Effect of prostaglandin inhibition on the prolactin, renin, and aldosterone responses to dopamine antagonism

Effect

of Prostaglandin Inhibition on the Prolactin, Renin, Aldosterone Responses to Dopamine Antagonism Michael S. Golub, James R. Sowers,

The

possible

aldosterone

interactions

between

the

prostaglandin

and

(10 mg. i.v.) were studied before and after prostaglandin (p < 0.05) with indomethacin

administration.

indomethacin

treatment.

indomethacin.

Plasma aldosterone

There

was no significant

pramide, (3048

dopamine

systems

However, difference

inhibition

meq/day)

3882

the renin increased between

f 146 ng. min/ml).

prolactin response to dopamine the aldosterone

response

antagonism.

to dopamine

with indomethacin

diet. Urinary

activity

following

control

of prolactin,

antagonist,

E excretion

was reduced

tended

to rise before,

peaking at ten to fifteen minutes days. Prolactin

0.01). The prolactin response

The

results

Although

antagonism

the response

suggest

was significantly

by cyclooxygenase

by

(p c 0.01).

following

metoclo-

(p < 0.05) decreased by

curve was significantly

that a cyclooxygenase

the renin response to metoclopramide

is not mediated

increased

61%

affected

and fall after,

the control

and indomethacin

and

(50 mg every 8 hr for 3 doses) while

prostaglandin

metoclopramide

renin

metoclopramide

rapidly after metoclopramide,

at four of six time points and the area beneath

? 132 versus

in the

to the dopamine

Plasma renin activity (active and inactive) was not significantly

peaking at fifteen to thirty minutes (p i

indomethacin

Peter Eggena, and Steven H. Baron

secretion were studied in seven normal subjects. The responses

the subjects were in balance on a low sodium (40

and

(p c 0.05)

product

blunted

may modulate

the

was altered by indomethacin,

products

or the renin-angiotensin

system.

D

OPAMINERGIC MECHANISMS are known to modulate secretion of several hormones. Prolactin (PRL) secretion is controlled to a considerable extent by the central tubero-infundibular-dopaminergic (TIDA) system.‘-’ Accordingly, any stimulation of TIDA activity reduces PRL secretion from pituitary lactotropes, and mechanisms leading to decreased tubero-infundibular-neuronal secretion of dopamine increase PRL secretion. Metoclopramide (MCP) a competitive inhibitor of dopamine4 is a potent stimulator of PRL secretion in man.’ ’ Recently MCP has been shown to stimulate aldosterone secretion in man8~‘4 with’-” and without”,‘* increases in plasma renin activity (PRA). Bromocriptine, a dopamine agonist, has been reported to inhibit the plasma aldosterone response to furosemide diuresis,” to upright posture and to angiotensin II infusion in man.16 Thus, there is considerable evidence for dopaminergic modulation of aldosterone and perhaps renin secretion in man. Similarly, prostaglandins (PC’s) have been implicated in the regulation of adenohypophseal PRL secretion”-*’ and the renin-angiotensin-aldosterone axis.2’m25However, there have been no previous investigations of the interaction between dopaminergic and prostaglandin mechanisms of control of prolactin,

renin and aldosterone secretion. To investigate the possible interaction of these two systems, we evaluated the effect of PC inhibition with indomethacin (Indo) on PRL, aldosterone and renin responses to metoclopramide in normal subjects. MATERIALS

AND

7 normal volunteers (6 men and

METHODS

I

woman)

IO meq Na was followed for 5 days before the first study. On the first butterfly needle in place in an arm vein for one hour at which time a baseline blood sample aldosterone

(PA),

pramide (MCP)

for plasma

and PRL

renin activity

determinations

(PRA),

10 mg was given intravenously

plasma

Metoclo-

was drawn.

and blood samples

were drawn at 5. IO. 15. 30, 45. and 60 min after drug administration. All studies were performed between 0800 and 1000 hours. The subjects continued indomethacin

on the low sodium diet and began taking oral

(Indo),

being administered following

day.

