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Effect of metoclopramide and domperidone on aldosterone, 18-hydroxycorticosterone and prolactin secretion in the rhesus monkey
Effect of Metoclopramide and Domperidone on Aldosterone, WHydroxycorticosterone and Prolactin Secretion in the Rhesus Monkey James
R. Sowers,
Peter
Eggena
and
Dennis
Phillips
This study was designed to investigate dopaminergic mechanisms in the control of corticosteroid secretion. Eight rhesus monkeys received metoclopramide (206 fig/kg) or domperidone (200 and 400 bglkg) with 5% dextrose (vehicle), or with dopamine (4 figlkglmin) infusions begun 60 min before administration of the dopamine antagonist. Metoclopramide, in the presence of vehicle, increased plasma aldosterone concentrations from 4.8 + 0.6 ng/dl to a maximum of 36 r 4.7 ng/dl and PRL concentrations from 7.6 + 1.1 ng/ml to a maximum of 120.5 f 8.0 ng/ml. Administration of metoclopramide resulted in a rise in plasma 18-hydroxycorticosterone from 10.2 ? 1.3 ng/dl to a maximum concentration of 49.6 + 4.5 ng/dl. Plasma concentrations of electrolytes, PRA, plasma cortisol, 11-deoxycorticosterone, corticosterone, 18-hydroxy11-deoxycorticosterone, were not altered by metoclopramide. Domperidone, in both doses, markedly increased plasma PRL concentrations but had no effect on plasma 18-OHB or aldosterone concentrations. Dopamine infusion inhibited the aldosterone response to metoclopramide and the prolactin response to metoclopramide and domperidone. The results of this investigation demonstrate that aldosterone responses to metoclopramide and prolactin responses to metoclopramide and domperidone, are mediated by their antagonist activity at dopamine receptors.
M
ETOCLOPRAMIDE, a dopamine antagonist which readily crosses the blood-brain barrier’ stimulates prolactin secretion in manz4 and rats.’ Recent studies have demonstrated that metoclopramide increases plasma aldosterone levels in rnan6-12 monkeys,‘-’ and ratsI independent of changes in factors known to affect aldosterone secretion. Since the increase of aldosterone following metoclopramide administration is blocked by dopamine,‘-” the aldosterone response to metoclopramide appears to be mediated by its antagonist activity at dopamine receptors. On the basis of biochemical criteria at least two categories of dopamine receptors have been demonstrated.14 One dopamine receptor, the D-l receptor, is linked to adenylcyclase; prototypes of D-l receptors are renal vascular dopamine receptors. A second type of dopamine receptor, the D-2 receptor, is not adenylate cyclase-linked; pituitary lactotrophs are prototype cells containing D-2 receptors. Results of studies to date are consistent with both subclasses of dopamine receptors mediating the adrenal aldosterone response to metoclopramide.9~‘0 Although aldosterone responses to dopamine antagonism with metoclopramide have been demonstrated to occur independent of known factors affecting aldosterone secretion 6-‘4it is not known whether metoclopramide stimulates aldosterone secretion directly or via effects on the central nervous system. To further investigate the mechanism of dopaminergic modulation of aldosterone secretion we have measured mineralcorticoid response to domperidone, a dopamine receptor-blocking agent which does not cross the blood brain barrier15,16 in rhesus monkeys which have previously been demonstrated to have aldosterone responses to metoclopramide.‘3 To determine if metoclopramide stimulates secretion of any of the precursors in the aldosterone biosynethetic pathway we Merabolism,
Vol. 3 1, No. 12 (December), 1982
have measured the effect of metoclopramide on 18-hydroxydeoxycorticosterone (18-OH-DOC), cortisol, 1I-deoxycorticosterone (DOC), corticosterone (B), 1Shydroxycorticosterone (1%OHB) and aldosterone in rhesus monkeys. MATERIALS
AND
METHODS
Studies were performed on 8 healthy mature male rhesus monkeys (Macaca mulatta), weighing 8.6 -10.3 kg, who were individually in rooms with regulated temperature (23-2X?) and light (lights on from 0600-1800 hr daily). They were fed Purina Monkey Chow twice daily and given fresh fruit supplements 5 times a week. Tap water was provided ad libitum. All studies were conducted in the morning (OSO&lOOO hr).
Metoclopramide/Domperidone/Dopamine
Studies
Ketamine in a dose of 5 mg/kg i.m. was used to produce light anesthesia and maintain the monkeys in a supine position. An indwelling cannula was placed in an arm vein for infusion, and a heparin lock was placed in a vein in the contralateral arm for blood sampling. After basal blood samples for measurement of electrolytes, aldosterone, prolactin, PRA and cortisol were obtained, an i.v. infusion of 5% dextrose (DrW) at 1 ml/mm was begun with an infusion pump and continued for 105 min. Blood sampling was repeated at 60 min after onset of D,W infusion and an i.v. bolus of metoclopramide (200 pg/kg) was given. Blood samples were then obtained at 5, IO, 15, 30, and 45 min after metoclopramide administration. Two weeks later an identical protocol was carried out except that instead of D,W dopamine hydrochloride (4 rg/kg/min) was infused for 105 min. Two weeks after completing the metoclopramide studies the same protocol (D,W or dopamine infusion) was repeated at a 2 wk interval except that domperidone (200 *g/kg) was administered instead of metoclopramide.
From the Veterans Administration Medical Center, Sepulveda. CA. Receivedforpublication June 17. 1982. Address reprint requests to James R. Sowers. M.D.. VA Medical Center, 16111 Plummer St., Sepulveda, CA 91343. 0 1982 by Grune & Stratton, Inc. 0026-0495/82/3112-0007$01.00/0. 1219
SOWERS, EGGENA AND PHILLIPS
1220
Corticosteroid Responses to Metoclopramide
80% after oxidation and chromatography. Accuracy studies using 0, 100, and 200 pg 18-OHB added to water or steroid-free plasma showed recoveries of (mean ? SEM) 15 c 0.8, 118 + 6, and 222 t 12 pg/sample, respectively. Precision was evaluated using pooled plasma samples containing high, normal, and low levels of 18-OHB and showed respective coefficients of variation of 6%, 8%, and 11%. Specificity was demonstrated by low blank values and by showing that alternative paper chromatography separation systems gave results not differing from those obtained by the present method. Prolactin (PRL) was measured by a homologous RIA using reagents provided by NIAMDD.4 The sensitivity of this assay is 1.0 ng/ml and the intra-assay CV is 5%.
