Exp. Clin. Endocrinol. Vol. 96, No. 2, 1990, pp. 213-218
J. A. Barth, Leipzig
Institute of Endocrinology and Gerontology (Director: Ass. Prof. Dr. sc. Sc. Med. Med. D. D. Koev), Koev), Medical Academy, Sofia/Bulgaria
S. ZACHARIEVA, ZACHARIEVA,M. M.ANDRFEVA ANDREEVAand andK.K.ANDONOVA AND0N0vA
Summary. The effects of 5 days low sodium diet and diuretic were studied in 7 normotensive acromegalics, 8 hypertensive acromegalics and 12 normal subjects. Plasma renin activity was significantly lower in both groups acromegalics, compared with that of normal subjects. Plasma aldohypertensive acromegaacromegasterone was similar in normotensive normotensive acromegalics acromegalics and andhealthy healthycontrols. controls.The Thehypertensive lics showed increased plasma aldosterone levels and blunted responses of plasma renin activity and lies plasma aldosterone to sodium depletion. Urinary prostaglandin E2 was significantly lower in hyperemive acromegalics before before and and after after sodium sodium depletion in comparison with normal subjects. Urinary enive acromegalics 6-keto prostaglandin F1 and thromboxane B2 were similar in all groups studied. The decreased proproduction of PGE2 could contribute to the development of arterial hypertension in actomegaly.
Key wo words: r ds:Acromegaly Acromegaly--Sodium Sodiumdepletion depletion -- Renin Renin - Prostaglandins
Introduction general Arterial hypertension occurs occurs more more often often in in acromegalic acromegalic patients patientsthan thanin inthe thegeneral population. .The incidence of hypertension in acromegalics has been reported to be about 30% (Karlberg and Ottosson 1982). The reason of this predisposiion to hypertension in acromegalics is not clear, but alteration in the renin-angiotensin-aldosterone system (RAAS) has been suggested (O'Moore, 1973; Snow et al., 1977; Taylor and Bartter, 1977).
Previous studies demonstrated demonstrated aa relationship relationship between between RAAS RAASand andrenal renalprostaglanprostaganclins dins (Freeman (Freeman et al., 1984). On the other hand several lines of evidence evidence suggest suggest that prostaglandin and and thromboxane thromboxane metabolism metabolismmay maybe beinvolved involved in in the abnormalities in prostaglandin pathophysiology of hypertension (Campbell et al., 1982; Sato et al., 1983; Abe et al., 1985). It has been demonstrated demonstrated previously previously the the dependence dependenceof ofrenal renal prostaglandin production on dietary sodium intake (Stahl et al., 1982; Somova et al., 1984). The present study was undertaken to evaluate the effect of chronic sodium depletion on renal prostaglandins and RAAS in normotensive and hypertensive agromegalic patients. Materials and Methods Patients and Controls. Fifteen patients with active acromegaly were studied. Their clinical and biochemical data are summarized in Table 1. The diagnosis of acromegaly was based on clinical features, elevated basal serum serum growth growth hormone hormone (GH), (Gil), levels, lack lack of of GH Gil suppression after oral ad-
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Effect of Sodium Depletion on the ReninAngiotensin-Aldosterone Angiotensi n -Aldosterone System System and Renal Prostaglandins in Acromegalic Patients
ministration of 75 g glucose, sella turcic radiograms and computed tomography. The diagnosis was confirmed in operated patients by the histological examination of the resected adenoma. Seven of the acromegalics (6 females and 1 male, mean age 35.1 ± 5.9 years) were normotensive, and 8 of them (2 females and 6 males, males, mean mean age age 51.1 51.1 ±± 7.9 7.9 years) years)were werehypertensive. hypertensive.Arterial Arterialhypertension hypertension was was defined by repeated blood pressure measurement measurement >> 140/90 140/90 mmHg. mmilg Two Two of of the the hypertensive hypertensive acromegalics had insulin-dependent diabetes mellitus. None of the patients showed clinical or laboacromegalies ratory evidence of congestive heart failure, renal