Endocrinol.
Jaon.
1975,
22(4),
357∼360
NOTE Suppressive
Effect Growth YOSHIKATSU
of Cyproheptadine Hormone Release NAKAI
AND
on L-DOPA-induced in Man
HIROO
IMURA
Second Division, Department of Medicine, Kyoto University School of Medicine, Kyoto 606 and Third Division, Department of Medicine, Kobe University School of Medicine, Kobe 650
Synopsis In order to elucidate the relationship between dopaminergic and serotoninergic mechanisms in regulating secretion of human growth hormone (hGH), the effect of cyproheptadine, an antiserotoninergic agent, on 1-DOPA-induced hGH secretion was studied in normal subjects. Oral administration of 500 mg of 1-DOPA caused a rise in plasma hGH in 6 of 7 subjects studied. This rise in plasma hGH was significantly blunted by the intravenous infusion of 5 mg of cyproheptadine. These results suggest the close relationship between dopamine and serotonin in the control of hGH secretion.
Accumulating evidence in recent years suggests that adrenergic, dopaminergic and serotoninergic mechanisms are involved in regulating secretion of human growth hormone (hGH) (Imura et al., 1968, 1971, 1973a, 1973b; Blackard and Heidingsfelder, 1968; Boyd et al., 1970; Bivens et al., 1973; Nakai et al., 1974a). However, exact interrelationships between these monoaminergic mechanisms remain unclear. It has been reported that the plasma hGH response to 1-DOPA, a precursor of dopamine, is enhanced by propranolol, a beta adrenergic blocking agent (Imura et al., 1973a) and inhibited by phentolamine, an alpha adrenergic blocking agent (Kansal et al., 1972). We also observed that propranolol enhances plasma hGH response to 5-hydroxytryptophan (5-HTP), a precursor of serotonin, while phentolamine inhibits it (Nakai and Imura, 1974b). These results suggest a close relationship between an adrenergic mechanism and a dopaminergic or a seroReceived
for publication
May
8, 1975.
toninergic mechanism. An antiserotoninergic agent, cyproheptadine, is known to inhibit plasma hGH response to 5-HTP, arginine (Nakai et al., 1974) and insulin-induced hypoglycemia (Bivens et al., 1973). The present study was designed to elucidate the effect of cyproheptadine on plasma hGH response to 1-DOPA.
Materials
and
Methods
Seven male volunteers, aged 19 to 25, were used in the present experiments. They were non-obese (less than 15% over the ideal body weight) and apparently normal in endocrine and metabolic function. After overnight fasting and absolute bed rest for at least 30 min, the following experiments were performed, starting at 9: 00 A.M. Five hundred mg of 1-DOPA was administered orally to 7 normal subjects. One week later, 500 mg of 1-DOPA was again administered orally and 5 mg of cyproheptadine, an antiserotoninergic agent, dissolved in 500 ml of saline was injected intravenously during the next 3 hr. As a control experiment, 500 ml of saline was infused intravenously over a period of 3 hr in 8 normal subjects.
358
NAKAI
AND
Blood samples were obtained through an indwelling needle into heparinized syringes at intervals of 30 min for 3 hr. An aliquot of each blood sample was saved for the determination of blood glucose. The remaining portion was quickly centrifuged at low temperature. Plasma was separated, frozen and stored for the measurement of plasma hGH. Blood glucose was measured by a ferricyanide reduction method with a Technicon AutoAnalyzer. Plasma hGH was measured by the double antibody radioimmunoassay of Schalch and Parker (1964). Peak plasma hGH values in each experiment were compared using Student's t test.
Results When as
a
saline
hGH
in
levels
the DOPA of
more
than
in
6
7
of
a
with
sea
the
in
9.7
drug.
No
other
peak
(mean+ in
the
SEM)
the
control
7
subjects
1 of of
after
levels
mean
ng/ml
1-
values
hGH
ng/ml
Only
min
(peak
The
complained 60
On of
plasma
tested.
