-Hydroxytryptamine by fluoxetine in the rat
NeuropharmacologyVo1.25, No.7, pp.799-802, 1986 Printed in Great Britain
HYPERTENSION
AND TACHYCARDIA
PRODUCED
OOZE-3908/86 $3.00 + 0.00 Pergamon Journals Ltd
BY INHIBITION
FLUOXETINE
M.L.Tsai
Department
of Physiology, College,
(Accephi
OF 5-HYDROXYTRYPTAMINE
BY
IN THE RAT
and M.T. Lin
National
Tainan,
OF REUPTAKE
Cheng Kung University
Taiwan,
Republic
17 Apti
Medical
of China
1986)
Summary. In rats anaesthetieed with urethane, increasing the activity of 5-hydroxytryptamine receptors or the level of cuntional serotonin in the brain with the'inhibitors of the reuptake of serotonin, fluxetine, produced both hypertension and tachycardia. The hypertension induced by fluoxetine was significantly inhibited by pretreatment of the animals with ketanserin (a serotonin receptor antagonist), by bilateral vagotomy, spinal transection or bilateral adrenalectomy. On the other hand, the tachycardia induced by fluoxetine was significantly inhibited by pretreatment with ketanserin or bilateral vagotomy, but not by spinal transection or adrenalectomy. The data indicate that fluoxetine acts through serotonin receptors in the central nervous system by influencing autonomic outflow to induce both hypertension and tachycardia.
It has been demonstrated that the intracerebral injection of small amounts of 5-hydroxytryptamine (5-HT; serotonin) in the rat, produced an increase in blood pressure (Lambert, Friedman and Gershon, 1975; Smits and Struyher-Boudier, 1976; Robinson, Austin an and Gibbens, 1985). However, the systemic administration of p-chlorophenylalanine, agent which depletes 5-HT, produced an increase, rather than a decrease, in blood pressure that could be blocked by simultaneous or subsequent treatment with 5-hydroxytryptophan (the precursor of'5-HT) (Ito and Schomberg, 1972). Thus, there appears to be a conflict in the available data about the possible role played by 5-HT in the brain, in cardiovascular control. In order to deal with this question, the present study attempted to assess the effects of increasing the activity of 5-HT receptors or the level of functional 5-HT in the brain, by central administration of fluoxetine (an inhibitor of the reuptake of 5-HT) (Carlsson, Corrodi, Fuxe and Hokfelt, 1969; Wong, Korng, Bymaster, Hauser and Molloy, 1974) on cardiovascular function in intact control rats, in spinal, vagotomised and adrenalectomised rats, and in rats which had received an intracerebral injection of the selective antagonist of the S2 subtype of 5-HT receptor, ketanserin (Van Nueten, Janssen, Van Beek, Xhonneux, Verbeuren and Vanhoutte, 1981; Wenting, Veld, Woittiex, Boomsma and Schalekamp, 1982).
METHODS
Female Sprague-Dawley rats, weighing 180-28G g, were used. Six groups of animals were used: (1) saline-treated rats which received an intraventricular injection of 0.9% saline; (2) ketanserin-treated rats which received an intraventricular injection of ketanserin (6 ug in 5 ul); (3) rats with spinal transection at C7; (4) rats with bilateral vagotomy; (5) rats with bilateral adrenalectomy; and (6) rats which were sham-operated. The cardiovascular responses of these groups of animals to an intraventricular injection of 0.9% saline or fluoxetine were observed. Each animal was anaesthetised with urethane (1.2 g/kg, i.p.) and a burr hole was drilled in the calvarium above the parietal cortex. The cannula guide tubes, with trocars, were implanted into the lateral cerebral ventricle, using the stereotaxic atlas and coordinates of Paxinos and Watson (1982). At the time of injection, the cannula insert was connected