0013-7227/92/1302-0914$03.00/0 Endocrinology Copyright 0 1992 by The Endocrine
Vol. Printed
Society
Indirect Evidence to Suggest Adrenal Action of Haloperidol and Corticosterone Secretion STEPHAN GOEBEL, MARGARETHE WOLFGANG WUTTKE Division of Experimental of Gtittingen, Germany
and Clinical
DIETRICH,
Endocrinology,
Department
that Prolactin to Stimulate in Rats HUBERTUS of
JARRY,
130, No. 2 in U.S.A.
Mediates the Aldosterone
AND
Obstetrics and Gynecology,
University
PRL secretion and stimulated aldosterone and corticosterone production significantly. In contrast, intraadrenal dialysis of HAL had no effect on the secretory pattern of PRL or either steroid hormone, indicating no direct drug action on cells of the rat adrenal cortex. Similarly, ip injection of 2.5 mg HAL in hypophysectomized rats did not alter PRL or steroid hormone levels. We conclude that the dopamine-antagonist HAL stimulates aldosterone and corticosterone secretion in rats through a pituitary factor, probably PRL, but not through direct effects at the adrenal cortex. (Endocrinology 130: 914-919,1992)
ABSTRACT. The effect of dopamine-antagonists on steroid secretion has revealed conflicting results regarding the contirmation of in uiuo findings in uitro. In order to discriminate in uiuo systemic and local action of the dopamine-antagonist haloperidol (HAL) on aldosterone and corticosterone secretion, microdialysis of the adrenal cortex in conscious, freely moving rats was employed. The effects of 2.5 mg HAL ip or intraadrenal dialysis of 20 pg/ml HAL in rats with an intact pituitary gland on PRL, aldosterone, and corticosterone secretion were examined. Systemic HAL application resulted in a IO-fold increase in
M
(MCP), a dopamine antagETOCLOPRAMIDE onist, administered acutely as an iv-bolus causes a rapid increase in plasma aldosterone in humans (1, 2), rhesus monkeys (3), and sheep (4,5). The mechanism of action is thought to be due to counteraction of the inhibitory control of aldosterone secretion by dopamine (2). Most authors localized the site of action of MCP to the zona glomerulosa cell, although this hypothesis was not definitely confirmed by in vitro experiments (for a review see 6,7). In those studies in which plasma cortisol was examined, plasma levels were unaffected by dopamine antagonists (l-5). In rats however, the effect of dopamine antagonists on corticosteroid secretion remains controversial. In some studies acute systemic injection (8-10) or chronic infusion (11) of dopamine antagonists elevated plasma aldosterone, whereas others (12, 13) were not able to confirm this finding. The possibility of direct action of dopamine on the adrenal cortex was validated by the demonstration of dopamine receptors in zona glomerulosa cells of the rat adrenal (14, 15). There remains considerable controversy regarding the physiological sig-
nificance of their presence, because in vitro studies were unable to demonstrate direct stimulation of steroid secretion through dopaminergic antagonists (10,12,13,16) or inhibition of steroidogenesis by dopaminergic agonists (11) in rat adrenal glomerulosa cell preparations. One report revealed inhibition of aldosterone secretion by MCP in zona glomerulosa cells (17). In order to study systemic as well as local effects of the dopamine antagonist haloperidol (HAL) on steroid secretion in rats, we employed a microdialysis system implanted into the adrenal cortex of conscious, freely moving rats (18). Determination of aldosterone and corticosterone in the dialysis medium gives an estimate of the local steroid secretion before and after systemic injection of HAL. On the other hand addition of HAL to the dialysis medium enabled us to examine the direct drug effect on cells of the adrenal cortex, since the drug does not enter general circulation such that systemic effects are prevented. Therefore it was possible to discriminate between a systemic and a local effect of HAL on steroidogenesis. To further determine the mechanism of action of HAL, serum PRL was measured in addition to serum aldosterone and corticosterone. One group of animals underwent hypophysectomy before experimentation to eradicate pituitary factors as possible mediators of HAL action.
Received September 6,1991. Address correspondence and requests for reprints to: Professor Dr. W. Wuttke, Universitats-Frauenklinik, Robert-Koch-Strasse 40, D3400 Gottingen, Germany. 914
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ADRENOCORTICAL
Materials
and Methods
Male Sprague-Dawley rats (mean weight, 300 g) were used in all experiments. They were housed under standardized conditions (lights on, 0700-1900 h; 24 C; food and water ud lib&urn). One group of animals was hypophysectomized by a pharyngeal approach 48 h before experimentation. The dialysis system was prepared by inserting dialysis tubing (Diafilter 20 Amicon mol wt off 20,000, Witten, Germany) into the end of two silastic tubings (602-105, Dow Corning, Midland, MI), such that the free dialysis surface was approximately 2 mm (19). Under ether anesthesia, the left adrenal gland was exposed through a ventrolateral incision. A 25-gauge hypodermic needle, connected to the end of one silastic tubing, was used to penetrate the adrenal cortex tangentially. The tubing system was pulled through the adrenal gland and the free dialysis tubing located inside the adrenal cortex. The ends of the silastic tubings were SC exteriorized through an incision at the neck, the adrenal gland relocated, and the muscle and skin incision closed. Under the same anesthesia, a jugular vein catheter was also implanted. The animals were allowed to recover from surgery for 24 h before undergoing experimentation. At the beginning of the dialysis experiment one end of the tubing system was connected to a peristaltic pump. Dialysate fractions were collected from the other end at 15-min intervals after an initial washout period of 3 h. The system was perfused with Ringer solution at a flow rate of 20 rl/min. At the end of each fraction period, a blood sample was collected via the indwelling jugular vein catheter. With such prepared animals three experiments were carried out: 1. The adrenal glands of intact rats (n = 32) were dialyzed with Ringer solution 90 min before and 90 min after an ip injection of 0.5 ml Haldol(=2.5 mg HAL, Janssen, Hamburg, Germany). 2. HAL was dissolved in Ringer solution at a concentration of 20 pg/ml. Since the transfer efficiency of the dialysis membrane is about 1% this resulted in an intraadrenal concentration of approximately 200 rig/ml (20). After an initial dialysis period of 90 min with Ringer solution, the drug was locally administered to the adrenal gland by dialysis with the HAL solution for another 90 min (n = 10). 3. Exp 1 was repeated in hypophysectomized rats (n = 21). After the experiment rats were decapitated and the adrenal gland implanted with the microdialysis system was removed. The placement of the dialysis system within the cortex was verified by slicing the adrenal glands on a cryostat. In hypophysectomized rats the skull was opened, the brain removed, and the sella turcica inspected. Serum and dialysate fractions were stored at -20 C until assayed. All measurements for each hormone were performed in duplicates in the same assay. The concentrations of aldosterone and corticosterone in dialysate and of ACTH in serum were determined by commercially available RIAs (DPC, Bad Nauheim, Germany). PRL levels in the serum were quantified by RIA supplied by the NIDDK. Baseline secretion rates of steroid hormones in the dialysates showed interindividual differences. Therefore, all data were expressed as percentages. In each animal concentrations of hormones in all pretreatment fraction periods were averaged
ACTION
OF PRL
915
and the mean set as 100%; all other individual data were then calculated in relation to this 100% value. Differences between means of the last pretreatment and all posttreatment values were tested for statistical significance by analysis of variance followed by Duncan’s multiple range test.