The effect of metoclopramide on plasma corticosteroids was determined in the same 8 rhesus monkeys. Baseline blood samples were obtained, via an indwelling cannula, for measurement of plasma DOC, B, I&OH-DOC, 18-OHB, and cortisol. Plasma samples (I ml) for measurement of these steroids were then obtained at 5, 10, 15, 30, and 45 min after metoclopramide 200 rg/kg i.v.
Domperidone Study Approximately 6 mo after completion of previous studies the effects of an increased dose (400 &kg) of domperidone was studied in the same 8 rhesus monkeys. Ketamine in a dose of 5 mg/kg i.m. was used to produce light anesthesia and maintain the monkeys in a supine position. An indwelling cannula was placed in an arm vein for drug administration and blood sampling. An iv infusion of 5% dextrose 0.5 ml/min was initiated to maintain the cannula patent. Basal blood samples for 18-OHB, aldosterone and PRA was obtained at 30 min after onset of 5% dextrose and an i.v. bolus of domperidone (400 rg/kg) was given. Blood samples were then obtained at 10,30,45,60, and 90 min after domperidone administration.
Statistical Analysis Results are expressed as the mean +SEM. Comparisons of responses between various combinations of drugs and vehicle were evaluated using Dunnett’s multivariant analysisz4 after logarithmic transformation. Hormonal responses to individual drugs were made in comparison to zero values which were used as control values for statistical comparisons.
Analytical Methods RESULTS
Samples were colleted in prechilled heparinized tubes and centrifuged at 4°C within 30 min. All samples from the studies employing either dopamine of vehicle (D,W) infusions were run in the same assays to avoid inter-assay variability. Sodium and potassium levels were measured by atomic absorption spectrophotometry. PRA was measured by radioimmunoassay of angiotensin I after titration to pH 7.4 with phosphate buffer and incubation at 37°C in the presence of angiotensinase inhibitors.” Sensitivity of this assay is 0.2 ng/ml . h- ’ and the intra-assay CV is 5.9%. Aldosterone was extracted from plasma samples using 15-fold volumes of methylene chloride and was separated from other steroids by means by a Sephadex LH-20 column. The extracted aldosterone was measured by radioimmunoassay utilizing an antiserum provided by the NIAMDD.” Assay sensitivity is 0.4 ng/dl and intra-assay CV is 7%. Plasma B and cortisol were measured by displacement analysis techniques.” Plasma IS-OH-DOC was measured by the method of Chandler et al.” Plasma DOC was measured by a previously described RIA procedure.“*22 Plasma 18-OH-B was measured by an assay using antiserum to 18-OHB y-lactone.‘3~*‘.23 In this assay, plasma samples were extracted, lactonized, then purified by paper chromatography in the solvent system hexane-benzene-methanol-H,0 (50:50:70:30). Prior to lactonization triethylamine (0.1%) was added to solvents used to prevent ketalization of 18-OHB. Recovery through the
Table 1 shows aldosterone, cortisol, PRA and PRL responses to metoclopramide in the presence of dopamine (4 pg/kg/min) and DSW (vehicle) infusion in the 8 rhesus monkeys. There was no change in aldosterone concentration after infusion of dopamine or vehicle for 60 min. In response to metoclopramide and vehicle administration, aldosterone increased (p < 0.05) from a control value of 4.8 f 0.6 ng/dl to 16.9 * 2.6 ng/dl at 5 min. A peak response (p < 0.001) of 36 + 4.7 ng/dl occurred at 10 min, and plasma aldosterone was still elevated (15.6 + 2.4 ng/dl) at 45 min after metoclopramide administration. Aldosterone responses to metoclopramide were blunted by dopamine (4 pg/ kg/min). In the presence of dopamine, incremental aldosterone responses to metoclopramide were significantly lower (p < 0.01) than with vehicle at 5, 10, 15, 30, and 45 min. Dopamine infusion had no effect on plasma cortisol or PRA levels. Plasma corlisol (12.4 t 0.6 pg/dl), did not change significantly over the 45 min
procedure for 400 samples over the past year has ranged from 65% to Table 1. Mean (*SEMI Metoclopramide
(200 pg/kg
Plasma Aldosterone
(ng/dl),
Cortisol (pgldl).
i.v.1 Given at 0 min in 8 Rhesus Monkeys
PRA (ng/ml
.
h-‘1 and Prolactin (nglml)
with Either Vehicle N&W) or Dopamine
Responses to
(4 gglkglmin)
Infusions
30 min
45
Begun 60 min Before Metoclopramide Pretreatment
Measurement
5 min
10 min
5.1 zk 0.6
4.8 + 0.6
16.9 + 2.6’
36.0
12.4 + 0.6
12.7 + 0.7
12.8 * 0.7
PRA
4.2 +_0.5
4.2 + 0.5
Prolactin
8.1 + 1.2
7.6 + 1.1
Cortisol
Aldosterone Dopamine
0 min
12.2 + 0.5
Aldosterone 5% Glucose
- 60 mm
Cortisol PRA
4.1 f 0.5 76.4
+ 6.5.
+ 4.7*
4.8 + 0.6 96.4
+ 7.1*
8.5 + 1.5t
15min
32.1
+ 4.1*
12.5 k 0.6 5.2 + 0.7 114.5
+ 7.6”
7.8 + 1.3t
24.1
+ 3.5”
12.4 k 0.5 6.1 f 0.8” 120.5
+ 8.0.
7.0 + 1.1t
min
15.6 + 2.4. 12.2 f 0.5 5.6 + 0.7 112.1
+ 7.2*
6.7 +_0.9t
5.4 t 0.6
5.1 t 0.5
6.9 k 0.8’
12.4 k 0.6
12.6 i 0.7
12.9 i 0.7
13.0 * 0.7
12.7 k 0.7
3.9 t 0.6
3.9 + 0.6
4.0 t 0.6
4.2 f 0.7
4.4 * 0.7
4.5 + o.at
4.4 + 0.8
8.3 ? 1.3
2.1 + 0.4t
2.4 + 0.5t
2.8 t 0.6t
2.9 * 0.7t
2.8 + 0.6t
2.8 +_0.6t
12.8 + 0.7
*Significant difference from values at 0 min. tsignificant difference in response to metoclopramide with dopamine infusion compared to the response with 5% glucose.