50 mg every 8 hr for three doses, the final dose 2 hr before a repeat of the MCP

infusion the

In two subjects. the order of administration

was

reversed with Indo preceding control and a washout day intervening. Urine

for sodium, creatinine

and volume was collected for 24 hr

preceding each study and serum for electrolytes was obtained prior to MCP

infusion.

In five subjects timed three hour urine samples

were obtained encompassing the time of the metoclopramide These samples were analyzed for prostaglandin Plasma renin activity was determined of generated angiotensin

I following

tests.

E excretion.

by the radioimmunoassay

incubation of plasma at pH 7.4

in the presence of inhibitors.26 Sensitivity of this assay is 0.1 ng/ml coefficient

of variability

activity was measured as the generation

740

were

day of study the subjects were supine after an overnight fast with a

and the intraassay

From the Divisions of Hypertension and Endocrinology Sepulveda Veterans Administration Medical Center UCLA-San Fernando Program, UCLA School of Medicine, Sepulveda. California. Received for publication August 31, 1981. Supported in part by Veterans Administration research funds. Address reprint requests to Michael S. Golub. M.D.. Sepulveda VAUC. 161 I I Plummer St.. Sepulveda. California 91343. 0 1982 by Grune & Stratton, Inc. 0026~495/82/3107~016$01.00/0

aged 27-59

studied on a clinical research unit after informed consent. A diet of

is 15%. Total

of angiotensin

I

renin

following

the addition of trypsin (I mg/ml).27 The reaction was terminated the addition of lima bean trypsin inhibitor

(0.2 mg/ml

Inactive renin activity was calculated by subtracting renin activity. Plasma aldosterone concentration the RIA variability prolactin

of Mayes

et al.”

on extracted

is 7% and the assay sensitivity was measured

radioimmunoassay.’ intraassay variability in unextracted

by a previously

PRA from total

was determined

plasma.

is 4 pg/ml.

described

prostaglandin

urinez9 by radioimmunoassay.’

by

The intraassay Serum

homologous

The sensitivity of this assay is 1.0 ng/ml is 5%. Urinary

by

of sample).

and

E was measured

The antibody, gener-

Merabobsm, Vol. 3 1, No. 7 (July), 1982

PROSTAGLANOINS

741

AND DOPAMINE ANTAGONISM

ated in a rabbit to a PGE,-thyroglobulin conjugate” has 31% cross-reactivity with PGE, and the results are expressed as prostaglandin E2 equivalents. The intraassay variability is 8%. All the assays were performed in a single run to reduce the error of measurement. Serum and urinary electrolytes were measured by flame photometry using lithium as an internal standard. Paired comparisons of values before and after MCP were performed with Student’s t test, and changes from baseline were evaluated with Dunnett’s multiple comparison procedure.” Areas under the response curves were calculated by integration using a desk top computer program as previously descrihed.33 Results are reported as the mean f SE. RESULTS

Urinary sodium determinations on the day prior to each study validated dietary compliance and measured less than 20 meq/day in each instance. Creatinine excretion on Indo (1562 f 307 mg) did not change significantly from the non-Indo collection (1250 * 339 mg). Serum sodium (136.8 2 3.0 vs. 138.8 + 1.5) and serum potassium (3.9 + 0.3 versus 3.8 f 0.2) did not differ significantly between the Indo and control days. Urinary prostaglandin E excretion during the studies was 61% lower (p < 0.05) with indomethacin administration (224 f 20 ng) than during the control period (570 + 102 ng) in five subjects. The PRA responses to MCP before and after Indo are shown in Fig. 1. Baseline PRA values were not significantly different on the Indo and control days (13.7 f 4.3 versus 9.9 + 1.9 ng/ml/hr). Following MCP, PRA tended to rise on the control day but decreased on the Indo day with a significant (p < 0.05) decrease from baseline occurring at 30

