Exp. Clin. Cliii. Endocrino!. Vol. 95, No. 3, 1990, pp. 331-338
J. A. Barth, Leipzig
Institute of Endocrinology Endocrinology and and Gerontology Gerontology (Director: (Director:Ass. Ass.Prof. Prof.Dr. Dr.Sc. Sc.Med. Med.D. D.Koev), Koev), Medical Academy, Sofia/Bulgaria
Serum Aldosterone Response to Metoclopramide in Normal Subjects and Acromegalic Patients
With 3 Figures
Summary. The acute effects of metoclopramide on aldosterone and prolactin levels were studied in 11 normal subjects, 8 normotensive and 8 hypertensive acromegalics. Metoclopramide (10 mg i.v.) induced a similar serum aldosterone increase in normal subjects and normotensive acromegalics. Hypertensive acromegalics showed elevated basal serum aldosterone level and blunted aldosterone rponse totometoclopramide. response metoclopramide.The Theprolactin prolactinresponse responsetetemetoclopramide metoclopramidewas was blunted blunted in in acromegalics
in comparison with normal subjects but the difference was statistically significant only in hypertensive tensive patients. patients. The The blunted blunted aldosterone aldosterone and and prolactin prolactin responses responses to to metoclopramide metoclopramide in in hypertensive hypertensive acromegalics suggest that there is a dopamine deficiency at central and adrenal level in these patients.
Key words: Aldosterone - Prolactin - Metoclopramide - Acromegaly
Introduction Evidence suggests that aldosterone secretion is under tonic dopaminergic inhibition (Sowers, 1984). The acute administration of metoclopramide, a non-selective dopamine receptor antagonist, stimulates aldosterone secretion in normal man Norbiato et al., 1977). However, little is known about the mechanism of this inhibitory action of dopa.. dopamine and about the dopaminergic pathways involved. Previous reports indicate that the central dopamine function is abnormal in most patients with acromegaly (Spitz et al., 1980). On the other hand, a number of studies confirm a high frequency of alteration in the renin-angiotensin-aldosterone system in acromegalic patients (Mantero et al., 1979; Karlberg and Ottosson, 1982). In the present study, we examined the aldosterone and prolactin responses to metoclopramide in normal subjects and acromegalic patients in order to clarify a possible alteration of the dopaminergic control in this disease. Material and Methods Sixteen patients with active active acromegaly acromegaly were were studied. studied.Their Theirclinical clinicaland andbiochemical biochemicaldata dataare are summarized in Table 1. The diagnosis of acromegaly was based on clinical features, elevated basal of 75 75 gg glucose, glucose, serum growth hormone (Gil) levels, lack of GH suppression after after oral oral administration administrationof Gil suppression sella turcica radiograms and computed tomography. The diagnosis was confirmed in operated patients
Downloaded by: University of Pittsburgh. Copyrighted material.
S. ZACTL&RIEVA, I.I. STOEVA, STOEVA, P. P. MATROZOV MATROZOVand andK. K.ANDONOVA AND0NOVA
Exp. Olin. Clin. Endocrinol. 95 (1990) 3
332
by the histological examination of the resected adenoma. Eight of the acromegalics (6 (Gfemales femalesand and 2 males, mean age 32.4 ± 3.2 years) were normotensive and 8 of them (6 females and 2 males, mean age 45.2 ± 5.2 years) were hypertensive. Arterial hypertension was defined by repeated blood pressure measurements measurements >> 140/90 140/90 mmilg mmilg One One patient patient had had insulin-dependent insulin-dependent diabetes diabetes mellitus. mellitus. None None of of the the patients showed clinical clinical or or laboratory laboratory evidence evidence of of congestive congestiveheart heartfailure, failure,renal renalfailure, failure,ororliver liverdidiseases.
The group of normal subjects consisted of 11 healthy volunteers (5 females and 6 males, mean age 33.2 ± 2.4 years). Female subjects were studied during the follicular phase of their menstrual cycle.