to a 10 ul Ramilton microsyringe by PE 10 tubing. The position of the cannula was considered to be correct if 5 u1 of saline or of the solutions of drugs, flowed in by gravity over 20 s. The rectal temperature was maintained at 37floC throughout the experiment by means of an infrared light. The right femoral artery was catheterized. The femoral arterial pressure was monitored with a Statham P23AC transducer and the heart rate with a Grass 7C tachometer, triggered by arterial pulses. All recordings were made on a four-channel Grass 7C Polygraph. 799
Preliminary Notes
800
RESULTS Table 1 summarises the cardiovascular responses to intraventricularadministration of fluoxetine in rats treated with either saline or ketanserin. In saline-treated rats, the intraventricularadministration of 0.9% saline or 1OOng of fluoxetine, caused an insignificant change in mean arterial pressure or in heart rate. However, an intraventricularinjection of 250 or 500 pg of fluoxetine caused an elevation of the peak arterial pressure of 46-52 madIgand a peak elevation of heart rate of of 97-105 beats/min. It is evident from the table that over a dose range of 250-500 ug of fluoxetine, a dose-response relationship was not obtained. A typical example is shown in Figure 1. In the present study, an intraventricular dose of 250 ug of fluoxetine was chosen for the later experiments. Table 1 also demonstrates that both the hypertension and the tachycardia induced by fluoxetine (250-500 ng) were significantly reduced reduced by pretreatment with an intraventricular injection of 6 pg of ketanserin. The control injection of ketanserin alone caused no change in mean arterial pressure but a significant reduction in the basal level of the heart rate. As this dose of ketanserin exerted a marked influence on the cardiovascular responses induced by fluoxetine, no other doses of ketanserin were tested in the present study. Table 2 summarises the cardiovascular responses to intraventricular injection of fluoxetine in sham-operated rats, in vagotomixed rats, in spinal rats and in adrenalectomized rats. It was found that the hypertension induced by fluoxetine was significantly inhibited by spinal transection, adrenalectomy or vagotomy. On the other hand, the tachycardia induced by fluoxetine was significantly inhibited only by vagotomy.
FU0XElYNE
3 ti
(30? pg/6 cc, i.c.v.)
200
100
4-4_-_ 0E
Figure 1. The changes in both arterial pressure and heart rate produced by an intraventricularinjection of fluoxetine in a rat under urethane anaesthesia.
801
Preliminary Notes
Table 1. Effects of pretreatment with ketanserin on the cardiovascular responses induced by intracerebroventricularadministration of fluoxetine in rats anaesthetizedwith urethane.
Mean arterial pressure (mmHg)
Treatments
Heart rate sbeats/min)
Control ~~~:etion Difference Control tf$f,i,
Difference
Saline-treated rats (n=8) 0.9% saline Fluoxetine 100 lx Fluoxetine 250 pg Fluoxetine 500 !Jg
96f6
95x7 98f6 97f5
98x6 99*5 144f9 149f8
Yf2
2f2 4_+2 46x8 52?7
410+20 406f19 412x21 408x18
412+19 409f18 509fl9 513x21
3f2 97x11 105f12
5x1 3x1 7+1* 6x1*
330x28 338+19 345x27 339*25
330x30 343*23 380x22 369x24
4x2 35x5* 30x6*
Ketanserin-treatedrats (n=8) 0.9% saline Fluoxetine 100 pg Fluoxetine 250 1Jg Fluoxetine 500 iJg
86kll 87f9 81x9 83x8
91x10 90+9 88x14 89+11
0
* Significantly different from corresponding control values (saline group), P
Table 2. Effects of bilateral vagotomy, adrenalectomy and spinal transection on the cardiovascular responses induced by intracerebroventricularadministration of fluoxetine in rats anaesthetized with urethane.