Results The effect of an ip injection of 2.5 mg HAL on serum PRL, ACTH, aldosterone, and corticosterone concentrations is shown in Fig. 1. HAL injection caused a 40-fold increase of serum PRL within 15 min and remained significantly elevated throughout the remaining experiment. Measurement of ACTH revealed no change in the secretion pattern after administration of HAL. Serum aldosterone and corticosterone levels approximately doubled after HAL injection. The results of hormone analysis of the corresponding dialysate fractions are pictured in Fig. 2. The ip injection of 2.5 mg HAL caused an increase of aldosterone release reaching a significant level in the second dialysate fraction (i.e. between 15-30 min) after injection. The enhanced aldosterone secretion was paralleled by a rise in corticosterone levels in the dialysate samples. The results of intraadrenal dialysis with HAL (20 pg/ ml) on serum PRL, and steroid concentrations in serum and dialysate samples are summarized in Table 1 and Fig. 3. In rats with intact pituitary glands intraadrenal HAL dialysis had no significant effect on PRL secretion. Aldosterone and corticosterone secretion were similarly unaffected by the change of dialysis media. Neither serum nor dialysate steroid hormone levels were altered after replacement of Ringer solution by HAL containing Ringer solution. Higher doses of HAL up to 500 pg/ml were also without any effect on either hormone (data not shown). The effect of 2.5 mg HAL injected ip in hypophysectomized rats on serum PRL is shown in Table 2. Although low PRL levels were detectable (100% = 1.5 ng/ ml) there is no response of PRL secretion to HAL injection. Absolute steroid hormone levels also were significantly
lower
in hypophysectomized
rats than in ani-
mals with a pituitary gland. Aldosterone levels after drug administration did not vary significantly from basal levels before injection. Corticosterone secretion also remained unaffected by HAL application. Hormone levels in the corresponding dialysate fractions in hypophysectomized rats are depicted in Fig. 4. No significant change of aldosterone or corticosterone secretion occurred after drug treatment. Discussion The role of dopamine antagonists in the control of corticosteroid secretion in rats has not been clearly out-
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ADRENOCORTICAL
916
1. Serum levels of PRL and ACTH (k/t pands) and of aldosterone and corticosterone (right panels) before and after an ip injection of 0.5 ml Haldol (=2.5 mg HAL) in rats with an intact pituitary gland. Adrenal glands were constantly perfused with Ringer’s solution. All values are depicted as percentage values, the 100% value is given in the diagram. Blood was collected at 15min intervals. After HAL injection levels of PRL, aldosterone and corticosterone increased significantly whereas ACTH levels remained unchanged. Arrows indicate the drug injection; vertical lines indicate SEM; *, P < 0.05 us. the last pretreatment value.
OF PRL
B - “‘; 7000
FIG.
ACTION
1
1
100 x = 44.5 “p/ml
1992 No 2
.
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lined. In the majority of experiments MCP was used as dopamine-antagonistic drug and has resulted in conflicting reports (10-13, 16, 17). These have, at least in part, been attributed to antiserotoninergic properties of MCP (17). The dopamine-antagonist HAL has also been shown to have variable effects on corticosteroid secretion in rats. In most studies acute administration of HAL resulted in an increase of aldosterone secretion (8,9,21). On the other hand, one group was not able to demonstrate induction of aldosterone secretion by HAL (22). Our results indicate that aldosterone and corticosterone secretion in rats is enhanced by systemic HAL administration. This elevation is not due to direct blockade of dopamine receptors at the adrenal cortex since intraadrenal application of HAL via the microdialysis system has no effect on steroid secretion. Thus our in uiuo experiments confirm the observation of in vitro studies that application of dopamine-antagonists to rat glomerulosa cells has no effect on aldosterone release. If the dopaminergic control of corticosteroid secretion does not occur directly at the level of the adrenocortical cell, as suggested by our data, what factor(s) mediate the drug action? The principal factors regulating aldosterone secretion are the renin-angiotensin system, ACTH and the serum electrolytes sodium and potassium. The majority of the reports suggest that the stimulatory action of MCP on aldosterone production is independent of the renin-angiotensin system (10, 16, 23), although modulation of the adrenal actions of angiotensin II in rats through dopamine, depending on the sodium intake, has been reported (11). The authors of the latter study demonstrate enhancement of aldosterone secretion after MCP application in rats on a low sodium intake. They drew the conclusion that MCP acts synergistically with
1
l
2
4
6
6
10
12
sample
angiotensin II only during states of elevated angiotensin II levels. In our studies, rats were kept on a regular sodium diet making this interaction unlikely. The present report confirms the observation that the effect of dopamine-antagonists on corticosteroidogenesis is not mediated by ACTH (12, 16, 17, 21), because no increase of ACTH levels was noted after systemic HAL injection. Another fact decreasing the likelihood of such an interaction is the predominating stimulatory action of ACTH on corticosterone. ACTH-mediated corticosterone secretion should have far exceeded aldosterone secretion, a finding we could not demonstrate. The increase in serum aldosterone and corticosterone after HAL injection was accompanied by a parallel rise in serum PRL. This suggests that the rise in steroid hormones levels might be secondary to the increase in PRL, rather than to blockade of dopamine receptors at the level of the adrenal cortex itself. This assumption is supported by the observation that in hypophysectomized rats neither ip injection nor intraadrenal dialysis of HAL (data not shown) enhanced hormone secretion. In humans this mechanism has been denied. Patients with hypopituitarism show no difference in reaction to MCP to normal subjects (24). This coincides with an observation made by several investigators (25-27) that hyperprolactinaemia induced by TRH does not stimulate steroid secretion in humans. In addition MCP-induced hyperprolactinaemia also had no effect on aldosterone secretion in humans (28). Albeit these findings in humans, Marshall and Calvo et al. (29, 30) found PRL specifically bound to cells of the rat adrenal gland, indicating the presence of PRL receptors. Nolin (31) identified the cells of the zona fasciculata as the site of specific PRL uptake by using immunohistochemical methods.