failure, or liver diseases. The The group group of of normal normal subjects subjects consisted consisted of of 12 12 healthy healthy volunteers volunteers (7 (7 females females and and 55 males, males, mean mean age 33.5 ± 1.2 years). The normal subjects were without evidence of renal disease or hypertension according to the routine examinations in the clinic. Previous antihypertensive therapy was discontinued for 10 days in hypertensive acromegalics. All subjects gave informed consent to participation in the study. The investigations were performed ni accordance with the principles of the Declaration of Helsinki. biochemical data data in in patients patients with with acromegaly acromegaly Table 1 Clinical and biochemical
Patients
Sex Sex
Age Age
Basal GH Gil
Previous therapy
(mIU/l) Normotensive acromegalics 25 1 F 45 F 2 3
M
4 5 6
FF F F F
7
36 39 35 30 39
80 55 80
-
45 65
-
30 60
Hypertensive acromegalics 1
2
3 4 5 6 7
8
M M M
F F M M M
45 57 60 53 41 58 55 40
5S 5S
75 Th 60 0 70 42 53 75 32 80
-
R+S R
-
S5
S - Surgery; R - Radiotherapy Study Protocol. To evaluate the effect of low sodium intake, sodium chloride was restricted in the diet to 1 g/24 h (by not adding salt in the food and avoiding food known to be loaded with sodium), for 5 days, and 40 mg Furosemide was given daily orally. Prior and at the end of low sodium diet blood pressure was measured and blood was taken for for the the determination determination of of plasma plasma renin renin activity activity (PRA), (PRA), plasma plasma aldosterone aldosterone (PA), (PA), serum serum electrolytes electrolytes and osmolality. The 24 h urine urinc was collected at the same time. Measurements were made in the morning after an overnight overnight fast. fast. PRA was determined by radioimmunoassay (RIA), using the commercially available Angiotensin I kit (Pharmacia Diagnostics, Uppsala, Sweden). PA was estimated by RIA, using commercial (6kits by SORIN Biomedica, Italy. Urinary prostaglandin E2 (PGE2), 6-keto prostaglandin F1 (6.
keto PGF1) and thromboxane B2 (TXB2) (TXB,) were weremeasured measuredby byRIA RIA(Dray (Drayetetal., al.,1975), 1975),using usingantibodies antibodies PGE.2),commercial commercialkits kits and tracers supplied by Institut Pasteur, France (for the determination of PGE2), by Amersham, England (for the determination of 6-keto PGF1) and commercial kits by Hungarian
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Endocrinol. 96 (1990) 2 Exp. Clin. Endocrino!.
214
S. Zoauuv et al., Sodium Depletion and Prostaglandins in Acromegaly
215
Academy of Science (for the determination of TXB). Sep Pak C columns (Waters Associates) were used for the urine extractions (Powell, 1980). All samples from the same subject were assayed in a single run to minimize the influence of inter-assay variations. The results were presented as mean ± SEM. Student's paired and non paired t-tests were used for statistical evaluation of the results. A p-value of 0.05 or lcss was considered statistically signif icant.
Results The results are presented on Table 2.
A crome g a lic Patients. The normotensive acromegalics showed significantly increased systolic blood pressure and significantly reduced PRA in comparison with normal subjects prior to the low sodium diet. Diastolic blood pressure was significantly increased and urinary potassium was significantly reduced as compared to the normal subjects after sodium depletion. A low sodium intake reduced significantly systolic blood pressure and urinary sodium,
and induced a significant increase in PRA, PA and urinary PGE2. Serum and urinary potassium, serum and urinary osmolality, serum sodium, urinary 6-keto PGF1 and TXB2 did not change significantly after sodium depletion. The hypertensive acromegalics showed significantly elevated systolic and diastolic blood pressure in comparison with normal subjects and normotensive acromegalics. Serum and urinary potassium, PRA and urinary PGE2 were significantly reduced, while PA was significantly elevated in comparison with normal subjects.