Mean Arterial pressure (mmIig)
Treatments
Sham-operated rats (n=8) 0.9% saline Fluoxetine 250 pg
Control $:~tion
Heart rate (beats/min)
Difference Control :$tetion Difference
98x7
98x8
0
425x24
425x22
0
98f7 97x6
98x8 142x8
0
45x9
425x24 425t22
425+22 518x21
93x13
128+5 127f6
126+6 148x5
-2x3 21*2*
480x19 481f21
489x20 511x17
9x4 30*13*
82x4 83x7
83f7 89fS
If1 6f3*
375x20 369x24
379x24 446x26
4x2 71+22
101x4 123x6
4+2 22x5*
376f14 388x15
378x13 498x17
2+2 110*24
0
Vagotomized rats (n=8) 0.9% saline Fluoxetine 250 ug Spinal transected rats (n=8) 0.9% saline Fluoxetine 250 ug Adrenalectomiaed rats (n=8) 0.9% saline Fluoxetine 250 pg
97f4
lOlf4
* Significantly different from corresponding control values (sham-operatedgroup, P
802
Preliminary Notes
DISCUSSION Intraventricular administration of 5-HT in rats anaesthetised with urethane has been found to produce a rise in blood pressure and a biphasic change in heart rate (Lambert et al. 1975). Furthermore, many investigators have demonstrated that the injection of 5-HT into the hypothalamus, or electrical stimulation of the dorsal raphe nuclei resulted in an increase in blood pressure ia rats (Smits and Struyber-Boudier, 1976; Robinson -.) et al 1985; Smits, van Essen and Struyker-Boudier, 1978; Kuhn, Wolf and Lovenberg, 1980). The pressor response to stimulation of the dorsal raphe or intrahypothalamic injection of 5-HT was reduced by pretreatment of the animals with selective lesions of 5-HT-containing neurones in the dorsal raphe nuclei or injection of a serotonergic receptor antagonist into the hypothalamus (Robinson -*I et al 1985; Kuhn et al., 1980). These observations suggest that 5-HT neurones in the dorsal raphe nucleus are involved in a pressor mechanism in the hypothalamus. The hypothesis is substantiated by the present results which show that intraventricular administration of a specific inhibitor of the reuptake of 5-FIT, such as fluoxetine, produced both pressor and tachycardia responses in rats. 'Inhibition of the reuptake of 5-HT would result in an increased level of 5-HT being available to serotonergic receptors (Carlsson et -. al J responses to 1969; Wong -. et al 1 1974). Indeed, in the present study the cardiovascular administration of fluoxetine were antagonised by pretreatment with an antagonist of serotonergic receptors. The present results also provide evidence that the hypertension induced by fluoxetine is due both to activation of sympatho-adrenal efferent pathways and to inactivation of vagal systems, whereas the tachycardia induced by fluoxetine is solely due to inactivation of the vagal system.
Acknowledgements.
The work was supported Republic of China.
by grants
from the National
Science
Council
of the
REFERENCES drugs Carlsson, A., Corrodi, II., Fuxe, K. and Hokfelt, T. (1969). Effect of antidepressant on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by I-methylalpha-ethyl-metatyramine. Euh.J.Phamacok, 5:357-364. Ito, A. and Schomberg, S.M. (1972). Central nervous system mechanisms responsible for blood pressure elevation induced by p-chlorophenylalanine. J.Phamacot.exp.TheA., 181:65-74. Kunh, D.M., Wolf, W.A. and Lovenberg, W. (1980). Pressor effects of electrical stimulation of the dorsal raphe and median raphe nuclei in anaesthetized rats. J.PhamacoL.exp.Theh., 214:403-409. LamGt, G., Friedman, E. and Gershon, S. (1975). Centrally mediated vascular responses to serotonin. Li& sci., 17:915-920. Paxinos, G. and Watson, C.71982). The Rat Brain: in Stereotaxic Coordinates. Academic Press, Sydney. Robinson, S.E., Austin, M.J.F. and Gibbens, D.M. (1985). The role of serotonergic neurons in dorsal raphe, median raphe and anterior hypothalamic pressor mechanisms. Neuzophcvcmaco~ogy, 3: 51-58. serotonin and cardioSmits, J.F. and Struyber-Boudier, H.A. (1976). Intrahypothalamic vascular control in rats. B&n R&A., 111:422-427. H.A.J. (1978). Serotonin-mediated Smits, J.F.M., van Essen, II. and Struykerxudier, cardiovascular responses to electrical stimulation of the raphe nuclei in the rat. L.i& sci., 23:173-178. Van Nueten, J.E, Janssen, P.A.J., Van Beek, J., Xhonneux, R., Verbeuren, T.J. and Vanhoutte, P.M. (1981). Vascular effects of ketanserin (R41468), a novel antagonist of 5-1i~2 serotonergic receptors. J.Phmacol.exp.TheJc.., 218:217-230. F. and Schalekamp, M.A.D.M. Wenting, G.J., Man in't Veld, A.J., Woittiez, A.J., Boom=, (1982). Treatment of hypertension with ketanserin a new selective 5-RT2 receptor antagonist. Ctin.Ren., %84:53’?-5%. Wong, D.T., Horng, J.S., Bymaster, F.P., Haiser, K.L. and Molloy, B.B. (1974). A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3phenylpropylamine. Li&e Sci., 15:471-479.