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ADRENOCORTICAL Haloperidol
2.5 mg
ip, intact
pituitary
ACTION
OF PRL
gland
Haloperidol
917 20 vg/ml
intraadrenal,
intact
pituitary
gland
300 A
$ f;; f dp t
1
100%.
477e
PO/ml
250
200
150
E %
100
1? a
50
-I
0
*
T+*
300
B;i;
250
f dp
200
e
150
e r
100 8
z B 0
50
0
1
No of fraction
No of fraction
FIG. 2. Aldosterone (top panel) and corticosterone (bottom panel) levels in the dialysate before (open columns) and after an ip injection of 0.5 ml Haldol (black columns) in rats with an intact pituitary gland. Adrenal glands were constantly perfused with Ringer’s solution. Fractions were collected at 15-min intervals. All values are depicted as percentage values, the 100% value is given in the diagram. Vertical lines indicate SEM. *, P < 0.05 us. the last pretreatment value. Within 15 min after systemic HAL application levels of both steroids were significantly elevated.
FIG. 3. Aldosterone (top panel) and corticosterone (bottom panel) levels in the dialysate during intraadrenal dialysis with Ringer’s solution (open columns) and dialysis with HAL solution (black columns) in rats with an intact pituitary gland. All values are depicted as percentage values, the 100% value is given in the diagram. Vertical lines indicate SEM. During intraadrenal HAL application secretion of both steroids remained unaffected. TABLE 2. Effect of HAL (2.5 mg) corticosterone in hypophysectomized of Ringer’s solution (n = 21) Min
TABLE 1. Effect PRL, aldosterone, gland (n = 10) Intraadrenal dialvsis Ringer’s solution
HAL
of intraadrenal HAL dialysis (20 rg/ml) on serum and corticosterone in rats with an intact pituitary
-30 -15 2.5 mg Hal+
Min
PRL
-30
105.5 + 12.5
-15
88.8 105.7 90.3 108.0 77.3 87.2
0 15 30 45 90
+ + + f + +
Aldosterone
15.5 12.2 14.7 37.5 14.7 21.1
98.1 zk 7.8 100.2 101.7 81.0 90.2 93.0 101.1
f f f f f +
7.0 11.0 8.6 11.2 10.5 11.1
Corticosterone 101.8 + 13.7 97.6 100.6 99.4 100.4 104.6 117.2
Means + SEM expressed as percentages. 100% = PRL, Aldosterone, 3.3 rig/ml; Corticosterone, 336.6 rig/ml.
+ + + + + +
8.7 14.3 25.4 22.4 15.0 17.2
14.2 rig/ml;
0 15 30 45 90
ip on serum PRL, aldosterone, and rats during intraadrenal dialysis
PRL 95.5 106.6 97.9 92.3 100.4 108.1 87.8
+ + + + + + +
Aldosterone 19.0 8.7 9.2 8.0 15.0 16.6 15.2
110.6 89.2 100.2 116.1 106.2 94.0 80.7
k + f + + + f
23.0 4.7 5.2 14.0 12.2 8.0 5.2
Means -C SEM expressed as percentages. 100% Aldosterone, 0.6 rig/ml; corticosterone, 11.3 rig/ml.
Corticosterone 103.5 92.0 104.5 116.8 123.7 114.8 76.6 = PRL,
+ + + f + f -t
28.1 6.0 6.4 15.2 16.2 23.6 28.7
1.5 rig/ml;
The physiological significance of these receptors may be a potentiating action of PRL on ACTH-stimulated corticosterone secretion after long term PRL administration to hypophysectomized rats (32, 33). Both groups proposed that 5Lu-reductase, the major enzyme for intraa-
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ADRENOCORTICAL
918 Haloperidol
lOOI
-
90.2
Endo. Voll30.
OF PRL
1992 No 2
cause aldosterone and corticosterone release far exceeded progesterone stimulation. In an earlier study, iv injection of PRL in rats with a pituitary gland (therefore not primarily inducing increased 5a-reductase activity) had resulted in the release of corticosterone and progesterone (35). Hence we concluded that the effect of systemic HAL on steroid secretion in nonhypophysectomized rats is mediated by PRL. If this proposed mechanism only functions in the presence of ACTH and subsequent stimulation of cholesterol side chain cleavage enzymes remains to be clarified. In summary using an in uiuo microdialysis system in rats we give evidence that the stimulation of aldosterone and corticosterone secretion by the dopamine antagonist HAL is not due to a blockade of adrenocortical dopamine receptors. The observed increase of steroid release appears to be mediated by a pituitary factor, most likely PRL.
2.5 mg ip. hypophysectomized
PO/ml
T
ACTION
T
References
3
4
5
0
7
0
0
10
No of fraction FIG. 4. Aldosterone (top panel) and corticosterone (bottom panel) levels in the dialysate before (open columns) and after an ip injection of 0.5 ml Haldol (black columns) in hypophysectomized rats. Adrenal glands were constantly perfused with Ringer’s solution. Fractions were collected at 15-min intervals. All values are depicted as percentage values, the 100% value is given in the diagram. Vertical lines indicate SEM. In hypophysectomized rats systemic application of HAL was without any effect on steroid levels in the dialysate samples.