minutes post MCP. However, there was a significant difference (p < 0.05) in PRA responses between the two studies only at 10 min. The areas beneath the PRA-time curves were not different before or after indomethacin. The areas above or below the baseline value (A PRA)-time curve (as in Fig. 1) are significantly (p < 0.05) different, however (133 f 89 versus - 121 + 79 ng/ml/hr - min). Inactive renin was slightly, but insignificantly, higher on the Indo day (15.6 f 6.6 versus 9.8 + 6.0 ng/ml/hr) and did not change significantly following MCP on either study. Baseline PA levels were not affected by Indo (28.4 + 2.5 versus 27.6 + 2.3 ng/dl). Following MCP there was a prompt rise in PA on both study days (Fig. 2). Although the peak response was slightly delayed on the Indo day there were no significant differences at each time point. Individual peak increases over baseline and the areas under the response curves were not significantly affected by Indo pretreatment. Baseline PRL levels were not changed by Indo (9.3 + 2.2 versus 9.3 + 2.1 ng/ml). The increase over baseline following MCP is shown in Fig. 3. The PRL responses were significantly (p < 0.05) depressed following Indo for four of six time points. Although the peak responses were decreased after Indo (65.0 f 8.2 30

25

** IL

6

1

, *\*

/

* I

i Time (minutes)

*I

If

‘\ \\

** ** ’

y

I :

J*\*\ *

\n

\

‘\ \

5

f 0 -6 J Fig. 1. The change from beseline of PRA following MCP. Solid line = control, deehed line - Indo. l - p c 0.06 vs. beseline. t - p < 0.06 vs. control.

\\

*

I5

30

45

60

Time (minutes) Fig. 2. Change from beseline of PA following MCP. Solid line control, dashed line = MO. l - P -z 0.06. l * - P c 0.01 vs.

742

GOLUB

80 -

60 -

40-

20 -

6

Pt* lb

3b

415

$0

Time (minutes) Change from baseline of PRL following MCP. Solid Fig. 3. line = control, dashed line = Indo. l = p < 0.05, ** = p i 0.01 vs.

baseline,

t = p < 0.05 VS. control.

versus 76.2 f 3.8 ng/ml), this difference did not reach statistical significance. The area beneath the response curve after Indo (3048 -I- 132 ng - mitt/ml) was significantly (p < 0.05) lower than the control response (3882 + 146 ng - mitt/ml). The results from the only female subject were comparable to that of the male subjects. Five of the subjects experienced mild to moderate restlessness following metoclopramide. DISCUSSION The present study was designed to explore possible interrelationships between the actions of dopamine and members of the PG family. Both systems have been implicated in the modulation of control of prolactin, renin and aldosterone secretion. The natriuretic potential and vascular effects of these two systems has also engendered speculation about their roles in blood pressure regulation. Although we have evidence that the indomethacin dose was effective in reducing urinary prostaglandin E excretion, the degree of prostaglandin synthetase inhibition in the renal cortex, pituitary. hypothalmus or adrenal is unknown. Actions of indomethacin independent of cyclooxygenase inhibition also might have influenced the data. None the less, the potency of indomethacin as an inhibitor of prostaglandin synthesis suggests that significant effects of the drug might be mediated by this action. Although PG’s have been shown to have effects on the hypothalamic control of PRL release in the rat, our observation of a decreased PRL response following Indo also may be compatible with an adenohypophyseal effect. lndomethacin penetrates poorly into cerebrospinal Ruid34 and is a poor inhibitor of brain prostaglandin synthesis when given in vivo. ” In vitro there are data demonstrating PGE can stimulate PRL directly from the pituitary,16 that E and F series PG’s can stimulate cultured rat pituitary tumor cells to secrete PRL,20 and that indomethacin can suppress pituitary PRL release.” These data are consistent with an effect on the pituitary. However, Ojeda et al.38 found that Indo reduced the PRL response to estrogen in ovariectomized rats. As Indo did not impair the PRL response to TRH, and intraventricular PC’s increased PRL without entering the pituitary, these authors favored a hypothalamic site of PG action. In