2.2+1.1
1-DOPA
5 ng/ml.
rise
(P hGH
administration
experiment
in
cyproheptadine
peak
oral
(Table the
difference
administration
However,
following
significant
levels
of
1-DOPA
lower
during
than
given
in
1-DOPA
the alone
(P
Endocrinol. Japon. August 1975
IMURA
Discussion
The present study confirms previous observations (Boyd et al., 1970; Kansal et al., 1972) that oral administration of 1-DOPA causes a rise in plasma hGH in most subjects. The mechanism by which 1-DOPA stimulates hGH secretion remains unresolved. Recent studies carried out in animals have shown that the administration of a large amount of 1-DOPA produces not only a marked rise in dopamine content in various parts of the central nervous system, but also a slight increase in norepinephrine content, especially in the hypothalamus (Hornykiewicz, 1970; Chalmers et al., 1971). However,. this increase in norepinephrine content seems not to be responsible for the 1-DOPA-induced hGH release because fusaric acid, an inhibitor of dopamine beta hydroxylase, did not alter the stimulatory effect of 1-DOPA on canine GH (Takahashi et al., 1973). It appears, therefore, that dopamine may itself stimulate hGH secretion. Present studies further demonstrate that plasma hGH response to 1-DOPA was significantly suppressed by the concomitant administration of cyproheptadine, a wellknown antiserotoninergic agent. This suggests that cyproheptadine may block the 1DOPA-induced hGH rise through blockade of serotoninergic receptors. Moreover, it has been demonstrated recently that, besides refilling central catecholamine stores, a portion of exogenously administered 1-DOPA may enter central 5-HT terminals, undergo decarboxylation to dopamine and then displace the endogenous indoleamine from vesicular stores (Butcher et al., 1970, Ng et al., 1970). These results suggest the possibility that the stimulatory effect of 1DOPA on hGH secretion might be due to the final activation of serotoninergic receptors by acute release of serotonin.
Vol.22,
No.4 Table
CYPROHEPTADINE 1.
Effect
of cyproheptadine
0* indicates the time of oral administration iv from 0 to 180min.
on
AND plasma
GH
growth
359
RELEASE hormone
of 500mg of 1-DOPA.
response
Cyproheptadine
to 1-DOPA.
(5mg) was infused
360
NAKAI
AND
Alternately, it is also possible that 1DOPA and cyproheptadine act at different sites. That is, 1-DOPA stimulates hGH secretion at the hypothalamus or even higher centers, whereas cyproheptadine inhibits it at the final common pathway, because cyproheptadine inhibits the plasma hGH response to various stimuli, such as arginine, 5HTP (Nakai et al., 1974), insulin-induced hypoglycemia (Bivens et al., 1973) and sleep (unpublished observation) besides 1-DOPA. The exact relationship among adrenergic, dopaminergic and serotoninergic mechanisms involving hGH secretion needs further clarification.
References
Bivens, C. H., H. E. Lebovitz and J. M. Feldman (1973). New Engl. J. Med. 289, 236. Blackard, W. G., and S. A. Heidingsfelder (1968). J. Clin. Invest. 47, 1407. Boyd, A. E., III, H. E. Lebovitz and J. B. Pfeiffer (1970). New Engl. J. Med. 283, 1425. Butcher, L., J. Engel and K. Fuxe (1970). J. Pharm. Pharmacol. 22, 313. Chalmers, J. P., R. J. Baldessarini and R. J. Wurtman (1971). Proc. Nat. Acad. Sci. 68, 662.
Endocrinol. Japon. August 1975
IMURA
Fuxe,
K., and T. Hokfelt.
Frontiers
in Neu-
roendocrinology, (edited by Ganong and Martini). Oxford University Press, London. p. 47, (1969). Hornykiewicz, O. D. (1970). Neurology 20, Suppl. 1. Imura, H., Y. Kato, M. Ikeda, M. Morimoto, M. Yawata and M. Fukase (1968). J. Clin. Endocrinol. Metab. 28, 1079. Imura, H., Y. Kato, M. Ikeda, M. Morimoto and M. Yawata (1971). J. Clin. Invest. 50, 1069. Imura, H., Y. Nakai, S. Matsukura and H. Matsuyama (1973a). Horm. Metab. Res. 5, 41. Imura, H., Y. Nakai and T. Yoshimi (1973b). J. Clin. Endocrinol. Metab. 36, 204. Kansal, P. C., J. Buse, O. R. Talbert and M. G. Buse (1972). I bid. 34, 99. Nakai, Y., H. Imura, H. Sakurai, H. Kurahachi and T. Yoshimi (1974a). I bid. 38, 460. Nakai, Y. and H. Imura (1974b). Endocrinol. Japon. 21, 493. Ng, K. Y, T. N. Chase, R. W. Colburn and I. J. Kopin (1970). Science 170, 76. Schalch, D. S. and M. L. Parker (1964). Nature (London) 203, 1141. Takahashi, K., T. Tsushima and M. Irie (1973). Endocrinol. Japon. 20, 323.