drenal degradation of corticosterone, played a key role in this finding. Enzyme activity was primarily increased after hypophysectomy. They concluded that subsequent inhibition of 5a-reductase activity was responsible for the potentiating action of PRL rather than increased corticosteroidogenesis. Although chronic PRL administration alone did not increase corticosterone levels overall in their studies, acute PRL administration to rat adrenal cells in vitro enhanced adrenal steroid secretion in the order aldosterone > corticosterone > progesterone (34). The latter study also provided evidence that PRL potentiated ACTH-stimulated hormone secretion at low doses. The authors proposed that the mechanism of action of PRL, in addition to inhibition of the major degrading enzyme, 5a-reductase, was stimulation of enzymes in late steroidogenesis, e.g. 21-hydroxylase, be-
1. Norbiato G, Bevilacqua M, Raggi U, Micossi P, Moroni C 1977 Metoclopramide increases plasma aldosterone in man. J Clin Endocrinol Metab 45:1313-1316 2. Carey RM, Thorner MO, Ortt EM 1979 Effects of metoclopramide and bromocriptine on the renin-angiotensin-aldosterone system in man: dopaminergic control of aldosterone secretion. J Clin Invest 631727-735 3. Sowers JR 1982 Modulation of corticosteroid secretion by dopaminergic mechanisms in rhesus monkeys. Am J Physiol243:E375E379 4. McDougall JG, Scoggins BA, Aldona Butkus, Coghlan JP, Denton DA, Fei DT, Hardy KJ, Wright RD 1981 Dopaminergic modulation of aldosterone secretion? J Endocrinol91:271-280 5. Huang BS, Melvin RL, Lee J, Grekin RJ 1987 Central dopaminergic regulation of aldosterone secretion in the sheep. Hypertension 10:157-163 6. Ganguly A 1984 Dopaminergic regulation of aldosterone secretion: how credible? Clin Sci 66631-637 7. Aguilera G, Mendelsohn FAO, Catt KJ 1984 Dopaminergic regulation of aldosterone secretion. In: Ganong WF, Martini L (eds) Frontiers in Neuroendocrinology. Raven Press, New York, pp 265293 8. Jungmann E, Wachtler M, Schwedes U, Usadel KH, Schoffling K 1983 The effect of metoclopramide and haloperidol on plasma renin activity and aldosterone levels in rats. Res Exp Med (Berl) 183:133-138 9. Jungmann E, Germann G, Austin I, Mack B, Storp-Wenke D, Fassbinder W, Schwedes U, Usadel KH, Encke A, Schoffling K 1986 The role of adrenal medulla in endogenous dopaminergic inhibition of aldosterone secretion. Res Exp Med (Berl) 186:427434 10. Nagahama S, Fujimaki M, Suzuki H, Kawabe H, Saito I, Saruta T 1987 In uiuo and in vitro effects of metoclopramide on aldosterone secretion in rats. Acta Endocrinol (Copenh) 102:589-593 11. Aguilera G, Catt KJ 1984 Dopaminergic modulation of aldosterone secretion in the rat. Endocrinology 114:176-181 12. Campbell DJ, Mendelsohn FAO, Adam WR, Funder JW 1981 Metoclopramide does not elevate aldosterone in the rat. Endocrinology 109:1484-1491 13. Hampton T, Ganguly A 1986 Metoclopramide fails to stimulate aldosterone secretion and inhibits serotonin-mediated aldosterone secretion in the rat. Horm Metab Res 18:754-756 14. Dunn MG, Bosmann GH 1981 Peripheral dopamine receptor identification: properties of a specific dopamine receptor in the rat adrenal zona glomerulosa. Biochem Biophys Res Commun
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 October 2015. at 06:58 For personal use only. No other uses without permission. . All rights reserved.
ADRENOCORTICAL 99:1081-1087 15. Missale C, Liberini P, Memo M, Carruba MO, Spano P 1986 Characterization of dopamine receptors associated with aldosterone secretion in rat adrenal glomerulosa. Endocrinology 119:22272232 16. Edwards CRW, Al-Dujaili EAS, Boscaro M, Quyyumi S, Miall PA, Rees LH 1980 In vivo and in vitro studies on the effect of metoclopramide on aldosterone secretion. Clin Endocrinol (Oxf) 13:45-50 17. Lauer CG, Braley LM, Menachery AI, Williams GH 1982 Metoclopramide inhibits aldosterone biosynthesis in vitro. Endocrinology 111:238-243 18. Jarry H, Duker E, Wuttke W 1985 Adrenal release of catecholamines and met-enkephalin before and after stress as measured by a novel in vivo dialysis method in the rat. Neurosci Lett 60:273278 19. Jarry H, Dietrich M, Duker E, Wuttke W 1987 Effect of systemic and local administration of etomidate on adrenocortical steroidogenesis in male rats. Acta Endocrinol (Copenh) 114:402-409 20. Jarry H, Dietrich M, Barthel A, Giesler A, Wuttke W 1989 In vivo demonstration of a paracrine, inhibitory action of met-enkephalin on adrenomedullary catecholamine release in the rat. Endocrinology 125:624-629 21. Barrett RJ, Wright KF, Taylor DR, Proakis AG 1987 Involvement of dopamine receptor subtypes in dopaminergic modulation of aldosterone secretion in rats. Life Sci 40:1499-1506 22. Sowers JR, Golub M, Tuck M, Sowers DK 1981 Role of prolactin and the renin-angiotensin system in mediating dopaminergic control of aldosterone secretion in the rat. J Clin Hypertension 3:114 23. Sowers JR, Tuck ML, Golub MS, Sollars EC 1980 Dopaminergic modulation of aldosterone secretion is independent of alterations in renin secretion. Endocrinology 107:937-941 24. Pratt JH. Ganaulv A. Parkinson CA. Weinbereer MH 1981 Stimulation of aldosterone secretion by metoclopramide in humans: apparent independence of renal and pituitary mediation. Metabo-
ACTION
OF PRL
919
lism 51:129-134 25. Baumann G, Loriaux DL 1976 The effect of endogenous prolactin on renal salt and water excretion and adrenal function in man. J Clin Endocrinol Metab 43:643-649 26. Holland OB, Gomez-Sanchez LE, Kern DC, Weinberger MH, Kramer NJ, Higgins JR 1977 Evidence against prolactin stimulation of aldosterone in normal human subjects and patients with primary aldosteronism, including a patient with primary aldosteronism and a prolactin-producing pituitary microadenoma. J Clin Endocrinol Metab 45:1064-1076 27. Re RN, Kourides IA, Weihl AC, Maloof F 1979 The relationship between endogenous hyperprolactinemia and plasma aldosterone. Clin Endocrinol (Oxf) 10:187-193 28. Ogihara T, Matsumura S, Onishi T, Miyai K, Uozumi T, Kumahara Y 1977 Effect of metoclopramide-induced prolactin on aldosterone secretion in normal subjects. Life Sci 20:523-526 29. Marshall S, Huang HH, Kledzik GS, Campbell GA, Meites J 1978 Glucocorticoid regulation of prolactin receptors in kidneys and adrenals of male rats. Endocrinology 102:869-875 30. Calvo JC, Finocchiaro L, Liithy I, Charreau EH, Calandra RS, Engstrom B, Hansson V 1981 Specific prolactin binding in the rat adrenal gland: its characterization and hormonal regulation. J Endocrinol89:317-325 31. Nolin JM 1978 Intracellular prolactin in rat corpus luteum and adrenal cortex. Endocrinology 102:402-406 32. Ogle TF, Kitay JI 1979 Interactions of prolactin and adrenocorticotropin in the regulation of adrenocortical secretions in the female rat. Endocrinology 104:40-44 33. Colby HD 1979 Mechanism of action of nrolactin on adrenocortical steroid secretion in hypophysectomized female rats. Endocrinology 104:1299-1303 34. Eldridge JC, Lymangrover JR 1984 Prolactin stimulates and potentiates adrenal steroid secretion in vitro. Horm Res 20:252-260 35. Mann DR, Cost MG, Jacobson CD, MacFarland LA 1977 Adrenal gland rhythmicity and pituitary regulation of adrenal steroid secretion. Proc Sot Exp Biol Med 156:441-445
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Vol. Printed
Society
Indirect Evidence to Suggest Adrenal Action of Haloperidol and Corticosterone Secretion STEPHAN GOEBEL, MARGARETHE WOLFGANG WUTTKE Division of Experimental of Gtittingen, Germany
and Clinical
DIETRICH,
Endocrinology,
Department
that Prolactin to Stimulate in Rats HUBERTUS of
JARRY,
130, No. 2 in U.S.A.