After sodium depletion systolic and diastolic blood pressure, serum and urinary sodium and urinary osmolality decreased significantly in comparison with basal values. PRA and urinary PGE2 increased significantly. Serum and urinary potassium, serum osmolality, PA, 6-keto PGF1 and TXB2 did not change significantly after sodium depletion. Discussion
Our findings of a decreased PRA, increased PA and blunted response of RAAS to sodium depletion in hypertensive acromegalics confirm the previous reports demonstrating alterations in the RAAS in acromegaly (Strauch et al., 1972; Mantero et al., 1979). The reason that PA in hypertensive acromegalics was increased is not clear. It may be a direct consequence of the effect of GH on the adrenal production of aldosterone. However, in the present study no difference was observed between GH levels of hypertensive acromegalics with increased PA levels and normotensive ones with normal PA levels. The normotensive acromegalics demonstrated low basal PRA, but their PRA and PA responses to sodium depletion were similar to those in normal subjects, suggesting that the alteration in RAAS are functional rather than organic. The interaction between RAAS and prostaglandins have been clearly demonstrated in essential hypertension. To our knowledge there are no data concerning the relationship between these humoral systems in patients with acromegaly.
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Normal Subjects. Sodium depletion induced a significant decrease in systolic blood pressure, serum and urinary sodium. Diastolic blood pressure tended to decrease but without statistical significance. There were no differences in serum and urinary potassium, serum and urinary osmolality after sodium depletion. PRA, PA and urinary PGE2 significantly increased. Urinary 6-keto PGF and TXB2 did not change significantly after sodium depletion.
137.3 ± 0.83*
140.8 ± 1.16
493.5 ± 39.3
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< 0.05; ... p < 0.001 vs normotensive acromegalics.
p < 0.001 vs normal subjects;
478 ± 90.9 492 ± 30.6
415.6 ± 53.7
360.3 ± 83.2 518.9 ± 79.9
316 ± 42.0 427.6 427.6 ± 68.7
382.2 ± 24.4
710 ± 943*
507.56 ±±79.6 507.56 '9.6
996.1 ± 70.7
366.05 ± 43.3
913 ± 87.5
58.2 ± 8.2
338.2 ± 56.2
1070 ± 85.5
46.9 ± 3.6
2.9 54.6 ± 2.9+
108.6 ± 14.2***
285 ± 2.3
1.78 ± 0.33*+++ Ø33*+++ 246.3 ± 32.1 726.5 ± 759***+
850 ±± 72.5 SSO 72.5
948 ± 79.7
46.7 ± 4.8+ 4.8
203.8 ± 16.2
94.4 ± 12.3
289.4 ± 2.8
4.2 ± 0.12++ 0.12+
139.2 139.2 ±± 0.70** 0.70**
95.6 ±± 2.O**++... 2.0**++...
153.8 1.8***... 153.8 ± ± 1.8***+++...