HYPERTENSION
AND TACHYCARDIA
PRODUCED
OOZE-3908/86 $3.00 + 0.00 Pergamon Journals Ltd
BY INHIBITION
FLUOXETINE
M.L.Tsai
Department
of Physiology, College,
(Accephi
OF 5-HYDROXYTRYPTAMINE
BY
IN THE RAT
and M.T. Lin
National
Tainan,
OF REUPTAKE
Cheng Kung University
Taiwan,
Republic
17 Apti
Medical
of China
1986)
Summary. In rats anaesthetieed with urethane, increasing the activity of 5-hydroxytryptamine receptors or the level of cuntional serotonin in the brain with the'inhibitors of the reuptake of serotonin, fluxetine, produced both hypertension and tachycardia. The hypertension induced by fluoxetine was significantly inhibited by pretreatment of the animals with ketanserin (a serotonin receptor antagonist), by bilateral vagotomy, spinal transection or bilateral adrenalectomy. On the other hand, the tachycardia induced by fluoxetine was significantly inhibited by pretreatment with ketanserin or bilateral vagotomy, but not by spinal transection or adrenalectomy. The data indicate that fluoxetine acts through serotonin receptors in the central nervous system by influencing autonomic outflow to induce both hypertension and tachycardia.
It has been demonstrated that the intracerebral injection of small amounts of 5-hydroxytryptamine (5-HT; serotonin) in the rat, produced an increase in blood pressure (Lambert, Friedman and Gershon, 1975; Smits and Struyher-Boudier, 1976; Robinson, Austin an and Gibbens, 1985). However, the systemic administration of p-chlorophenylalanine, agent which depletes 5-HT, produced an increase, rather than a decrease, in blood pressure that could be blocked by simultaneous or subsequent treatment with 5-hydroxytryptophan (the precursor of'5-HT) (Ito and Schomberg, 1972). Thus, there appears to be a conflict in the available data about the possible role played by 5-HT in the brain, in cardiovascular control. In order to deal with this question, the present study attempted to assess the effects of increasing the activity of 5-HT receptors or the level of functional 5-HT in the brain, by central administration of fluoxetine (an inhibitor of the reuptake of 5-HT) (Carlsson, Corrodi, Fuxe and Hokfelt, 1969; Wong, Korng, Bymaster, Hauser and Molloy, 1974) on cardiovascular function in intact control rats, in spinal, vagotomised and adrenalectomised rats, and in rats which had received an intracerebral injection of the selective antagonist of the S2 subtype of 5-HT receptor, ketanserin (Van Nueten, Janssen, Van Beek, Xhonneux, Verbeuren and Vanhoutte, 1981; Wenting, Veld, Woittiex, Boomsma and Schalekamp, 1982).
METHODS
Female Sprague-Dawley rats, weighing 180-28G g, were used. Six groups of animals were used: (1) saline-treated rats which received an intraventricular injection of 0.9% saline; (2) ketanserin-treated rats which received an intraventricular injection of ketanserin (6 ug in 5 ul); (3) rats with spinal transection at C7; (4) rats with bilateral vagotomy; (5) rats with bilateral adrenalectomy; and (6) rats which were sham-operated. The cardiovascular responses of these groups of animals to an intraventricular injection of 0.9% saline or fluoxetine were observed. Each animal was anaesthetised with urethane (1.2 g/kg, i.p.) and a burr hole was drilled in the calvarium above the parietal cortex. The cannula guide tubes, with trocars, were implanted into the lateral cerebral ventricle, using the stereotaxic atlas and coordinates of Paxinos and Watson (1982). At the time of injection, the cannula insert was connected to a 10 ul Ramilton microsyringe by PE 10 tubing. The position of the cannula was considered to be correct if 5 u1 of saline or of the solutions of drugs, flowed in by gravity over 20 s. The rectal temperature was maintained at 37floC throughout the experiment by means of an infrared light. The right femoral artery was catheterized. The femoral arterial pressure was monitored with a Statham P23AC transducer and the heart rate with a Grass 7C tachometer, triggered by arterial pulses. All recordings were made on a four-channel Grass 7C Polygraph. 799