ET AL.

man lndo pretreatment has failed to alter the PRL increase oi TRH,j9 arginine.” and perphenazine.4’ Changes in osmolality can also affect PRL release.42 PG inhibition can enhance the effect of antidiuretic hormone and thus lower serum osmolality.” In our subjects. however, the short term administration of Indo did not affect serum electrolytes or renal function. Thus, lndo effects on PRL secretion cannot be attributed to changes in plasma osmolality. Previous studies have shown a mild increase in PRA at 30 to 45 min following MCP.* ‘” In the present study a similar increase was seen which did not reach statistical significance. In contrast there was a decrease in PRA after MCP when lndo had been administered. The basal PRA was unaffected by 24 hr of lndo treatment. Thus. short term administration of lndo did not affect basal PRA but altered the renin release pattern of dopamine antagonism. Speckart et al.*’ reported that lndo uniformly lowered PRA in sodium-depleted normal subjects. However, in a subsequent study PRA suppression was not seen unless concomitant beta-adrenergic blockade was utilized,‘* and a third group showed PRA decreased in 505”of subjects.” Two to four days of lndo was used to produce PRA suppression in these trials. Thus, the lack of effect of Indo on basal PRA in the present study may reflect the short period of drug administration. It should be noted, however, that a similar dose results in a marked decrease in the major urinary metabolite of the E PG’s,# reflecting a substantial block in the total body synthesis of these PC’s, The finding of unchanged inactive renin after lndo is in accord with the data of Tan et al.” who did not find a change in this material in normal subjects following Indo treatment. Inhibition of PG synthesis may also affect aldosterone release through effects on the adrenal glomerulosa. Campbell et al.” found that two cyclooxygenase inhibitors. indomethacin and meclofenamate, impaired the aldosterone responses to angiotensin I I and I I I in rats. However, in man*’ Indo does not affect angiotensin Il-induced PA increases. Zusman et a1.4’ reported that lndo decreased aldosterone excretion in response to ACTH but attributed this effect to the decrease in PRA that was observed after three days of Indo. In the present study the similarity of the PA response before and after lndo suggests that the adrenal stimulatory effect of MCP is not mediated by a cyclooxygenase product. The contrasting renin responses before and after lndo reconfirms that this aldosterone response to dopamine antagonism is independent of the renin-angiotensin axis.” I4 In summary, dopamine antagonism with MCP results in an acute increase in PRI_ and PA. The inhibition of the cyclooxygenase enzyme with Indo significantly decreased PRL secretion but did not influence the PA response. The mechanism of this interaction and the possibility that renin release is stimulated by a PG mechanism following dopamine antagonism requires further evaluation. ACKNOWLEDGMENT The authors thank Ronald Marciano. P.A.. and Patricia Walker. P.A., for their help and Suzanne Fogel for typing the manuscript. REFERENCES I. Shaar CJ, Clemens JA: The role of catecholamines in the release of anterior pituitary prolactin in vitro. Endocrinology 95:1202-1212, 1974 2. Ben-Jonathan N: Catecholamines and pituitary prolactin release. J Reprcd Fert X%:501-512. 1980 3. Neil1 JD, Frawley LS. Plotsky PM, et al: Dopamine in hypophysial stalk blood of the rhesus monkey and its role in regulating prolactin secretion. Endocrinology 108:4899494. 198 1 4. Peringer EP, Jenner P, Donaldson IM. et al: Metoclopramide and dopamine receptor blockade. Neuropharmacology 15:463-469, 1976 5. McCallum RW, Sowers JR, Hershman JM, et al: Metoclo-