0.87 ± 190.6 ± 26.5 394.5 ± 26.2+ 26.2k
76 ± 7.7
63.3 ± 6.2
193.7 ± 34.7
286.1 ± 1.3
4.2 ± 0.18++ 0.18
144.4 ± 1.28
105 105 ±
165 1.9" 165 ±±1.9+»
3.25 ± 0.38***+++ 0.76 0.76 ±± 0.18+++ 401.4 ± 107.7* 135.55 ± 26.7 1037.1 ± 44*** 516.2 ± 42.9
105 ± 13.9**
198 ± 21.5
288.2 ± 1.6
4.0 ± 0.17
139.6 ± 1.5
141.6 ± 1.7
4.4 ± 0.16
72.8 ± 1.9
117.85 ± 2.8*+
77.1 ± 1.8
125.7 ± 2.8k
Hypertensive Acromegalics (n = 8) Hyportensive Basal Sodium depletion
1.91 ± 0.15 7.8 7.8 ± 0.46*** 99.02 ± 10.9 287.9 ± 30.5** 519.9 ± 44.2 1131. ± 136.3*** 519.9
284.5 ± 1.3
288.2 ± 2.04
4.65 ± 0.07
69.6 ± 2.8
75 ± 2.7
4.78 ± 0.08
105.8 ± 4.0*
116.6 ± 3.4 116.6
NormotensiveAcromegalics Normotnsive Acromegalies (n = 7) Sodium depletion Basal
(M ± SEM); * p < 0.05; ** p < 0.01; *** p < 0.001 vs basal values; + p < 0.05; ++ p < 0.01;
Serum osmolality (mOsm/kg) Urinary sodium (mmol/24 (mmol/24 h) Urinary potassium (mmolJ24 (mmol/24 h) Urinary osmolality (mOsm/24 (mOsm/24 h) h) PRA (ng/ml/h) PA (pg/mI) (pg/ml) Urinary PUE2 (ng/24h) Urinary 6-keto PUF1 (ng/24 h) Urinary TXB2 (ng/24h)
(mmol/1)
Serum potassium
(mmol/l) (mmol/1)
Systolic blood pressure pressure (mgHg) (mgllg) Diastolic blood pressure (mmllg) Serum sodium
Normal Subjects (n = 12) Basal Sodium depletion
Table 22 Changes in investigated parameters after sodium depletion in normal subjects and acromegalic patients
217
The urinary excretion of prostaglandins has been used as a measure of their renal production (Frölich, 1984). In the present study urinary PGE2 increased after sodium depletion in parallel with PRA in all groups studied. The increased excretion of PGE2 could be attributed attributed to tothe theelevated elevatedangiotensin angiotensinIIII(ATT) (All) in these conditions conditions (Stahl (Stahl et et al., 1982), since AIT All stimulates stimulatesPGE2 PGE2synthesis synthesis (Sehaschmidt (Schaschmidt and and Dunn, Dunn, 1983). 1983). Urinary 6-keto PGF1 (stable (stable metabolite metabolite of of prostacyclin) prostacyclin) and and TXB2 TXB2(stable, (stable metabolite of thromboxan A2) were similar in the groups of acromegalics and normal subboute jects. Sodium depletion did not alter urinary excretion of these prostaglandins. Similar results were reported by others (Campbell et al., 1982) in normotensive and hypertensive subjects in which rio changes in in urinary urinary TXB2 TXB2 on on varying varying sodium sodium intake intake was was obobno changes served. Our results suggest that the effect of sodium depletion on blood pressure and electrolyte balance did not involve changes in prostacyclin and TXA2, although it is possible that the urinary excretion of the metabolites could not entirely reflect their renal synthesis. PGE2 and and blunted blunted PGE2 PGE2 response response to tosodium sodiumdepletion depletionininhyperhyperThe reduced urinary PGE2 tensive acromegalics suggest a deficiency of this prostaglandin. It appears unlikely that acromegaly per se would account for the reduced production of PGE2, since normotensive acromegalics showed similar urinary PGE2 to that of normal subjects and intact PGE2 response to sodium depletion. Most studies reported low levels of POE2 PGE2 in patients with essential hypertension (Sato et al., 1983; Abe et al., 195), although others did not confirm these observations observations (Lebel (Lebel and and Grose, Grose, 1982). 1982). Tt It has been suggested that urinary PGE2 excretion may be depressed in older patients with essential hypertension (Mackenzie et al., 1984). The decreased POE2 PGE2 production in hypertensive acromegalics may be