Mediates the Aldosterone
AND
Obstetrics and Gynecology,
University
PRL secretion and stimulated aldosterone and corticosterone production significantly. In contrast, intraadrenal dialysis of HAL had no effect on the secretory pattern of PRL or either steroid hormone, indicating no direct drug action on cells of the rat adrenal cortex. Similarly, ip injection of 2.5 mg HAL in hypophysectomized rats did not alter PRL or steroid hormone levels. We conclude that the dopamine-antagonist HAL stimulates aldosterone and corticosterone secretion in rats through a pituitary factor, probably PRL, but not through direct effects at the adrenal cortex. (Endocrinology 130: 914-919,1992)
ABSTRACT. The effect of dopamine-antagonists on steroid secretion has revealed conflicting results regarding the contirmation of in uiuo findings in uitro. In order to discriminate in uiuo systemic and local action of the dopamine-antagonist haloperidol (HAL) on aldosterone and corticosterone secretion, microdialysis of the adrenal cortex in conscious, freely moving rats was employed. The effects of 2.5 mg HAL ip or intraadrenal dialysis of 20 pg/ml HAL in rats with an intact pituitary gland on PRL, aldosterone, and corticosterone secretion were examined. Systemic HAL application resulted in a IO-fold increase in
M
(MCP), a dopamine antagETOCLOPRAMIDE onist, administered acutely as an iv-bolus causes a rapid increase in plasma aldosterone in humans (1, 2), rhesus monkeys (3), and sheep (4,5). The mechanism of action is thought to be due to counteraction of the inhibitory control of aldosterone secretion by dopamine (2). Most authors localized the site of action of MCP to the zona glomerulosa cell, although this hypothesis was not definitely confirmed by in vitro experiments (for a review see 6,7). In those studies in which plasma cortisol was examined, plasma levels were unaffected by dopamine antagonists (l-5). In rats however, the effect of dopamine antagonists on corticosteroid secretion remains controversial. In some studies acute systemic injection (8-10) or chronic infusion (11) of dopamine antagonists elevated plasma aldosterone, whereas others (12, 13) were not able to confirm this finding. The possibility of direct action of dopamine on the adrenal cortex was validated by the demonstration of dopamine receptors in zona glomerulosa cells of the rat adrenal (14, 15). There remains considerable controversy regarding the physiological sig-
nificance of their presence, because in vitro studies were unable to demonstrate direct stimulation of steroid secretion through dopaminergic antagonists (10,12,13,16) or inhibition of steroidogenesis by dopaminergic agonists (11) in rat adrenal glomerulosa cell preparations. One report revealed inhibition of aldosterone secretion by MCP in zona glomerulosa cells (17). In order to study systemic as well as local effects of the dopamine antagonist haloperidol (HAL) on steroid secretion in rats, we employed a microdialysis system implanted into the adrenal cortex of conscious, freely moving rats (18). Determination of aldosterone and corticosterone in the dialysis medium gives an estimate of the local steroid secretion before and after systemic injection of HAL. On the other hand addition of HAL to the dialysis medium enabled us to examine the direct drug effect on cells of the adrenal cortex, since the drug does not enter general circulation such that systemic effects are prevented. Therefore it was possible to discriminate between a systemic and a local effect of HAL on steroidogenesis. To further determine the mechanism of action of HAL, serum PRL was measured in addition to serum aldosterone and corticosterone. One group of animals underwent hypophysectomy before experimentation to eradicate pituitary factors as possible mediators of HAL action.
Received September 6,1991. Address correspondence and requests for reprints to: Professor Dr. W. Wuttke, Universitats-Frauenklinik, Robert-Koch-Strasse 40, D3400 Gottingen, Germany. 914
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ADRENOCORTICAL
Materials
and Methods
Male Sprague-Dawley rats (mean weight, 300 g) were used in all experiments. They were housed under standardized conditions (lights on, 0700-1900 h; 24 C; food and water ud lib&urn). One group of animals was hypophysectomized by a pharyngeal approach 48 h before experimentation. The dialysis system was prepared by inserting dialysis tubing (Diafilter 20 Amicon mol wt off 20,000, Witten, Germany) into the end of two silastic tubings (602-105, Dow Corning, Midland, MI), such that the free dialysis surface was approximately 2 mm (19). Under ether anesthesia, the left adrenal gland was exposed through a ventrolateral incision. A 25-gauge hypodermic needle, connected to the end of one silastic tubing, was used to penetrate the adrenal cortex tangentially. The tubing system was pulled through the adrenal gland and the free dialysis tubing located inside the adrenal cortex. The ends of the silastic tubings were SC exteriorized through an incision at the neck, the adrenal gland relocated, and the muscle and skin incision closed. Under the same anesthesia, a jugular vein catheter was also implanted. The animals were allowed to recover from surgery for 24 h before undergoing experimentation. At the beginning of the dialysis experiment one end of the tubing system was connected to a peristaltic pump. Dialysate fractions were collected from the other end at 15-min intervals after an initial washout period of 3 h. The system was perfused with Ringer solution at a flow rate of 20 rl/min. At the end of each fraction period, a blood sample was collected via the indwelling jugular vein catheter. With such prepared animals three experiments were carried out: 1. The adrenal glands of intact rats (n = 32) were dialyzed with Ringer solution 90 min before and 90 min after an ip injection of 0.5 ml Haldol(=2.5 mg HAL, Janssen, Hamburg, Germany). 2. HAL was dissolved in Ringer solution at a concentration of 20 pg/ml. Since the transfer efficiency of the dialysis membrane is about 1% this resulted in an intraadrenal concentration of approximately 200 rig/ml (20). After an initial dialysis period of 90 min with Ringer solution, the drug was locally administered to the adrenal gland by dialysis with the HAL solution for another 90 min (n = 10). 3. Exp 1 was repeated in hypophysectomized rats (n = 21). After the experiment rats were decapitated and the adrenal gland implanted with the microdialysis system was removed. The placement of the dialysis system within the cortex was verified by slicing the adrenal glands on a cryostat. In hypophysectomized rats the skull was opened, the brain removed, and the sella turcica inspected. Serum and dialysate fractions were stored at -20 C until assayed. All measurements for each hormone were performed in duplicates in the same assay. The concentrations of aldosterone and corticosterone in dialysate and of ACTH in serum were determined by commercially available RIAs (DPC, Bad Nauheim, Germany). PRL levels in the serum were quantified by RIA supplied by the NIDDK. Baseline secretion rates of steroid hormones in the dialysates showed interindividual differences. Therefore, all data were expressed as percentages. In each animal concentrations of hormones in all pretreatment fraction periods were averaged
ACTION
OF PRL
915
and the mean set as 100%; all other individual data were then calculated in relation to this 100% value. Differences between means of the last pretreatment and all posttreatment values were tested for statistical significance by analysis of variance followed by Duncan’s multiple range test.