12.5 + 0.6
DOPAMINE AND CORTICOSTEROID PRODUCTION
1221
Table 2. Mean (+SEM) Plasma Aldosterone (ng/dl), Cortisol (jrg/dl). PRA (ng/ml
- h-‘1
and Prolactin (ng/ml) Responses to
Domperidone (200 pglkg) in 8 Rhesus Monkeys with Either Vehicle (D,W) or Dopamine (4 flg/kg/min)
Infusions Begun
60 min Before Domperidone Administration Pretreatment
M&W.lJrLWWll Aldosterone
5% Glucose
Cortisol
0 m,n
15mtn
30 Ill,”
4.8 + 0.6
6.2 t 1.2
5 mill
5.8 + 1.0
10min
5.4 + 0.8
4.9 + 0.7
4.7 c 0.6 11.9 i 0.5
12.0 + 0.6
12.2 -t 0.6
12.7 c 0.6
12.4 t 0.6
12.2 + 0.5
12.1 + 0.6
PRA
4.0 2 0.9
3.7 * 1.2
3.9 + 0.7
3.9 + 0.8
4.0 * 0.9
4.0 + 1.1
Prolactin
9.0 + 1.4
8.5 + 1.2
155 + 8.2’
140 & 7.9’
Aldosterone Dopamine
- 60 min 4.8 t 0.6
120.7
-e_7.2’
142.4
r 7.6*
45 In,”
3.9 + 0.8 125.6
? 7.1.
4.6 + 0.6
4.3 + 0.6
4.5 + 0.6
4.8 + 0.6
4.9 ? 0.6
4.8 + 0.6
4.9 + 0.6
12.2 + 0.6
12.2 t 0.5
12.5 f 0.6
12.4 + 0.5
12.5 ? 0.6
12.2 f 0.6
12.3 + 0.3
PRA
3.9 * 0.7
3.9 * 0.7
4.0 _c0.8
4.0 i 0.8
3.8 & 0.7
3.9 i 0.7
4.0 + 0.8
Prolactin
8.6 + 1.0
2.3 + 0.4t
3.0 +_0.6t
3.3 2 0.7t
3.6 + 0.9t
3.4 * 0.6t
3.2 f 0.6t
Cortisol
*Significant difference from values at 0 min. tsignificant difference in response to domperidone with dopamine infusion compared to the response with 5% glucose.
sampling interval after metoclopramide administration (Table 1). PRA levels were increased (p < 0.05) at 30 min after administration of metoclopramide. Vehicle infusion was not associated with a change in PRL concentrations (Table 1). Metoclopramide increased (p < 0.001) PRL from basal levels of 7.6 _+ 1.1 ng/ml to 76.4 + 6.5 ng/ml at 5 min and to a peak concentration of 120.5 ir 8.0 ng/ml at 30 min. Dopamine (4 bg/kg/min) decreased basal PRL from 8.3 t 1.3 ng/ml to 2.1 t 0.4 ng/ml at zero time. In the presence of dopamine infusion the incremental PRL responses to metoclopramide were markedly depressed (p < 0.001) at all sampling times. Electrolytes did not change over the 45 min sampling time after metoclopramide administration (data not shown). Table 2 shows aldosterone, PRA, PRL, and cortisol responses to domperidone (1.25 mg) in the presence of dopamine (4 pg/kg/ min) and vehicle in the 8 monkeys. Dopamine infusion for 60 min depressed mean PRL concentrations from 8.5 2 1.2 ng/ml to 2.3 + 0.4 ng/ml but did not alter the concentration of the other hormones. There was no change in plasma aldosterone or cortisol following the administration of domperidone. Administration of domperidone and vehicle resulted in a rise (p < 0.001) in plasma PRL from 8.5 f 1.2 ng/ml at 0 min to 128.7 2 7.2 ng/ml at 5 min and to a maximum level of 155.0 +- 8.2 ng/ml at 15 min after domperidone administration. Administration of dopamine depressed (p < 0.01) PRL from 8.6 + 1.0 ng/ml to 2.3 * 0.4 ng/ml at 0 min and eliminated the PRL response to domperidone.
Table 3 demonstrates that there was no change in the concentrations in plasma B, DOC, 18-OH-DOC and cortisol following metoclopramide administration. Plasma 18-OH-B increased (p -c 0.01) from basal levels of 10.2 k 1.3 ng/dl to 32.6 + 4.6 ng/dl at 5 min and reached a maximum concentration of 49.6 _t 4.5 ng/dl at 15 min after metoclopramide. Table 4 demonstrates the plasma 18-OHB, aldosterone, PRA, and prolactin responses to domperidone (400 pg/kg) over a 90 min interval after administration of the drug. This dose of domperidone resulted in a similar maximum PRL response as the 200 pg/kg dose of domperidone previously observed. There was no rise in levels of plasma 18-OHB, aldosterone or PRA following domperidone administration in these 8 monkeys. DISCUSSION
This study confirms a previous reportI that metoclopramide stimulates aldosterone secretion in monkeys as well as in man. Metoclopramide-induced increases in plasma aldosterone concentration were inhibited by dopamine. Thus, metoclopramide appears to stimulate aldosterone secretion through its dopamine antagonist properties as previously proposed.8.9,” In this study we observed a rise in PRA 30 min after metoctopramide administration. Although dopamine did not affect basal levels of PRA it did abolish the PRA response to metoclopramide. This observation suggests that the effects of metoclopramide on renin release are mediated by actions on central or periph-
Table 3. Mean (+SEM) Plasma B, DOC. 18-OH-DOC, 18-OHB and Cortisol Responses to Metoclopramide (200 fig/kg
iv)
Given at 0 min in 8 Rhesus Monkeys Measurement I3
(ng/dl)
0 mm 456 & 42
5 min 467-t41
10 min
462 + 40
15mm
472 +z42
30 rnf”
466 + 42
45 in,”
457 i 42
DOC (ng/dl)
6.1 + 0.8
6.7 + 0.9
6.9 * 1.0
6.6 + 0.8
6.7 + 0.9
18OH-DDC (ng/dl)
6.9 + 1.1
6.9 + 1.2
6.6 * 1.1
6.4 + 1.0
6.5 + 0.9
6.6 + 0.7
18-OHB (ng/dlt
10.2 + 1.3
32.6 -t 4.6’
45.4 + 5.2’
49.6 t 4.5.
45.4 t 4.7’
39.2 I 4.4*
Cortisol (@g/d0
11.6 t 1.2
11.5 * 0.8
12.2 * 0.9
12.3 + 0.9
12.1 + 0.9
12.0 i
*Significant difference from values at 0 min. p < 0.05.