Preliminary Notes
800
RESULTS Table 1 summarises the cardiovascular responses to intraventricularadministration of fluoxetine in rats treated with either saline or ketanserin. In saline-treated rats, the intraventricularadministration of 0.9% saline or 1OOng of fluoxetine, caused an insignificant change in mean arterial pressure or in heart rate. However, an intraventricularinjection of 250 or 500 pg of fluoxetine caused an elevation of the peak arterial pressure of 46-52 madIgand a peak elevation of heart rate of of 97-105 beats/min. It is evident from the table that over a dose range of 250-500 ug of fluoxetine, a dose-response relationship was not obtained. A typical example is shown in Figure 1. In the present study, an intraventricular dose of 250 ug of fluoxetine was chosen for the later experiments. Table 1 also demonstrates that both the hypertension and the tachycardia induced by fluoxetine (250-500 ng) were significantly reduced reduced by pretreatment with an intraventricular injection of 6 pg of ketanserin. The control injection of ketanserin alone caused no change in mean arterial pressure but a significant reduction in the basal level of the heart rate. As this dose of ketanserin exerted a marked influence on the cardiovascular responses induced by fluoxetine, no other doses of ketanserin were tested in the present study. Table 2 summarises the cardiovascular responses to intraventricular injection of fluoxetine in sham-operated rats, in vagotomixed rats, in spinal rats and in adrenalectomized rats. It was found that the hypertension induced by fluoxetine was significantly inhibited by spinal transection, adrenalectomy or vagotomy. On the other hand, the tachycardia induced by fluoxetine was significantly inhibited only by vagotomy.
FU0XElYNE
3 ti
(30? pg/6 cc, i.c.v.)
200
100
4-4_-_ 0E
Figure 1. The changes in both arterial pressure and heart rate produced by an intraventricularinjection of fluoxetine in a rat under urethane anaesthesia.
801
Preliminary Notes
Table 1. Effects of pretreatment with ketanserin on the cardiovascular responses induced by intracerebroventricularadministration of fluoxetine in rats anaesthetizedwith urethane.
Mean arterial pressure (mmHg)
Treatments
Heart rate sbeats/min)
Control ~~~:etion Difference Control tf$f,i,
Difference
Saline-treated rats (n=8) 0.9% saline Fluoxetine 100 lx Fluoxetine 250 pg Fluoxetine 500 !Jg
96f6
95x7 98f6 97f5
98x6 99*5 144f9 149f8
Yf2
2f2 4_+2 46x8 52?7
410+20 406f19 412x21 408x18
412+19 409f18 509fl9 513x21
3f2 97x11 105f12
5x1 3x1 7+1* 6x1*
330x28 338+19 345x27 339*25
330x30 343*23 380x22 369x24
4x2 35x5* 30x6*
Ketanserin-treatedrats (n=8) 0.9% saline Fluoxetine 100 pg Fluoxetine 250 1Jg Fluoxetine 500 iJg
86kll 87f9 81x9 83x8
91x10 90+9 88x14 89+11
0
* Significantly different from corresponding control values (saline group), P
Table 2. Effects of bilateral vagotomy, adrenalectomy and spinal transection on the cardiovascular responses induced by intracerebroventricularadministration of fluoxetine in rats anaesthetized with urethane.