Results The effect of an ip injection of 2.5 mg HAL on serum PRL, ACTH, aldosterone, and corticosterone concentrations is shown in Fig. 1. HAL injection caused a 40-fold increase of serum PRL within 15 min and remained significantly elevated throughout the remaining experiment. Measurement of ACTH revealed no change in the secretion pattern after administration of HAL. Serum aldosterone and corticosterone levels approximately doubled after HAL injection. The results of hormone analysis of the corresponding dialysate fractions are pictured in Fig. 2. The ip injection of 2.5 mg HAL caused an increase of aldosterone release reaching a significant level in the second dialysate fraction (i.e. between 15-30 min) after injection. The enhanced aldosterone secretion was paralleled by a rise in corticosterone levels in the dialysate samples. The results of intraadrenal dialysis with HAL (20 pg/ ml) on serum PRL, and steroid concentrations in serum and dialysate samples are summarized in Table 1 and Fig. 3. In rats with intact pituitary glands intraadrenal HAL dialysis had no significant effect on PRL secretion. Aldosterone and corticosterone secretion were similarly unaffected by the change of dialysis media. Neither serum nor dialysate steroid hormone levels were altered after replacement of Ringer solution by HAL containing Ringer solution. Higher doses of HAL up to 500 pg/ml were also without any effect on either hormone (data not shown). The effect of 2.5 mg HAL injected ip in hypophysectomized rats on serum PRL is shown in Table 2. Although low PRL levels were detectable (100% = 1.5 ng/ ml) there is no response of PRL secretion to HAL injection. Absolute steroid hormone levels also were significantly
lower
in hypophysectomized
rats than in ani-
mals with a pituitary gland. Aldosterone levels after drug administration did not vary significantly from basal levels before injection. Corticosterone secretion also remained unaffected by HAL application. Hormone levels in the corresponding dialysate fractions in hypophysectomized rats are depicted in Fig. 4. No significant change of aldosterone or corticosterone secretion occurred after drug treatment. Discussion The role of dopamine antagonists in the control of corticosteroid secretion in rats has not been clearly out-
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ADRENOCORTICAL
916
1. Serum levels of PRL and ACTH (k/t pands) and of aldosterone and corticosterone (right panels) before and after an ip injection of 0.5 ml Haldol (=2.5 mg HAL) in rats with an intact pituitary gland. Adrenal glands were constantly perfused with Ringer’s solution. All values are depicted as percentage values, the 100% value is given in the diagram. Blood was collected at 15min intervals. After HAL injection levels of PRL, aldosterone and corticosterone increased significantly whereas ACTH levels remained unchanged. Arrows indicate the drug injection; vertical lines indicate SEM; *, P < 0.05 us. the last pretreatment value.
OF PRL
B - “‘; 7000
FIG.
ACTION
1
1
100 x = 44.5 “p/ml
1992 No 2
.
l *
l
5000
Endo. Voll30.
i
’
5 3000 % e n 1000
o’,
I
I
I
I
!
I,,
,
I*
,
,
1 100x . 37.5ng/ In,
300
B 3001
100
x. 307"g/ml
L1
.
‘I*
B
;ii
200-
i
loo:&
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12 No of blood
lined. In the majority of experiments MCP was used as dopamine-antagonistic drug and has resulted in conflicting reports (10-13, 16, 17). These have, at least in part, been attributed to antiserotoninergic properties of MCP (17). The dopamine-antagonist HAL has also been shown to have variable effects on corticosteroid secretion in rats. In most studies acute administration of HAL resulted in an increase of aldosterone secretion (8,9,21). On the other hand, one group was not able to demonstrate induction of aldosterone secretion by HAL (22). Our results indicate that aldosterone and corticosterone secretion in rats is enhanced by systemic HAL administration. This elevation is not due to direct blockade of dopamine receptors at the adrenal cortex since intraadrenal application of HAL via the microdialysis system has no effect on steroid secretion. Thus our in uiuo experiments confirm the observation of in vitro studies that application of dopamine-antagonists to rat glomerulosa cells has no effect on aldosterone release. If the dopaminergic control of corticosteroid secretion does not occur directly at the level of the adrenocortical cell, as suggested by our data, what factor(s) mediate the drug action? The principal factors regulating aldosterone secretion are the renin-angiotensin system, ACTH and the serum electrolytes sodium and potassium. The majority of the reports suggest that the stimulatory action of MCP on aldosterone production is independent of the renin-angiotensin system (10, 16, 23), although modulation of the adrenal actions of angiotensin II in rats through dopamine, depending on the sodium intake, has been reported (11). The authors of the latter study demonstrate enhancement of aldosterone secretion after MCP application in rats on a low sodium intake. They drew the conclusion that MCP acts synergistically with
1
l
2
4
6
6
10
12
sample
angiotensin II only during states of elevated angiotensin II levels. In our studies, rats were kept on a regular sodium diet making this interaction unlikely. The present report confirms the observation that the effect of dopamine-antagonists on corticosteroidogenesis is not mediated by ACTH (12, 16, 17, 21), because no increase of ACTH levels was noted after systemic HAL injection. Another fact decreasing the likelihood of such an interaction is the predominating stimulatory action of ACTH on corticosterone. ACTH-mediated corticosterone secretion should have far exceeded aldosterone secretion, a finding we could not demonstrate. The increase in serum aldosterone and corticosterone after HAL injection was accompanied by a parallel rise in serum PRL. This suggests that the rise in steroid hormones levels might be secondary to the increase in PRL, rather than to blockade of dopamine receptors at the level of the adrenal cortex itself. This assumption is supported by the observation that in hypophysectomized rats neither ip injection nor intraadrenal dialysis of HAL (data not shown) enhanced hormone secretion. In humans this mechanism has been denied. Patients with hypopituitarism show no difference in reaction to MCP to normal subjects (24). This coincides with an observation made by several investigators (25-27) that hyperprolactinaemia induced by TRH does not stimulate steroid secretion in humans. In addition MCP-induced hyperprolactinaemia also had no effect on aldosterone secretion in humans (28). Albeit these findings in humans, Marshall and Calvo et al. (29, 30) found PRL specifically bound to cells of the rat adrenal gland, indicating the presence of PRL receptors. Nolin (31) identified the cells of the zona fasciculata as the site of specific PRL uptake by using immunohistochemical methods.