6.7 2 0.8
1.0
SOWERS, EGGENA AND PHILLIPS
1222
Table 4. Mean (+SEM) Plasma 18-OH8 (ngldl), Aldosterone (ng/dl) and PRA (ng/ml
* h-‘1
and Prolactin (ng/ml) Responses to
Domperidone (400 bglkg) Given at 0 min in 8 Rhesus Monkeys Measurement
0 min
10 min
60 min
90 min
9.6 2 1.2
45 min
9.5 + 1.0
9.8 f 1.1
4.9 * 0.7
5.2 + 0.9
4.7 + 0.8
4.4 r 0.6
3.8 f 0.8
4.1 f 0.8
4.3 2 0.9
30 min
18-oH8
9.6 + 1.1
10.1 * 1.3
9.7 + 1.3
Aldosterone
4.7 + 0.6
4.5 + 0.6
PRA
3.6 k 0.7
3.3 r 0.6
Prolactin
8.1 + 0.9
92.5
+ 8.1’
124.8
+ 8.4”
116.1
+ 7.5”
91.8
+ 7.0*
4.4 f 1.0 64.6
+ 6.5.
*Significant difference from values at 0 min. p < 0.001.
eral dopamine receptors in agreement with previous observations.‘&‘4 Our observation that domperidone stimulates PRL secretion in rhesus monkeys confirms previous observations in monkeysI and man.25326Further, we have demonstrated that dopamine eliminates the PRL response to domperidone. This suggests that domperidone, like metoclopramide, stimulates PRL secretion through antagonistic activity at dopamine receptors. Domperidone does not reach brain dopamine receptors, since the drug does not cross the blood-brain barrier.15.16 Since the median eminence and pituitary lie outside of the barrier domperidone probably stimulates PRL secretion by directly blocking lactotroph dopamine receptors. In contrast to the marked aldosterone response to metoclopramide, administration of domperidone did not stimulate aldosterone secretion. This is in agreement with a prior observation that domperidone does not stimulate aldosterone secretion in man.26 On the basis of biochemical criteria at least two categories of dopamine receptors can be identified.*’ One type of dopamine receptor, the D-l receptor, is linked to adenylate cyclase; renal vascular dopamine receptors are prototype cells continuing D- 1 receptors. A second type of dopamine receptor, the D-2 receptor, is not adenylate cyclase-linked; pituitary lactotrophs are prototype cells containing D-2 receptors. Results of studies to date are consistent with the presence of both subclasses of dopaminergic receptors mediating the adrenal response.y5” However, the predominant receptor mediating dopaminergic effects on aldosterone secretion is probably the D-l receptor as bromocriptine, a pituitary D-2 receptor agonist, does not inhibit the aldosterone response to metoclopramide.9~” Dopamine agonists and antagonists may have a differ-
ential quantitative effect on D-l or D-2 receptors. Relatively large amounts (micromolar concentrations) of dopamine are required to stimulate D-l receptors compared with the relatively smaller quantities (nanomolar concentrations) required for stimulation of D-2 receptors. Thus the observation that domperidone does not stimulate aldosterone secretion despite its potent PRL stimulating properties may be explained by at least two possibilities. Domperidone, like metoclopramide, may be an antagonist at both D-l and D-2 receptors, but with its predominant antagonism action being exerted at the D-2 receptor. Secondly, these results are consistent with the concept that the effects of metoclopramide on aldosterone secretion are mediated through effects on central dopaminergic receptors or nonspecifically through effects on serotonergic, noradrenergic or opiate like peptidergic neural pathways. Plasma 18-OHB secretion moves in close parallel to aldosterone following a variety of physiological maneuvers.” Our observation that metoclopramideinduced aldosterone responses are accompanied by parallel increases in plasma 18-OHB levels suggests that metoclopramide affects aldosterone biosynthesis rather than simply increasing the release of this corticosteroid. That cortisol levels did not change after metoclopramide and domperidone is an agreement with previous observations’-” and suggests that dopamine does not regulate glucocorticoid biosynthesis. ACKNOWLEDGMENT The authors wish to thank Pamela Joyce for preparation of this manuscript, Dr. Victor I. Martin of Endocrine Sciences, Tarzana, CA for performing the 18-OHB assays, and Dr. Robert M. Carey for generously supplying us with domperidone.
REFERENCES 1. Peringer
EP, Jenner P, Donaldson IM, et al: Metoclopramide receptor blockade. Neuropharmacology 15:463469,
and dopamine 1976 2. McCallum RW, Sowers JR, Hershman JM, et al: Metoclopramide stimulates prolactin secretion in man. J Clin Endocrinol Metab 42:1148-l 152,1976 3. Sowers JR, McCallum RW, Hershman JM, et al: Comparison of Metoclopramide with other dynamic tests of prolactin secretion. J Clin Endocrinol Metab 43:679-681, 1976 4. Sowers JR, Carlson HE, Brautbar N, et al: Effects of dexa-
methasone on prolactin and TSH response to TRH and metoclopramide in man. J Clin Endocrinol Metab 44:327-331, 1977 5. Carlson HE, Briggs JE, McCallum RW: Stimulation of prolactin secretion by metoclopramide in the rat. Prcc Sot Exp Biol Med 154:475-478,1977 6. Norbiato G, Bevilacqua M, Raggi U, et al: Effect of metoclopramide, a dopamine inhibitor, on renin and aldosterone in ideopathic edema: possible therapeutic approach with levodopa and carbidopa. J Clin Endocrinol Metab 48:37-41, 1979 7. Carey RM, Thorner MO, Ortt EM: Effect of metoclopramide
1223
DOPAMINE AND CORTICOSTEROID PRODUCTION
and bromocriptine on the renin-angiotensin-aldosterone system in man: dopaminergic control of aldosterone. J Clin Invest 63:727-735, 1979 8. Noth RH, McCallum RW, Contino C, et al: Tonic dopaminergic suppression of plasma aldosterone. J Clin Endocrinol Metab 5 1:6&69, 1980 9. Carey RM, Thorner MO, Ortt EM: Dopaminergic inhibition of metoclopramideinduced aldosterone secretion in man. J Clin Invest 66: 1CL18, 1980 10. Sowers JR. Brickman AS, Asp N, et al: Altered dopaminergic modulation of prolactin and aldosterone secretion in pseudohypoparathyroidism. J Clin Endocrinol Metabl 52:914-918, 1981 1 I. Sowers JR, Brickman AS, Sowers DK, et al: Dopaminergic modulation of aldosterone secretion in man is unaffected by glucocroticoids and angiotensin blockage. J Clin Endocrinol Metab 52:1078-1984.1981 12. Brown RD, Wisgerhof M, Jiang N, et al: Effect of metoclopramide on the secretion and metabolism of aldosterone in man. J Clin Endocrinol Metab 52:1014-1018, 198 1 13. Sowers JR, Sharp B, Levin ER, et al: Metoclopramide, a dopamine antagonist, stimulates aldosterone secretion in Rhesus Monkeys but not in dogs or rabbits. Life Science 29:2171-2175, 1981 14. Sowers JR, Tuck ML, Golub MS, et al: Dopaminergic control of aldosterone secretion is independent of alterations in renin secretion. Endocrinology 137:937-94 1, 1980 15. Baudry M, Martres MP, Schwartz JC: ‘H-Domperidone: a selective ligand for dopamine receptors. Nauyn-Schmiedeberg’s Arch Pharmacol 308:23 l-237, 1979 16. Laduron PM, Leysen JE: Dompcridone, a specific in vitro dopamine antagonist, devoid of in vivo central dopaminergic activity. Biochem Pharmacol28:2161-2165, 1979 17. Eggena P, Barrett JD, Sambhi MP, et al: The validity of comparing measurements of angiotensin I generated in human plasma by radioimmunoassay and bioassay. J Clin Endocrinol Metab 39:865-870. 1974