PFIOSTAGLANDINS AND DDPAMINE ANTAGONISM

pramide stimulates prolactin secretion in man. J Clin Endocrinol Metab42:1148-1152.1976 6. Sowers JR, McCallum RW, Hershman JM, et al: Comparison of metoclopramide with other dynamic tests of prolactin secretion. J Clin Endocrinol Metab 43:67968 1, 1976 7. Sowers JR, Carlson HE, Brautbar N, et al: Effect of dexamethasone on prolactin and TSH responses to TRH and metcclopramide in man. J Clin Endocrinol Metab 44:237-241, 1977 8. Norbiato Cl, Bevilacqua M, Raggi U, et al: Metoclopramide increases plasma aldosterone concentration in man. J Clin Endocrino1 Metab45:1313-1316,1977 9. Sowers JR, Brickman AS, Asp N, et al: Altered dopaminergic modulation of prolactin and aldosterone secretion in pseudo hypoparathyroidism. J Clin Endocrinol Metab 52:914-918, 1981 10. Sowers JR, Brickman AS, Sowers DK, et al: Dopaminergic modulation of aldosterone secretion in man is unaffected by glucocorticoids and angiotensin blockade. J Clin Endocrinol Metab 52:1078-1084,198l 11. Carey RM, Thorner MO, Ortt EM: Effects of metoclopramide and bromocriptine on the renin-angiotensin-aldosterone system in man: dopaminergic control of aldosterone. J Clin Invest 63:727735,1979 12. Noth RH, McCallum RW, Contino C, et al: .Tonic dopaminergic suppression of plasma aldosterone. J Clin Endocrinol Metab 51:64-69, 1980 13. Carey RM, Thorner MO, Ortt EM: Dopaminergic inhibition of metoclopramide-induced aldosterone secretion in man. J Clin Invest 66:10-18, 1980 14. Brown RD. Wisgerhof M, Jiang N-S, et al: Effect of metoclopramide on the secretion and metabolism of aldosterone in man. J Clin Endocrinol Metab 52:1014-1018, 1981 15. Edwards CRW, Miall PA, Hanker JP, et al: Inhibition of the plasma-aldosterone response to furosemide by bromocriptine. Lancct 2:903-904, 1975 16. Whitfield L, Sowers JR, Tuck ML, et al: Dopaminergic control of plasma catecholamine and aldosterone responses to acute stimuli in normal man. J Clin Endocrinol Metab 51:724-729, 1980 17. Hedge GA: Roles for the prostaglandins in the regulation of anterior pituitary secretion. Life Sci 20:17-33, 1977 18. Sowers JR, Fayez J, Colantino M, et al: The effect of intra-amniotic prostaglandin Fz on anterior pituitary hormone release during mid-trimester abortion. Fertil Steril 30:403407, 1978 19. Ojeda SR, Naor Z, Negro-Vilar A: The role of prostaglandins in the control of gonadotropin and prolactin secretion. Prostaglandins Me-d 5:249-274, 1979 20. Gautvik KM, Kriz M: Effects of prostaglandins on prolactin and growth hormone synthesis and secretion in cultured rat pituitary cells. Endocrinology 98:352-358, 1976 21. Speckart P, Zia P, Zipser R, et al: The effect of sodium restriction and prostaglandin inhibition on the renin-angiotensin system in man. J Clin Endocrinol Metab 44832-837, 1977 22. Frolich JC, Hollifield JW, Michelakis AM, et al: Reduction of plasma renin activity by inhibition of the fatty acid cyclooxygenase in human subjects. Circ Res 44:781-787, 1979 23. Glasson P, Gaillard R, Riondel A. et al: Role of prostaglandins and relationship to renin, aldosterone and antidiuretic hormone during salt depletion in man. J Clin Endocrinol Metab 49: 17618 1, 1979 24. Campbell WB, Gomea-Sanchez CE, Adams BV, et al: Attenuation of angiotensin II and III-induced aldosterone release by prostaglandin synthesis inhibitors. J Clin Invest 641552-1557, 1979 25. Golub MS, Speckart PF, Zia PK, et al: The effect of