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ADRENOCORTICAL Haloperidol
2.5 mg
ip, intact
pituitary
ACTION
OF PRL
gland
Haloperidol
917 20 vg/ml
intraadrenal,
intact
pituitary
gland
300 A
$ f;; f dp t
1
100%.
477e
PO/ml
250
200
150
E %
100
1? a
50
-I
0
*
T+*
300
B;i;
250
f dp
200
e
150
e r
100 8
z B 0
50
0
1
No of fraction
No of fraction
FIG. 2. Aldosterone (top panel) and corticosterone (bottom panel) levels in the dialysate before (open columns) and after an ip injection of 0.5 ml Haldol (black columns) in rats with an intact pituitary gland. Adrenal glands were constantly perfused with Ringer’s solution. Fractions were collected at 15-min intervals. All values are depicted as percentage values, the 100% value is given in the diagram. Vertical lines indicate SEM. *, P < 0.05 us. the last pretreatment value. Within 15 min after systemic HAL application levels of both steroids were significantly elevated.
FIG. 3. Aldosterone (top panel) and corticosterone (bottom panel) levels in the dialysate during intraadrenal dialysis with Ringer’s solution (open columns) and dialysis with HAL solution (black columns) in rats with an intact pituitary gland. All values are depicted as percentage values, the 100% value is given in the diagram. Vertical lines indicate SEM. During intraadrenal HAL application secretion of both steroids remained unaffected. TABLE 2. Effect of HAL (2.5 mg) corticosterone in hypophysectomized of Ringer’s solution (n = 21) Min
TABLE 1. Effect PRL, aldosterone, gland (n = 10) Intraadrenal dialvsis Ringer’s solution
HAL
of intraadrenal HAL dialysis (20 rg/ml) on serum and corticosterone in rats with an intact pituitary
-30 -15 2.5 mg Hal+
Min
PRL
-30
105.5 + 12.5
-15
88.8 105.7 90.3 108.0 77.3 87.2
0 15 30 45 90
+ + + f + +
Aldosterone
15.5 12.2 14.7 37.5 14.7 21.1
98.1 zk 7.8 100.2 101.7 81.0 90.2 93.0 101.1
f f f f f +
7.0 11.0 8.6 11.2 10.5 11.1
Corticosterone 101.8 + 13.7 97.6 100.6 99.4 100.4 104.6 117.2
Means + SEM expressed as percentages. 100% = PRL, Aldosterone, 3.3 rig/ml; Corticosterone, 336.6 rig/ml.
+ + + + + +
8.7 14.3 25.4 22.4 15.0 17.2
14.2 rig/ml;
0 15 30 45 90
ip on serum PRL, aldosterone, and rats during intraadrenal dialysis
PRL 95.5 106.6 97.9 92.3 100.4 108.1 87.8
+ + + + + + +
Aldosterone 19.0 8.7 9.2 8.0 15.0 16.6 15.2
110.6 89.2 100.2 116.1 106.2 94.0 80.7
k + f + + + f
23.0 4.7 5.2 14.0 12.2 8.0 5.2
Means -C SEM expressed as percentages. 100% Aldosterone, 0.6 rig/ml; corticosterone, 11.3 rig/ml.
Corticosterone 103.5 92.0 104.5 116.8 123.7 114.8 76.6 = PRL,
+ + + f + f -t
28.1 6.0 6.4 15.2 16.2 23.6 28.7
1.5 rig/ml;
The physiological significance of these receptors may be a potentiating action of PRL on ACTH-stimulated corticosterone secretion after long term PRL administration to hypophysectomized rats (32, 33). Both groups proposed that 5Lu-reductase, the major enzyme for intraa-
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ADRENOCORTICAL
918 Haloperidol
lOOI
-
90.2
Endo. Voll30.
OF PRL
1992 No 2
cause aldosterone and corticosterone release far exceeded progesterone stimulation. In an earlier study, iv injection of PRL in rats with a pituitary gland (therefore not primarily inducing increased 5a-reductase activity) had resulted in the release of corticosterone and progesterone (35). Hence we concluded that the effect of systemic HAL on steroid secretion in nonhypophysectomized rats is mediated by PRL. If this proposed mechanism only functions in the presence of ACTH and subsequent stimulation of cholesterol side chain cleavage enzymes remains to be clarified. In summary using an in uiuo microdialysis system in rats we give evidence that the stimulation of aldosterone and corticosterone secretion by the dopamine antagonist HAL is not due to a blockade of adrenocortical dopamine receptors. The observed increase of steroid release appears to be mediated by a pituitary factor, most likely PRL.
2.5 mg ip. hypophysectomized
PO/ml
T
ACTION
T
References
3
4
5
0
7
0
0
10
No of fraction FIG. 4. Aldosterone (top panel) and corticosterone (bottom panel) levels in the dialysate before (open columns) and after an ip injection of 0.5 ml Haldol (black columns) in hypophysectomized rats. Adrenal glands were constantly perfused with Ringer’s solution. Fractions were collected at 15-min intervals. All values are depicted as percentage values, the 100% value is given in the diagram. Vertical lines indicate SEM. In hypophysectomized rats systemic application of HAL was without any effect on steroid levels in the dialysate samples.