Jaon.
1975,
22(4),
357∼360
NOTE Suppressive
Effect Growth YOSHIKATSU
of Cyproheptadine Hormone Release NAKAI
AND
on L-DOPA-induced in Man
HIROO
IMURA
Second Division, Department of Medicine, Kyoto University School of Medicine, Kyoto 606 and Third Division, Department of Medicine, Kobe University School of Medicine, Kobe 650
Synopsis In order to elucidate the relationship between dopaminergic and serotoninergic mechanisms in regulating secretion of human growth hormone (hGH), the effect of cyproheptadine, an antiserotoninergic agent, on 1-DOPA-induced hGH secretion was studied in normal subjects. Oral administration of 500 mg of 1-DOPA caused a rise in plasma hGH in 6 of 7 subjects studied. This rise in plasma hGH was significantly blunted by the intravenous infusion of 5 mg of cyproheptadine. These results suggest the close relationship between dopamine and serotonin in the control of hGH secretion.
Accumulating evidence in recent years suggests that adrenergic, dopaminergic and serotoninergic mechanisms are involved in regulating secretion of human growth hormone (hGH) (Imura et al., 1968, 1971, 1973a, 1973b; Blackard and Heidingsfelder, 1968; Boyd et al., 1970; Bivens et al., 1973; Nakai et al., 1974a). However, exact interrelationships between these monoaminergic mechanisms remain unclear. It has been reported that the plasma hGH response to 1-DOPA, a precursor of dopamine, is enhanced by propranolol, a beta adrenergic blocking agent (Imura et al., 1973a) and inhibited by phentolamine, an alpha adrenergic blocking agent (Kansal et al., 1972). We also observed that propranolol enhances plasma hGH response to 5-hydroxytryptophan (5-HTP), a precursor of serotonin, while phentolamine inhibits it (Nakai and Imura, 1974b). These results suggest a close relationship between an adrenergic mechanism and a dopaminergic or a seroReceived
for publication
May
8, 1975.
toninergic mechanism. An antiserotoninergic agent, cyproheptadine, is known to inhibit plasma hGH response to 5-HTP, arginine (Nakai et al., 1974) and insulin-induced hypoglycemia (Bivens et al., 1973). The present study was designed to elucidate the effect of cyproheptadine on plasma hGH response to 1-DOPA.
Materials
and
Methods
Seven male volunteers, aged 19 to 25, were used in the present experiments. They were non-obese (less than 15% over the ideal body weight) and apparently normal in endocrine and metabolic function. After overnight fasting and absolute bed rest for at least 30 min, the following experiments were performed, starting at 9: 00 A.M. Five hundred mg of 1-DOPA was administered orally to 7 normal subjects. One week later, 500 mg of 1-DOPA was again administered orally and 5 mg of cyproheptadine, an antiserotoninergic agent, dissolved in 500 ml of saline was injected intravenously during the next 3 hr. As a control experiment, 500 ml of saline was infused intravenously over a period of 3 hr in 8 normal subjects.
358
NAKAI
AND
Blood samples were obtained through an indwelling needle into heparinized syringes at intervals of 30 min for 3 hr. An aliquot of each blood sample was saved for the determination of blood glucose. The remaining portion was quickly centrifuged at low temperature. Plasma was separated, frozen and stored for the measurement of plasma hGH. Blood glucose was measured by a ferricyanide reduction method with a Technicon AutoAnalyzer. Plasma hGH was measured by the double antibody radioimmunoassay of Schalch and Parker (1964). Peak plasma hGH values in each experiment were compared using Student's t test.
Results When as
a
saline
hGH
in
levels
the DOPA of
more
than
in
6
7
of
a
with
sea
the
in
9.7
drug.
No
other
peak
(mean+ in
the
SEM)
the
control
7
subjects
1 of of
after
levels
mean
ng/ml
1-
values
hGH
ng/ml
Only
min
(peak
The
complained 60
On of
plasma
tested.