Patients Patients
Age (years)
Previous therapy
Basal Gil
Basal PRL
(mIUfl) (mIU!l)
(mIUfml)
43 36 30 30 32
R+S
26 2G
27 '27 39 26
-
22.7 39 so 50 42.5 80 80 70.7 0.7 73.7
3 4
F F F F
43 31 44
R S 5 S 5
S 5
M
55
6
60
7
F F
8
M
Sex
Normotensive acromegalics 11
F
2 3
M
4
M
5 6 7
F 1? F F
8
F
F
S sS S S
271 65 470 912 912
1186 525 5'25 378 65 65
Hypertensive acromegalics 11 2
52
45 32
-
46.3 32.4 80 20 20 25 5'2 52
5 S
40.2 69.5
59 214 65 904 904 65 219 '219
2850 440
surgery S - Surgery R - Radiotherapy All subjects gave informed consent to participation in the study. The investigations were performed in accordance with the principles of the Declaration of Helsinki. Previous antihypertensive therapy was discontinued for 10 days in hypertensive acromegalies. acromegalics. All other patients were without medication during the study. All All tests tests were were performed performed in in the the morning morning after after an an overnight overnight fast. fast. An An i.i. y. y. indwelling indwelling catheter catheter was was inserted into a forearm vein for blood withdrawal and administration of metoclopramide. After 1 hour hour of of supine supine position position patients patients and and control control subjects subjects received received 10 10 mg mg of of metoclopramide metoclopramide as as an an i.i. y. y. bolus between 8.30-9.00 h. Blood samples were drawn at 15, 15,0,0,15, 15,30, 30,60, 60,90, 90,120 120min minfor formeasuremeasurement of aldosterone, PRL and Gil. Blood was allowed to clot in glass tubes and the serum was separated by centrifugation at the end of the test. Serum samples were stored at - 20°C 20°Cprior prior to to assay. Serum aldosterone was determined by radioimmunoassay (RIA) using commercial kits (Biodata,
Milan, Italy). Assay sensitivity for the method was 15 pg/ml, pgfml, and the intraassay variability was ess than 10%. Serum PRL was estimated by RIA with a commercial kit supplied by National Re-
Downloaded by: University of Pittsburgh. Copyrighted material.
Table 1 Clinical and biochemical data in patients with acromegaly
333
S. ZACHABIEVA ZACHARIEVA et aL, al., Aldosterone Response Response to to Metoclopramide Metoclopramidein inAcromegalics Acromegalics
search Institute for Radiobiology and Radiohygiene (Hungary). The sensitivity of the method was 65 mILJ/ml, mIlJ/ml, and andthe theintraassay intraassayvariability variabilitywas wasless lessthan than10%. 10%.GH Gil serum serum levels levels were were measured measured by by RIA with a commercial kit supplied by the Institute of Atomic Energy, Poland. The sensitivity of the method was 1.0 mIUfl and the intraassay coefficient of variation was less than 10%. All serum samples from each patient were run in the same assay to minimize the influence of interassay variations.
The results are presented as mean ± SEM. Student's t-tests (paired and unpaired, as appropriate) were used for statistical evaluation of the results. A p-value of 0.05 or less was considered statistically significant.