18. Mayes DM, Furuyama S, Kern DC, et al: A radioimmunoassay for plasma aldosterone. J Clin Endocrinol Metab 30:682-685, 1970 19. Underwood RH, Williams GH: The simultaneous measurement of aldosterone, cortisol and corticosterone in human peripheral plasma by displacement analysis. J Lab Chn Med 79:848-862, 1972 20. Chandler DW, Tuck ML, Mayes DM: The measurement of 18-hydroxy- 11-deoxycorticosterone in human plasma by radioimmunoassay. Steroids 27:235-246, 1976 21. Tuck ML, Sowers JR, Asp ND, et al: Mineralocorticoid response to low dose adrenocorticotropin infusion. J Clin Endocrinol Metab 52:440-446, 1981 22. Williams GH. Underwood RH: Mineralocorticoids: aldosterone and deoxycorticosterone. In Methods of Hormone Radioimmunoassay, Academic Press, New York, p 37 1, 1974 23. Martin VI, Edwards CRW, Biglieri EG. et al: The development and application of a radioimmunoassay for 18-hydroxycorticosterone. Steroids 26591-598, 1975 24. Dunnet CW: A multiple comparison procedure for comparing several treatments with a control. Am Stat Assoc J 50: 1096-l 120. 1955 25. Delitala G, Devilla L, Lotti G: Domperidone, an extracerebra1 inhibitor of dopamine receptors, stimulates thyrotropin and prolactin release in man. J Clin Endocrinol Metab 50:1127-l 130, 1980 26. Sowers JR, Sharp B, McCallum R: Etfect of domperidone, an extracerebral inhibitor of dopamine receptors, on thyrotropin, prolactin, renin, aldosterone and 18-hydroxycorticosterone secretion in man. J Clin Endocrinol Metabl 54:673-676, 1982 27. Kebanian JW, Clane DB: Multiple Nature (London) 277:93-96, 1979
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for dopamine. a review. J
R. Sowers,
Peter
Eggena
and
Dennis
Phillips
This study was designed to investigate dopaminergic mechanisms in the control of corticosteroid secretion. Eight rhesus monkeys received metoclopramide (206 fig/kg) or domperidone (200 and 400 bglkg) with 5% dextrose (vehicle), or with dopamine (4 figlkglmin) infusions begun 60 min before administration of the dopamine antagonist. Metoclopramide, in the presence of vehicle, increased plasma aldosterone concentrations from 4.8 + 0.6 ng/dl to a maximum of 36 r 4.7 ng/dl and PRL concentrations from 7.6 + 1.1 ng/ml to a maximum of 120.5 f 8.0 ng/ml. Administration of metoclopramide resulted in a rise in plasma 18-hydroxycorticosterone from 10.2 ? 1.3 ng/dl to a maximum concentration of 49.6 + 4.5 ng/dl. Plasma concentrations of electrolytes, PRA, plasma cortisol, 11-deoxycorticosterone, corticosterone, 18-hydroxy11-deoxycorticosterone, were not altered by metoclopramide. Domperidone, in both doses, markedly increased plasma PRL concentrations but had no effect on plasma 18-OHB or aldosterone concentrations. Dopamine infusion inhibited the aldosterone response to metoclopramide and the prolactin response to metoclopramide and domperidone. The results of this investigation demonstrate that aldosterone responses to metoclopramide and prolactin responses to metoclopramide and domperidone, are mediated by their antagonist activity at dopamine receptors.
M
ETOCLOPRAMIDE, a dopamine antagonist which readily crosses the blood-brain barrier’ stimulates prolactin secretion in manz4 and rats.’ Recent studies have demonstrated that metoclopramide increases plasma aldosterone levels in rnan6-12 monkeys,‘-’ and ratsI independent of changes in factors known to affect aldosterone secretion. Since the increase of aldosterone following metoclopramide administration is blocked by dopamine,‘-” the aldosterone response to metoclopramide appears to be mediated by its antagonist activity at dopamine receptors. On the basis of biochemical criteria at least two categories of dopamine receptors have been demonstrated.14 One dopamine receptor, the D-l receptor, is linked to adenylcyclase; prototypes of D-l receptors are renal vascular dopamine receptors. A second type of dopamine receptor, the D-2 receptor, is not adenylate cyclase-linked; pituitary lactotrophs are prototype cells containing D-2 receptors. Results of studies to date are consistent with both subclasses of dopamine receptors mediating the adrenal aldosterone response to metoclopramide.9~‘0 Although aldosterone responses to dopamine antagonism with metoclopramide have been demonstrated to occur independent of known factors affecting aldosterone secretion 6-‘4it is not known whether metoclopramide stimulates aldosterone secretion directly or via effects on the central nervous system. To further investigate the mechanism of dopaminergic modulation of aldosterone secretion we have measured mineralcorticoid response to domperidone, a dopamine receptor-blocking agent which does not cross the blood brain barrier15,16 in rhesus monkeys which have previously been demonstrated to have aldosterone responses to metoclopramide.‘3 To determine if metoclopramide stimulates secretion of any of the precursors in the aldosterone biosynethetic pathway we Merabolism,
Vol. 3 1, No. 12 (December), 1982
have measured the effect of metoclopramide on 18-hydroxydeoxycorticosterone (18-OH-DOC), cortisol, 1I-deoxycorticosterone (DOC), corticosterone (B), 1Shydroxycorticosterone (1%OHB) and aldosterone in rhesus monkeys. MATERIALS
AND
METHODS
Studies were performed on 8 healthy mature male rhesus monkeys (Macaca mulatta), weighing 8.6 -10.3 kg, who were individually in rooms with regulated temperature (23-2X?) and light (lights on from 0600-1800 hr daily). They were fed Purina Monkey Chow twice daily and given fresh fruit supplements 5 times a week. Tap water was provided ad libitum. All studies were conducted in the morning (OSO&lOOO hr).