Mean Arterial pressure (mmIig)
Treatments
Sham-operated rats (n=8) 0.9% saline Fluoxetine 250 pg
Control $:~tion
Heart rate (beats/min)
Difference Control :$tetion Difference
98x7
98x8
0
425x24
425x22
0
98f7 97x6
98x8 142x8
0
45x9
425x24 425t22
425+22 518x21
93x13
128+5 127f6
126+6 148x5
-2x3 21*2*
480x19 481f21
489x20 511x17
9x4 30*13*
82x4 83x7
83f7 89fS
If1 6f3*
375x20 369x24
379x24 446x26
4x2 71+22
101x4 123x6
4+2 22x5*
376f14 388x15
378x13 498x17
2+2 110*24
0
Vagotomized rats (n=8) 0.9% saline Fluoxetine 250 ug Spinal transected rats (n=8) 0.9% saline Fluoxetine 250 ug Adrenalectomiaed rats (n=8) 0.9% saline Fluoxetine 250 pg
97f4
lOlf4
* Significantly different from corresponding control values (sham-operatedgroup, P
802
Preliminary Notes
DISCUSSION Intraventricular administration of 5-HT in rats anaesthetised with urethane has been found to produce a rise in blood pressure and a biphasic change in heart rate (Lambert et al. 1975). Furthermore, many investigators have demonstrated that the injection of 5-HT into the hypothalamus, or electrical stimulation of the dorsal raphe nuclei resulted in an increase in blood pressure ia rats (Smits and Struyber-Boudier, 1976; Robinson -.) et al 1985; Smits, van Essen and Struyker-Boudier, 1978; Kuhn, Wolf and Lovenberg, 1980). The pressor response to stimulation of the dorsal raphe or intrahypothalamic injection of 5-HT was reduced by pretreatment of the animals with selective lesions of 5-HT-containing neurones in the dorsal raphe nuclei or injection of a serotonergic receptor antagonist into the hypothalamus (Robinson -*I et al 1985; Kuhn et al., 1980). These observations suggest that 5-HT neurones in the dorsal raphe nucleus are involved in a pressor mechanism in the hypothalamus. The hypothesis is substantiated by the present results which show that intraventricular administration of a specific inhibitor of the reuptake of 5-FIT, such as fluoxetine, produced both pressor and tachycardia responses in rats. 'Inhibition of the reuptake of 5-HT would result in an increased level of 5-HT being available to serotonergic receptors (Carlsson et -. al J responses to 1969; Wong -. et al 1 1974). Indeed, in the present study the cardiovascular administration of fluoxetine were antagonised by pretreatment with an antagonist of serotonergic receptors. The present results also provide evidence that the hypertension induced by fluoxetine is due both to activation of sympatho-adrenal efferent pathways and to inactivation of vagal systems, whereas the tachycardia induced by fluoxetine is solely due to inactivation of the vagal system.
Acknowledgements.
The work was supported Republic of China.
by grants
from the National
Science
Council
of the
REFERENCES drugs Carlsson, A., Corrodi, II., Fuxe, K. and Hokfelt, T. (1969). Effect of antidepressant on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by I-methylalpha-ethyl-metatyramine. Euh.J.Phamacok, 5:357-364. Ito, A. and Schomberg, S.M. (1972). Central nervous system mechanisms responsible for blood pressure elevation induced by p-chlorophenylalanine. J.Phamacot.exp.TheA., 181:65-74. Kunh, D.M., Wolf, W.A. and Lovenberg, W. (1980). Pressor effects of electrical stimulation of the dorsal raphe and median raphe nuclei in anaesthetized rats. J.PhamacoL.exp.Theh., 214:403-409. LamGt, G., Friedman, E. and Gershon, S. (1975). Centrally mediated vascular responses to serotonin. Li& sci., 17:915-920. Paxinos, G. and Watson, C.71982). The Rat Brain: in Stereotaxic Coordinates. Academic Press, Sydney. Robinson, S.E., Austin, M.J.F. and Gibbens, D.M. (1985). The role of serotonergic neurons in dorsal raphe, median raphe and anterior hypothalamic pressor mechanisms. Neuzophcvcmaco~ogy, 3: 51-58. serotonin and cardioSmits, J.F. and Struyber-Boudier, H.A. (1976). Intrahypothalamic vascular control in rats. B&n R&A., 111:422-427. H.A.J. (1978). Serotonin-mediated Smits, J.F.M., van Essen, II. and Struykerxudier, cardiovascular responses to electrical stimulation of the raphe nuclei in the rat. L.i& sci., 23:173-178. Van Nueten, J.E, Janssen, P.A.J., Van Beek, J., Xhonneux, R., Verbeuren, T.J. and Vanhoutte, P.M. (1981). Vascular effects of ketanserin (R41468), a novel antagonist of 5-1i~2 serotonergic receptors. J.Phmacol.exp.TheJc.., 218:217-230. F. and Schalekamp, M.A.D.M. Wenting, G.J., Man in't Veld, A.J., Woittiez, A.J., Boom=, (1982). Treatment of hypertension with ketanserin a new selective 5-RT2 receptor antagonist. Ctin.Ren., %84:53’?-5%. Wong, D.T., Horng, J.S., Bymaster, F.P., Haiser, K.L. and Molloy, B.B. (1974). A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3phenylpropylamine. Li&e Sci., 15:471-479.