Results
J
J
slowly and at 120 min were significantly higher than the basal values (959.3 + 315.1 mIU/ml) vs 98.3 ± 29.9 mIU/ml, p < 0.001) (Figs. 2 and 3). 40
Mefocloprcmide lOmgAv. Mefoclopramide
-
I
30
A
\\
./
2W
I
LU
I-
U)
o o-J
/
I
/
10'
-15
0
I
15 15
30
60
90
120
Time(min)
responses to to metoclopr&mide metoclopramide (10 (10 mg mg i.v.) i.v.) in 11 normal subjects (), Fig. 1 Serum aldosterone responses
8 normotensive normotensive acromegalics acromegalics(..(.-._.)--)and and8 8hypertensive hypertensiveacromegalics acromegalics (-( -).).Mean Mean ± SEM; xX pp
J. A. Barth, Leipzig
Institute of Endocrinology Endocrinology and and Gerontology Gerontology (Director: (Director:Ass. Ass.Prof. Prof.Dr. Dr.Sc. Sc.Med. Med.D. D.Koev), Koev), Medical Academy, Sofia/Bulgaria
Serum Aldosterone Response to Metoclopramide in Normal Subjects and Acromegalic Patients
With 3 Figures
Summary. The acute effects of metoclopramide on aldosterone and prolactin levels were studied in 11 normal subjects, 8 normotensive and 8 hypertensive acromegalics. Metoclopramide (10 mg i.v.) induced a similar serum aldosterone increase in normal subjects and normotensive acromegalics. Hypertensive acromegalics showed elevated basal serum aldosterone level and blunted aldosterone rponse totometoclopramide. response metoclopramide.The Theprolactin prolactinresponse responsetetemetoclopramide metoclopramidewas was blunted blunted in in acromegalics
in comparison with normal subjects but the difference was statistically significant only in hypertensive tensive patients. patients. The The blunted blunted aldosterone aldosterone and and prolactin prolactin responses responses to to metoclopramide metoclopramide in in hypertensive hypertensive acromegalics suggest that there is a dopamine deficiency at central and adrenal level in these patients.
Key words: Aldosterone - Prolactin - Metoclopramide - Acromegaly
Introduction Evidence suggests that aldosterone secretion is under tonic dopaminergic inhibition (Sowers, 1984). The acute administration of metoclopramide, a non-selective dopamine receptor antagonist, stimulates aldosterone secretion in normal man Norbiato et al., 1977). However, little is known about the mechanism of this inhibitory action of dopa.. dopamine and about the dopaminergic pathways involved. Previous reports indicate that the central dopamine function is abnormal in most patients with acromegaly (Spitz et al., 1980). On the other hand, a number of studies confirm a high frequency of alteration in the renin-angiotensin-aldosterone system in acromegalic patients (Mantero et al., 1979; Karlberg and Ottosson, 1982). In the present study, we examined the aldosterone and prolactin responses to metoclopramide in normal subjects and acromegalic patients in order to clarify a possible alteration of the dopaminergic control in this disease. Material and Methods Sixteen patients with active active acromegaly acromegaly were were studied. studied.Their Theirclinical clinicaland andbiochemical biochemicaldata dataare are summarized in Table 1. The diagnosis of acromegaly was based on clinical features, elevated basal of 75 75 gg glucose, glucose, serum growth hormone (Gil) levels, lack of GH suppression after after oral oral administration administrationof Gil suppression sella turcica radiograms and computed tomography. The diagnosis was confirmed in operated patients
Downloaded by: University of Pittsburgh. Copyrighted material.
S. ZACTL&RIEVA, I.I. STOEVA, STOEVA, P. P. MATROZOV MATROZOVand andK. K.ANDONOVA AND0NOVA
Exp. Olin. Clin. Endocrinol. 95 (1990) 3
332
by the histological examination of the resected adenoma. Eight of the acromegalics (6 (Gfemales femalesand and 2 males, mean age 32.4 ± 3.2 years) were normotensive and 8 of them (6 females and 2 males, mean age 45.2 ± 5.2 years) were hypertensive. Arterial hypertension was defined by repeated blood pressure measurements measurements >> 140/90 140/90 mmilg mmilg One One patient patient had had insulin-dependent insulin-dependent diabetes diabetes mellitus. mellitus. None None of of the the patients showed clinical clinical or or laboratory laboratory evidence evidence of of congestive congestiveheart heartfailure, failure,renal renalfailure, failure,ororliver liverdidiseases.
The group of normal subjects consisted of 11 healthy volunteers (5 females and 6 males, mean age 33.2 ± 2.4 years). Female subjects were studied during the follicular phase of their menstrual cycle.