Metoclopramide/Domperidone/Dopamine
Studies
Ketamine in a dose of 5 mg/kg i.m. was used to produce light anesthesia and maintain the monkeys in a supine position. An indwelling cannula was placed in an arm vein for infusion, and a heparin lock was placed in a vein in the contralateral arm for blood sampling. After basal blood samples for measurement of electrolytes, aldosterone, prolactin, PRA and cortisol were obtained, an i.v. infusion of 5% dextrose (DrW) at 1 ml/mm was begun with an infusion pump and continued for 105 min. Blood sampling was repeated at 60 min after onset of D,W infusion and an i.v. bolus of metoclopramide (200 pg/kg) was given. Blood samples were then obtained at 5, IO, 15, 30, and 45 min after metoclopramide administration. Two weeks later an identical protocol was carried out except that instead of D,W dopamine hydrochloride (4 rg/kg/min) was infused for 105 min. Two weeks after completing the metoclopramide studies the same protocol (D,W or dopamine infusion) was repeated at a 2 wk interval except that domperidone (200 *g/kg) was administered instead of metoclopramide.
From the Veterans Administration Medical Center, Sepulveda. CA. Receivedforpublication June 17. 1982. Address reprint requests to James R. Sowers. M.D.. VA Medical Center, 16111 Plummer St., Sepulveda, CA 91343. 0 1982 by Grune & Stratton, Inc. 0026-0495/82/3112-0007$01.00/0. 1219
SOWERS, EGGENA AND PHILLIPS
1220
Corticosteroid Responses to Metoclopramide
80% after oxidation and chromatography. Accuracy studies using 0, 100, and 200 pg 18-OHB added to water or steroid-free plasma showed recoveries of (mean ? SEM) 15 c 0.8, 118 + 6, and 222 t 12 pg/sample, respectively. Precision was evaluated using pooled plasma samples containing high, normal, and low levels of 18-OHB and showed respective coefficients of variation of 6%, 8%, and 11%. Specificity was demonstrated by low blank values and by showing that alternative paper chromatography separation systems gave results not differing from those obtained by the present method. Prolactin (PRL) was measured by a homologous RIA using reagents provided by NIAMDD.4 The sensitivity of this assay is 1.0 ng/ml and the intra-assay CV is 5%.
The effect of metoclopramide on plasma corticosteroids was determined in the same 8 rhesus monkeys. Baseline blood samples were obtained, via an indwelling cannula, for measurement of plasma DOC, B, I&OH-DOC, 18-OHB, and cortisol. Plasma samples (I ml) for measurement of these steroids were then obtained at 5, 10, 15, 30, and 45 min after metoclopramide 200 rg/kg i.v.
Domperidone Study Approximately 6 mo after completion of previous studies the effects of an increased dose (400 &kg) of domperidone was studied in the same 8 rhesus monkeys. Ketamine in a dose of 5 mg/kg i.m. was used to produce light anesthesia and maintain the monkeys in a supine position. An indwelling cannula was placed in an arm vein for drug administration and blood sampling. An iv infusion of 5% dextrose 0.5 ml/min was initiated to maintain the cannula patent. Basal blood samples for 18-OHB, aldosterone and PRA was obtained at 30 min after onset of 5% dextrose and an i.v. bolus of domperidone (400 rg/kg) was given. Blood samples were then obtained at 10,30,45,60, and 90 min after domperidone administration.
Statistical Analysis Results are expressed as the mean +SEM. Comparisons of responses between various combinations of drugs and vehicle were evaluated using Dunnett’s multivariant analysisz4 after logarithmic transformation. Hormonal responses to individual drugs were made in comparison to zero values which were used as control values for statistical comparisons.
Analytical Methods RESULTS
Samples were colleted in prechilled heparinized tubes and centrifuged at 4°C within 30 min. All samples from the studies employing either dopamine of vehicle (D,W) infusions were run in the same assays to avoid inter-assay variability. Sodium and potassium levels were measured by atomic absorption spectrophotometry. PRA was measured by radioimmunoassay of angiotensin I after titration to pH 7.4 with phosphate buffer and incubation at 37°C in the presence of angiotensinase inhibitors.” Sensitivity of this assay is 0.2 ng/ml . h- ’ and the intra-assay CV is 5.9%. Aldosterone was extracted from plasma samples using 15-fold volumes of methylene chloride and was separated from other steroids by means by a Sephadex LH-20 column. The extracted aldosterone was measured by radioimmunoassay utilizing an antiserum provided by the NIAMDD.” Assay sensitivity is 0.4 ng/dl and intra-assay CV is 7%. Plasma B and cortisol were measured by displacement analysis techniques.” Plasma IS-OH-DOC was measured by the method of Chandler et al.” Plasma DOC was measured by a previously described RIA procedure.“*22 Plasma 18-OH-B was measured by an assay using antiserum to 18-OHB y-lactone.‘3~*‘.23 In this assay, plasma samples were extracted, lactonized, then purified by paper chromatography in the solvent system hexane-benzene-methanol-H,0 (50:50:70:30). Prior to lactonization triethylamine (0.1%) was added to solvents used to prevent ketalization of 18-OHB. Recovery through the
Table 1 shows aldosterone, cortisol, PRA and PRL responses to metoclopramide in the presence of dopamine (4 pg/kg/min) and DSW (vehicle) infusion in the 8 rhesus monkeys. There was no change in aldosterone concentration after infusion of dopamine or vehicle for 60 min. In response to metoclopramide and vehicle administration, aldosterone increased (p < 0.05) from a control value of 4.8 f 0.6 ng/dl to 16.9 * 2.6 ng/dl at 5 min. A peak response (p < 0.001) of 36 + 4.7 ng/dl occurred at 10 min, and plasma aldosterone was still elevated (15.6 + 2.4 ng/dl) at 45 min after metoclopramide administration. Aldosterone responses to metoclopramide were blunted by dopamine (4 pg/ kg/min). In the presence of dopamine, incremental aldosterone responses to metoclopramide were significantly lower (p < 0.01) than with vehicle at 5, 10, 15, 30, and 45 min. Dopamine infusion had no effect on plasma cortisol or PRA levels. Plasma corlisol (12.4 t 0.6 pg/dl), did not change significantly over the 45 min
procedure for 400 samples over the past year has ranged from 65% to Table 1. Mean (*SEMI Metoclopramide
(200 pg/kg
Plasma Aldosterone
(ng/dl),
Cortisol (pgldl).
i.v.1 Given at 0 min in 8 Rhesus Monkeys
PRA (ng/ml
.
h-‘1 and Prolactin (nglml)
with Either Vehicle N&W) or Dopamine
Responses to
(4 gglkglmin)
Infusions
30 min
45
Begun 60 min Before Metoclopramide Pretreatment
Measurement
5 min
10 min
5.1 zk 0.6
4.8 + 0.6
16.9 + 2.6’
36.0
12.4 + 0.6
12.7 + 0.7
12.8 * 0.7
PRA
4.2 +_0.5
4.2 + 0.5
Prolactin
8.1 + 1.2
7.6 + 1.1
Cortisol
Aldosterone Dopamine
0 min
12.2 + 0.5
Aldosterone 5% Glucose
- 60 mm
Cortisol PRA
4.1 f 0.5 76.4
+ 6.5.