drenal degradation of corticosterone, played a key role in this finding. Enzyme activity was primarily increased after hypophysectomy. They concluded that subsequent inhibition of 5a-reductase activity was responsible for the potentiating action of PRL rather than increased corticosteroidogenesis. Although chronic PRL administration alone did not increase corticosterone levels overall in their studies, acute PRL administration to rat adrenal cells in vitro enhanced adrenal steroid secretion in the order aldosterone > corticosterone > progesterone (34). The latter study also provided evidence that PRL potentiated ACTH-stimulated hormone secretion at low doses. The authors proposed that the mechanism of action of PRL, in addition to inhibition of the major degrading enzyme, 5a-reductase, was stimulation of enzymes in late steroidogenesis, e.g. 21-hydroxylase, be-
1. Norbiato G, Bevilacqua M, Raggi U, Micossi P, Moroni C 1977 Metoclopramide increases plasma aldosterone in man. J Clin Endocrinol Metab 45:1313-1316 2. Carey RM, Thorner MO, Ortt EM 1979 Effects of metoclopramide and bromocriptine on the renin-angiotensin-aldosterone system in man: dopaminergic control of aldosterone secretion. J Clin Invest 631727-735 3. Sowers JR 1982 Modulation of corticosteroid secretion by dopaminergic mechanisms in rhesus monkeys. Am J Physiol243:E375E379 4. McDougall JG, Scoggins BA, Aldona Butkus, Coghlan JP, Denton DA, Fei DT, Hardy KJ, Wright RD 1981 Dopaminergic modulation of aldosterone secretion? J Endocrinol91:271-280 5. Huang BS, Melvin RL, Lee J, Grekin RJ 1987 Central dopaminergic regulation of aldosterone secretion in the sheep. Hypertension 10:157-163 6. Ganguly A 1984 Dopaminergic regulation of aldosterone secretion: how credible? Clin Sci 66631-637 7. Aguilera G, Mendelsohn FAO, Catt KJ 1984 Dopaminergic regulation of aldosterone secretion. In: Ganong WF, Martini L (eds) Frontiers in Neuroendocrinology. Raven Press, New York, pp 265293 8. Jungmann E, Wachtler M, Schwedes U, Usadel KH, Schoffling K 1983 The effect of metoclopramide and haloperidol on plasma renin activity and aldosterone levels in rats. Res Exp Med (Berl) 183:133-138 9. Jungmann E, Germann G, Austin I, Mack B, Storp-Wenke D, Fassbinder W, Schwedes U, Usadel KH, Encke A, Schoffling K 1986 The role of adrenal medulla in endogenous dopaminergic inhibition of aldosterone secretion. Res Exp Med (Berl) 186:427434 10. Nagahama S, Fujimaki M, Suzuki H, Kawabe H, Saito I, Saruta T 1987 In uiuo and in vitro effects of metoclopramide on aldosterone secretion in rats. Acta Endocrinol (Copenh) 102:589-593 11. Aguilera G, Catt KJ 1984 Dopaminergic modulation of aldosterone secretion in the rat. Endocrinology 114:176-181 12. Campbell DJ, Mendelsohn FAO, Adam WR, Funder JW 1981 Metoclopramide does not elevate aldosterone in the rat. Endocrinology 109:1484-1491 13. Hampton T, Ganguly A 1986 Metoclopramide fails to stimulate aldosterone secretion and inhibits serotonin-mediated aldosterone secretion in the rat. Horm Metab Res 18:754-756 14. Dunn MG, Bosmann GH 1981 Peripheral dopamine receptor identification: properties of a specific dopamine receptor in the rat adrenal zona glomerulosa. Biochem Biophys Res Commun
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ADRENOCORTICAL 99:1081-1087 15. Missale C, Liberini P, Memo M, Carruba MO, Spano P 1986 Characterization of dopamine receptors associated with aldosterone secretion in rat adrenal glomerulosa. Endocrinology 119:22272232 16. Edwards CRW, Al-Dujaili EAS, Boscaro M, Quyyumi S, Miall PA, Rees LH 1980 In vivo and in vitro studies on the effect of metoclopramide on aldosterone secretion. Clin Endocrinol (Oxf) 13:45-50 17. Lauer CG, Braley LM, Menachery AI, Williams GH 1982 Metoclopramide inhibits aldosterone biosynthesis in vitro. Endocrinology 111:238-243 18. Jarry H, Duker E, Wuttke W 1985 Adrenal release of catecholamines and met-enkephalin before and after stress as measured by a novel in vivo dialysis method in the rat. Neurosci Lett 60:273278 19. Jarry H, Dietrich M, Duker E, Wuttke W 1987 Effect of systemic and local administration of etomidate on adrenocortical steroidogenesis in male rats. Acta Endocrinol (Copenh) 114:402-409 20. Jarry H, Dietrich M, Barthel A, Giesler A, Wuttke W 1989 In vivo demonstration of a paracrine, inhibitory action of met-enkephalin on adrenomedullary catecholamine release in the rat. Endocrinology 125:624-629 21. Barrett RJ, Wright KF, Taylor DR, Proakis AG 1987 Involvement of dopamine receptor subtypes in dopaminergic modulation of aldosterone secretion in rats. Life Sci 40:1499-1506 22. Sowers JR, Golub M, Tuck M, Sowers DK 1981 Role of prolactin and the renin-angiotensin system in mediating dopaminergic control of aldosterone secretion in the rat. J Clin Hypertension 3:114 23. Sowers JR, Tuck ML, Golub MS, Sollars EC 1980 Dopaminergic modulation of aldosterone secretion is independent of alterations in renin secretion. Endocrinology 107:937-941 24. Pratt JH. Ganaulv A. Parkinson CA. Weinbereer MH 1981 Stimulation of aldosterone secretion by metoclopramide in humans: apparent independence of renal and pituitary mediation. Metabo-
ACTION
OF PRL
919
lism 51:129-134 25. Baumann G, Loriaux DL 1976 The effect of endogenous prolactin on renal salt and water excretion and adrenal function in man. J Clin Endocrinol Metab 43:643-649 26. Holland OB, Gomez-Sanchez LE, Kern DC, Weinberger MH, Kramer NJ, Higgins JR 1977 Evidence against prolactin stimulation of aldosterone in normal human subjects and patients with primary aldosteronism, including a patient with primary aldosteronism and a prolactin-producing pituitary microadenoma. J Clin Endocrinol Metab 45:1064-1076 27. Re RN, Kourides IA, Weihl AC, Maloof F 1979 The relationship between endogenous hyperprolactinemia and plasma aldosterone. Clin Endocrinol (Oxf) 10:187-193 28. Ogihara T, Matsumura S, Onishi T, Miyai K, Uozumi T, Kumahara Y 1977 Effect of metoclopramide-induced prolactin on aldosterone secretion in normal subjects. Life Sci 20:523-526 29. Marshall S, Huang HH, Kledzik GS, Campbell GA, Meites J 1978 Glucocorticoid regulation of prolactin receptors in kidneys and adrenals of male rats. Endocrinology 102:869-875 30. Calvo JC, Finocchiaro L, Liithy I, Charreau EH, Calandra RS, Engstrom B, Hansson V 1981 Specific prolactin binding in the rat adrenal gland: its characterization and hormonal regulation. J Endocrinol89:317-325 31. Nolin JM 1978 Intracellular prolactin in rat corpus luteum and adrenal cortex. Endocrinology 102:402-406 32. Ogle TF, Kitay JI 1979 Interactions of prolactin and adrenocorticotropin in the regulation of adrenocortical secretions in the female rat. Endocrinology 104:40-44 33. Colby HD 1979 Mechanism of action of nrolactin on adrenocortical steroid secretion in hypophysectomized female rats. Endocrinology 104:1299-1303 34. Eldridge JC, Lymangrover JR 1984 Prolactin stimulates and potentiates adrenal steroid secretion in vitro. Horm Res 20:252-260 35. Mann DR, Cost MG, Jacobson CD, MacFarland LA 1977 Adrenal gland rhythmicity and pituitary regulation of adrenal steroid secretion. Proc Sot Exp Biol Med 156:441-445
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