Patients Patients
Age (years)
Previous therapy
Basal Gil
Basal PRL
(mIUfl) (mIU!l)
(mIUfml)
43 36 30 30 32
R+S
26 2G
27 '27 39 26
-
22.7 39 so 50 42.5 80 80 70.7 0.7 73.7
3 4
F F F F
43 31 44
R S 5 S 5
S 5
M
55
6
60
7
F F
8
M
Sex
Normotensive acromegalics 11
F
2 3
M
4
M
5 6 7
F 1? F F
8
F
F
S sS S S
271 65 470 912 912
1186 525 5'25 378 65 65
Hypertensive acromegalics 11 2
52
45 32
-
46.3 32.4 80 20 20 25 5'2 52
5 S
40.2 69.5
59 214 65 904 904 65 219 '219
2850 440
surgery S - Surgery R - Radiotherapy All subjects gave informed consent to participation in the study. The investigations were performed in accordance with the principles of the Declaration of Helsinki. Previous antihypertensive therapy was discontinued for 10 days in hypertensive acromegalies. acromegalics. All other patients were without medication during the study. All All tests tests were were performed performed in in the the morning morning after after an an overnight overnight fast. fast. An An i.i. y. y. indwelling indwelling catheter catheter was was inserted into a forearm vein for blood withdrawal and administration of metoclopramide. After 1 hour hour of of supine supine position position patients patients and and control control subjects subjects received received 10 10 mg mg of of metoclopramide metoclopramide as as an an i.i. y. y. bolus between 8.30-9.00 h. Blood samples were drawn at 15, 15,0,0,15, 15,30, 30,60, 60,90, 90,120 120min minfor formeasuremeasurement of aldosterone, PRL and Gil. Blood was allowed to clot in glass tubes and the serum was separated by centrifugation at the end of the test. Serum samples were stored at - 20°C 20°Cprior prior to to assay. Serum aldosterone was determined by radioimmunoassay (RIA) using commercial kits (Biodata,
Milan, Italy). Assay sensitivity for the method was 15 pg/ml, pgfml, and the intraassay variability was ess than 10%. Serum PRL was estimated by RIA with a commercial kit supplied by National Re-
Downloaded by: University of Pittsburgh. Copyrighted material.
Table 1 Clinical and biochemical data in patients with acromegaly
333
S. ZACHABIEVA ZACHARIEVA et aL, al., Aldosterone Response Response to to Metoclopramide Metoclopramidein inAcromegalics Acromegalics
search Institute for Radiobiology and Radiohygiene (Hungary). The sensitivity of the method was 65 mILJ/ml, mIlJ/ml, and andthe theintraassay intraassayvariability variabilitywas wasless lessthan than10%. 10%.GH Gil serum serum levels levels were were measured measured by by RIA with a commercial kit supplied by the Institute of Atomic Energy, Poland. The sensitivity of the method was 1.0 mIUfl and the intraassay coefficient of variation was less than 10%. All serum samples from each patient were run in the same assay to minimize the influence of interassay variations.
The results are presented as mean ± SEM. Student's t-tests (paired and unpaired, as appropriate) were used for statistical evaluation of the results. A p-value of 0.05 or less was considered statistically significant.
Results
J
J
slowly and at 120 min were significantly higher than the basal values (959.3 + 315.1 mIU/ml) vs 98.3 ± 29.9 mIU/ml, p < 0.001) (Figs. 2 and 3). 40
Mefocloprcmide lOmgAv. Mefoclopramide
-
I
30
A
\\
./
2W
I
LU
I-
U)
o o-J
/
I
/
10'
-15
0
I
15 15
30
60
90
120
Time(min)
responses to to metoclopr&mide metoclopramide (10 (10 mg mg i.v.) i.v.) in 11 normal subjects (), Fig. 1 Serum aldosterone responses
8 normotensive normotensive acromegalics acromegalics(..(.-._.)--)and and8 8hypertensive hypertensiveacromegalics acromegalics (-( -).).Mean Mean ± SEM; xX pp