+ 4.7*
4.8 + 0.6 96.4
+ 7.1*
8.5 + 1.5t
15min
32.1
+ 4.1*
12.5 k 0.6 5.2 + 0.7 114.5
+ 7.6”
7.8 + 1.3t
24.1
+ 3.5”
12.4 k 0.5 6.1 f 0.8” 120.5
+ 8.0.
7.0 + 1.1t
min
15.6 + 2.4. 12.2 f 0.5 5.6 + 0.7 112.1
+ 7.2*
6.7 +_0.9t
5.4 t 0.6
5.1 t 0.5
6.9 k 0.8’
12.4 k 0.6
12.6 i 0.7
12.9 i 0.7
13.0 * 0.7
12.7 k 0.7
3.9 t 0.6
3.9 + 0.6
4.0 t 0.6
4.2 f 0.7
4.4 * 0.7
4.5 + o.at
4.4 + 0.8
8.3 ? 1.3
2.1 + 0.4t
2.4 + 0.5t
2.8 t 0.6t
2.9 * 0.7t
2.8 + 0.6t
2.8 +_0.6t
12.8 + 0.7
*Significant difference from values at 0 min. tsignificant difference in response to metoclopramide with dopamine infusion compared to the response with 5% glucose.
12.5 + 0.6
DOPAMINE AND CORTICOSTEROID PRODUCTION
1221
Table 2. Mean (+SEM) Plasma Aldosterone (ng/dl), Cortisol (jrg/dl). PRA (ng/ml
- h-‘1
and Prolactin (ng/ml) Responses to
Domperidone (200 pglkg) in 8 Rhesus Monkeys with Either Vehicle (D,W) or Dopamine (4 flg/kg/min)
Infusions Begun
60 min Before Domperidone Administration Pretreatment
M&W.lJrLWWll Aldosterone
5% Glucose
Cortisol
0 m,n
15mtn
30 Ill,”
4.8 + 0.6
6.2 t 1.2
5 mill
5.8 + 1.0
10min
5.4 + 0.8
4.9 + 0.7
4.7 c 0.6 11.9 i 0.5
12.0 + 0.6
12.2 -t 0.6
12.7 c 0.6
12.4 t 0.6
12.2 + 0.5
12.1 + 0.6
PRA
4.0 2 0.9
3.7 * 1.2
3.9 + 0.7
3.9 + 0.8
4.0 * 0.9
4.0 + 1.1
Prolactin
9.0 + 1.4
8.5 + 1.2
155 + 8.2’
140 & 7.9’
Aldosterone Dopamine
- 60 min 4.8 t 0.6
120.7
-e_7.2’
142.4
r 7.6*
45 In,”
3.9 + 0.8 125.6
? 7.1.
4.6 + 0.6
4.3 + 0.6
4.5 + 0.6
4.8 + 0.6
4.9 ? 0.6
4.8 + 0.6
4.9 + 0.6
12.2 + 0.6
12.2 t 0.5
12.5 f 0.6
12.4 + 0.5
12.5 ? 0.6
12.2 f 0.6
12.3 + 0.3
PRA
3.9 * 0.7
3.9 * 0.7
4.0 _c0.8
4.0 i 0.8
3.8 & 0.7
3.9 i 0.7
4.0 + 0.8
Prolactin
8.6 + 1.0
2.3 + 0.4t
3.0 +_0.6t
3.3 2 0.7t
3.6 + 0.9t
3.4 * 0.6t
3.2 f 0.6t
Cortisol
*Significant difference from values at 0 min. tsignificant difference in response to domperidone with dopamine infusion compared to the response with 5% glucose.
sampling interval after metoclopramide administration (Table 1). PRA levels were increased (p < 0.05) at 30 min after administration of metoclopramide. Vehicle infusion was not associated with a change in PRL concentrations (Table 1). Metoclopramide increased (p < 0.001) PRL from basal levels of 7.6 _+ 1.1 ng/ml to 76.4 + 6.5 ng/ml at 5 min and to a peak concentration of 120.5 ir 8.0 ng/ml at 30 min. Dopamine (4 bg/kg/min) decreased basal PRL from 8.3 t 1.3 ng/ml to 2.1 t 0.4 ng/ml at zero time. In the presence of dopamine infusion the incremental PRL responses to metoclopramide were markedly depressed (p < 0.001) at all sampling times. Electrolytes did not change over the 45 min sampling time after metoclopramide administration (data not shown). Table 2 shows aldosterone, PRA, PRL, and cortisol responses to domperidone (1.25 mg) in the presence of dopamine (4 pg/kg/ min) and vehicle in the 8 monkeys. Dopamine infusion for 60 min depressed mean PRL concentrations from 8.5 2 1.2 ng/ml to 2.3 + 0.4 ng/ml but did not alter the concentration of the other hormones. There was no change in plasma aldosterone or cortisol following the administration of domperidone. Administration of domperidone and vehicle resulted in a rise (p < 0.001) in plasma PRL from 8.5 f 1.2 ng/ml at 0 min to 128.7 2 7.2 ng/ml at 5 min and to a maximum level of 155.0 +- 8.2 ng/ml at 15 min after domperidone administration. Administration of dopamine depressed (p < 0.01) PRL from 8.6 + 1.0 ng/ml to 2.3 * 0.4 ng/ml at 0 min and eliminated the PRL response to domperidone.