2.2+1.1
1-DOPA
5 ng/ml.
rise
(P hGH
administration
experiment
in
cyproheptadine
peak
oral
(Table the
difference
administration
However,
following
significant
levels
of
1-DOPA
lower
during
than
given
in
1-DOPA
the alone
(P
Endocrinol. Japon. August 1975
IMURA
Discussion
The present study confirms previous observations (Boyd et al., 1970; Kansal et al., 1972) that oral administration of 1-DOPA causes a rise in plasma hGH in most subjects. The mechanism by which 1-DOPA stimulates hGH secretion remains unresolved. Recent studies carried out in animals have shown that the administration of a large amount of 1-DOPA produces not only a marked rise in dopamine content in various parts of the central nervous system, but also a slight increase in norepinephrine content, especially in the hypothalamus (Hornykiewicz, 1970; Chalmers et al., 1971). However,. this increase in norepinephrine content seems not to be responsible for the 1-DOPA-induced hGH release because fusaric acid, an inhibitor of dopamine beta hydroxylase, did not alter the stimulatory effect of 1-DOPA on canine GH (Takahashi et al., 1973). It appears, therefore, that dopamine may itself stimulate hGH secretion. Present studies further demonstrate that plasma hGH response to 1-DOPA was significantly suppressed by the concomitant administration of cyproheptadine, a wellknown antiserotoninergic agent. This suggests that cyproheptadine may block the 1DOPA-induced hGH rise through blockade of serotoninergic receptors. Moreover, it has been demonstrated recently that, besides refilling central catecholamine stores, a portion of exogenously administered 1-DOPA may enter central 5-HT terminals, undergo decarboxylation to dopamine and then displace the endogenous indoleamine from vesicular stores (Butcher et al., 1970, Ng et al., 1970). These results suggest the possibility that the stimulatory effect of 1DOPA on hGH secretion might be due to the final activation of serotoninergic receptors by acute release of serotonin.
Vol.22,
No.4 Table
CYPROHEPTADINE 1.
Effect
of cyproheptadine
0* indicates the time of oral administration iv from 0 to 180min.
on
AND plasma
GH
growth
359
RELEASE hormone
of 500mg of 1-DOPA.
response
Cyproheptadine
to 1-DOPA.
(5mg) was infused
360
NAKAI
AND
Alternately, it is also possible that 1DOPA and cyproheptadine act at different sites. That is, 1-DOPA stimulates hGH secretion at the hypothalamus or even higher centers, whereas cyproheptadine inhibits it at the final common pathway, because cyproheptadine inhibits the plasma hGH response to various stimuli, such as arginine, 5HTP (Nakai et al., 1974), insulin-induced hypoglycemia (Bivens et al., 1973) and sleep (unpublished observation) besides 1-DOPA. The exact relationship among adrenergic, dopaminergic and serotoninergic mechanisms involving hGH secretion needs further clarification.
References
Bivens, C. H., H. E. Lebovitz and J. M. Feldman (1973). New Engl. J. Med. 289, 236. Blackard, W. G., and S. A. Heidingsfelder (1968). J. Clin. Invest. 47, 1407. Boyd, A. E., III, H. E. Lebovitz and J. B. Pfeiffer (1970). New Engl. J. Med. 283, 1425. Butcher, L., J. Engel and K. Fuxe (1970). J. Pharm. Pharmacol. 22, 313. Chalmers, J. P., R. J. Baldessarini and R. J. Wurtman (1971). Proc. Nat. Acad. Sci. 68, 662.
Endocrinol. Japon. August 1975
IMURA
Fuxe,
K., and T. Hokfelt.
Frontiers
in Neu-
roendocrinology, (edited by Ganong and Martini). Oxford University Press, London. p. 47, (1969). Hornykiewicz, O. D. (1970). Neurology 20, Suppl. 1. Imura, H., Y. Kato, M. Ikeda, M. Morimoto, M. Yawata and M. Fukase (1968). J. Clin. Endocrinol. Metab. 28, 1079. Imura, H., Y. Kato, M. Ikeda, M. Morimoto and M. Yawata (1971). J. Clin. Invest. 50, 1069. Imura, H., Y. Nakai, S. Matsukura and H. Matsuyama (1973a). Horm. Metab. Res. 5, 41. Imura, H., Y. Nakai and T. Yoshimi (1973b). J. Clin. Endocrinol. Metab. 36, 204. Kansal, P. C., J. Buse, O. R. Talbert and M. G. Buse (1972). I bid. 34, 99. Nakai, Y., H. Imura, H. Sakurai, H. Kurahachi and T. Yoshimi (1974a). I bid. 38, 460. Nakai, Y. and H. Imura (1974b). Endocrinol. Japon. 21, 493. Ng, K. Y, T. N. Chase, R. W. Colburn and I. J. Kopin (1970). Science 170, 76. Schalch, D. S. and M. L. Parker (1964). Nature (London) 203, 1141. Takahashi, K., T. Tsushima and M. Irie (1973). Endocrinol. Japon. 20, 323.