743

prostaglandin A, on renin and aldosterone in man. Circ Res 39:574579.1976 26. 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 27. Eggena P, Barrett JD, Wiedeman CE, et al: Studies on renin activation in normal human plasma. Hypertension 1:523-528, 1979 28. Mayes DM, Furiuyama S, Kern DC, et al: A radioimmunoassay for plasma aldosterone. J Clin Endocrinol Metab 3Oz682-689, 1970 29. Oliw E, Anggard E: Different effects of furosemide on urinary excretion of prostaglandin Ez and Fti in rabbits. Acta Physiol Stand 105:367-370, 1979 30. Zia P, Zipser R, Speckart R, et al: The measurement of urinary prostaglandin E in normal subjects and in high-renin states. J Lab Clin Med 92:415-421,1978 31. Goldyne ME, Windelman RK, Ryan RJ: Prostaglandin activity in human cutaneous inflammation: detection by radioimmunoassay. Prostaglandins 4:737-744, 1973 32. Dunnett CW: A multiple comparison procedure for comparing several treatments with a control. J Am Stat Assoc 50:1096 1099,1955 33. Sowers JR, Hershman JM, Pekary AE, et al: Effect of N”“-methylthyrotropin releasing hormone on the human pituitarythyroid axis. J Clin Endocrinol Metab 43:741-748, 1976 34. Hucker HB, Zacchei G, Cox SV, et al: Studies on the absorption, distribution and excretion of indomethacin in various species. J Pharmacol ExpTherap 1531:237-249.1966 35. Dembinska-Kiec A, Grodzinska L, Piobrowicz J: The influence of indomethacin on the prostaglandin synthetase system in rat tissues in vivo. Pol J Pharmacol Pharm 26:79-82, 1974 36. Kragt CL, Bergstrom KK, Voogt JL: Interactions of prostaglandin E, and LRH on anterior pituitary function. Prostaglandins 10:833-851, 1975 37. Sundberg DK, Fawcett CP, Illner P, et al: The effect of various prostaglandins and a prostaglandin synthetase inhibitor on rat anterior pituitary cyclic AMP levels and hormone release in vitro. Proc Sot Exp Bio Med 148:5459, 1975 38. Ojeda SR, Jameson HE, McCann SM: Effects of indomethatin and prostaglandin injections on plasma prolactin and growth hormone levels in rats. Endocrinology 102:531-539, 1978 39. Ramey JN, Burrow GN, Spaulding SW, et al: The effect of aspirin and indomethacin on the TRH response in man. J Clin Endccrinol Metab 43:107-l 14, 1976 40. Vierhapper H, Bratusch-Marrain P, Waldhausl W: Unchanged arginineinduced stimulation of insulin, glucogon, growth hormone and prolactin after pretreafment with indoemthacin in normal man. J Clin Endocrinol Metab 50:1131-l 134, 1980 41. Buckman MT, Peake GT, Srivastara S: Indomethacin fails to alter basal or phenothiazine-induced prolactin concentrations in man. Horm Metab Res 11:395-398.1979 42. Sowers JR, Hershman JM, Skowsky WR, et al: Osmotic control of the release of prolactin and thyrotropin in euthyroid subjects and patients with pituitary tumors. Metabolism 26:187192.1977 43. Zusman RM, Vinci JM, Bowden RE, et al: Effect of indomethacin and adrenocorticotrophic hormone on renal function in man: An experimental model of inappropriate antidiuresis. Kidney Int 1562-70, 1979 44. Hamberg M: Inhibition of prostaglandin synthesis in man. Biochem Biophys Res Corn 4972c726.1972 45. Tan SY, Antonipillai I, Mulrow RJ: Inactive renin and prostaglandin E, production in hyporeninemic hypoaldosteronism. J Clin Endccrinol Metab 51:849-853, 1980