Table 3 demonstrates that there was no change in the concentrations in plasma B, DOC, 18-OH-DOC and cortisol following metoclopramide administration. Plasma 18-OH-B increased (p -c 0.01) from basal levels of 10.2 k 1.3 ng/dl to 32.6 + 4.6 ng/dl at 5 min and reached a maximum concentration of 49.6 _t 4.5 ng/dl at 15 min after metoclopramide. Table 4 demonstrates the plasma 18-OHB, aldosterone, PRA, and prolactin responses to domperidone (400 pg/kg) over a 90 min interval after administration of the drug. This dose of domperidone resulted in a similar maximum PRL response as the 200 pg/kg dose of domperidone previously observed. There was no rise in levels of plasma 18-OHB, aldosterone or PRA following domperidone administration in these 8 monkeys. DISCUSSION
This study confirms a previous reportI that metoclopramide stimulates aldosterone secretion in monkeys as well as in man. Metoclopramide-induced increases in plasma aldosterone concentration were inhibited by dopamine. Thus, metoclopramide appears to stimulate aldosterone secretion through its dopamine antagonist properties as previously proposed.8.9,” In this study we observed a rise in PRA 30 min after metoctopramide administration. Although dopamine did not affect basal levels of PRA it did abolish the PRA response to metoclopramide. This observation suggests that the effects of metoclopramide on renin release are mediated by actions on central or periph-
Table 3. Mean (+SEM) Plasma B, DOC. 18-OH-DOC, 18-OHB and Cortisol Responses to Metoclopramide (200 fig/kg
iv)
Given at 0 min in 8 Rhesus Monkeys Measurement I3
(ng/dl)
0 mm 456 & 42
5 min 467-t41
10 min
462 + 40
15mm
472 +z42
30 rnf”
466 + 42
45 in,”
457 i 42
DOC (ng/dl)
6.1 + 0.8
6.7 + 0.9
6.9 * 1.0
6.6 + 0.8
6.7 + 0.9
18OH-DDC (ng/dl)
6.9 + 1.1
6.9 + 1.2
6.6 * 1.1
6.4 + 1.0
6.5 + 0.9
6.6 + 0.7
18-OHB (ng/dlt
10.2 + 1.3
32.6 -t 4.6’
45.4 + 5.2’
49.6 t 4.5.
45.4 t 4.7’
39.2 I 4.4*
Cortisol (@g/d0
11.6 t 1.2
11.5 * 0.8
12.2 * 0.9
12.3 + 0.9
12.1 + 0.9
12.0 i
*Significant difference from values at 0 min. p < 0.05.
6.7 2 0.8
1.0
SOWERS, EGGENA AND PHILLIPS
1222
Table 4. Mean (+SEM) Plasma 18-OH8 (ngldl), Aldosterone (ng/dl) and PRA (ng/ml
* h-‘1
and Prolactin (ng/ml) Responses to
Domperidone (400 bglkg) Given at 0 min in 8 Rhesus Monkeys Measurement
0 min
10 min
60 min
90 min
9.6 2 1.2
45 min
9.5 + 1.0
9.8 f 1.1
4.9 * 0.7
5.2 + 0.9
4.7 + 0.8
4.4 r 0.6
3.8 f 0.8
4.1 f 0.8
4.3 2 0.9
30 min
18-oH8
9.6 + 1.1
10.1 * 1.3
9.7 + 1.3
Aldosterone
4.7 + 0.6
4.5 + 0.6
PRA
3.6 k 0.7
3.3 r 0.6
Prolactin
8.1 + 0.9
92.5
+ 8.1’
124.8
+ 8.4”
116.1
+ 7.5”
91.8
+ 7.0*
4.4 f 1.0 64.6
+ 6.5.
*Significant difference from values at 0 min. p < 0.001.
eral dopamine receptors in agreement with previous observations.‘&‘4 Our observation that domperidone stimulates PRL secretion in rhesus monkeys confirms previous observations in monkeysI and man.25326Further, we have demonstrated that dopamine eliminates the PRL response to domperidone. This suggests that domperidone, like metoclopramide, stimulates PRL secretion through antagonistic activity at dopamine receptors. Domperidone does not reach brain dopamine receptors, since the drug does not cross the blood-brain barrier.15.16 Since the median eminence and pituitary lie outside of the barrier domperidone probably stimulates PRL secretion by directly blocking lactotroph dopamine receptors. In contrast to the marked aldosterone response to metoclopramide, administration of domperidone did not stimulate aldosterone secretion. This is in agreement with a prior observation that domperidone does not stimulate aldosterone secretion in man.26 On the basis of biochemical criteria at least two categories of dopamine receptors can be identified.*’ One type of dopamine receptor, the D-l receptor, is linked to adenylate cyclase; renal vascular dopamine receptors are prototype cells continuing D- 1 receptors. A second type of dopamine receptor, the D-2 receptor, is not adenylate cyclase-linked; pituitary lactotrophs are prototype cells containing D-2 receptors. Results of studies to date are consistent with the presence of both subclasses of dopaminergic receptors mediating the adrenal response.y5” However, the predominant receptor mediating dopaminergic effects on aldosterone secretion is probably the D-l receptor as bromocriptine, a pituitary D-2 receptor agonist, does not inhibit the aldosterone response to metoclopramide.9~” Dopamine agonists and antagonists may have a differ-
ential quantitative effect on D-l or D-2 receptors. Relatively large amounts (micromolar concentrations) of dopamine are required to stimulate D-l receptors compared with the relatively smaller quantities (nanomolar concentrations) required for stimulation of D-2 receptors. Thus the observation that domperidone does not stimulate aldosterone secretion despite its potent PRL stimulating properties may be explained by at least two possibilities. Domperidone, like metoclopramide, may be an antagonist at both D-l and D-2 receptors, but with its predominant antagonism action being exerted at the D-2 receptor. Secondly, these results are consistent with the concept that the effects of metoclopramide on aldosterone secretion are mediated through effects on central dopaminergic receptors or nonspecifically through effects on serotonergic, noradrenergic or opiate like peptidergic neural pathways. Plasma 18-OHB secretion moves in close parallel to aldosterone following a variety of physiological maneuvers.” Our observation that metoclopramideinduced aldosterone responses are accompanied by parallel increases in plasma 18-OHB levels suggests that metoclopramide affects aldosterone biosynthesis rather than simply increasing the release of this corticosteroid. That cortisol levels did not change after metoclopramide and domperidone is an agreement with previous observations’-” and suggests that dopamine does not regulate glucocorticoid biosynthesis. ACKNOWLEDGMENT The authors wish to thank Pamela Joyce for preparation of this manuscript, Dr. Victor I. Martin of Endocrine Sciences, Tarzana, CA for performing the 18-OHB assays, and Dr. Robert M. Carey for generously supplying us with domperidone.
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DOPAMINE AND CORTICOSTEROID PRODUCTION
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