linked to the decreased activity activity of of RAAS RAAS or/and or/and advanced advanced age ageof ofthese thesepatients. patients.Tt It is well known that activity of RAAS decreases with ageing (Salvetti et al., 1980; Tsunada et al., 1986). The decreased production of PGE2 (vasodilatator and natriuretic) may contribute to the development of hypertension in acroniegaly. acrornegaly. However, it is difficult to assess whether the reduced production of PGE2 leads to hypertension, or it is a secondary response to variations of hormonal secretion, blood pressure, or sodium excretion. The results need further evaluation using inhibitors of prostaglandin synthesis. Acknowledgements. This work was supported in part by a grant from CHIMIMPORT PLC. We We thank thanl Prof. Fernand Dray for the supply of the antibodies antibodies and and tracers tracers of of PGE2. POE2.We Wealso also wish to thank Mrs. forher herskilled skilledtechnical technicalassistance assistance and and Mrs. Mrs. Plamena Penkova Mrs. Dimitrina Dimitrina Stomnova Stonova for for for expert expert typing typing of of the the manuscript. manuscript. RoYereneos ReYerenees ABE, K.; TSUN0DA, T5UN0DA, K.; YASUJIMA, M.; CHIBA, S.; SATO, M.; OMATA, K.; KUDO, K.; YosnIYosnl-
hypertension. AdHAGA, NAGA, K.: Implication of renal prostaglandins in pathogenesis of essential hypertension. 463. (1985) 461 461-463. vances in Prostaglandin, Prostaglandin, Thromboxane Thromboxane and and Leukotriene LeukotrieneResearch Research l (1985) CAMPBELL, W. B.; HOLLAND, O. B.; ADAMS, B. V.; GOMEZ-SANCHEZ, C. E.: Urinary excretion
of prostaglandin E2, prostaglandin F2 and thromboxane B2 in normotensive and hypertensive sodium intakes. intakes. Hypertension Hypertension 44 (1982) (1982)735-741. 735 741. subjects on varying sodium DRAy, F.; DRAY, F.; CHARBONNEL, CHARBONNEL, B.; MACLOUF, J.: Radioimmunoassay of prostaglandins prostaglandins F2, F2, E1 E1 and and (1975) 311-318. 311---318. L E in human plasma. Eur. Eur. J. J. Clin. Clin. Invest. Invest. 5 (1975) DAvIs, J.J.O.; FREEMAN, R. H.; DAVIS, O.;VILLARREAL, VILLARREAL,D.: D.:Role Roleofofrenal renalprostaglandins prostaglandinsininthe thecontrol control of renin release. Cire. Circ. Res. 54 (1984) 1-9. FRÖLICH, J. C.: Measurement Measurement of of eicosanoids. eicosanoids. Prostaglandins. Prostaglandins.27 27(1984) (1984)349--369. 349-369. KARLBERG, B. E.; OTTOSSON, OTTossoN, M. M.A.: A.:Acromegaly Acromegalyand andhypertension: hypertension:role roleofofthe therenin-angiorenin-angiotensin-aldosterone system. Acta Endocrinol. 100 (1982) 581-587.
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S. ZACHARIEVA et al., Sodium Depletion and Prostaglandins in Acromegaly
Endocrinol. 96 (1990) 2 Exp. Clin. Endocrino!.
218
['7] LEBEL, M.; GROSE, J. H.: Renal prostaglandins in borderline and sustained essential hypertension. Prostaglandins, Leukotrienes Med. 8 (1982) 409-418. MACKENZIE, T.; S.:The Theimportance importance of of age age on prostaMACKENZIE, T.;ZAWADA, ZAWADA,E.E.T.; T.;JOHNSON, JoHNsoN, M. M. D.; D.; GREEN, GRxN, S.:
glandin E2 excretion in normal and hypertensive man.
ephron. 38 38 (1984) (1984)178 1'8 182.
MANTERO, F.; MANTERO, F.; OPOCCER, OroccEn, G.;G.; ARMANINI, ARMANINI,D.; D.;PAvIOTTI, PAvIOTTI,G.; G.;BOSOARO, BOSCARO,W.; W.;MUQUE, MUGGE, M.: M.: Plasma
renin activity and urinary aldosterone in acromegaly. J. Endocrinol. Invest. 2 (1979) 13-18. [101 O'MooRE, O'Mooax, B. B. C.: C.: Plasma Plasma renin renin activity in acromegaly. J. Ir. Med. Assoc. 66 66 (1973) (1973) 481-483. 481 483. POWELL, W. C.: Rapid extraction of oxygenated metabolites of arachidonic acid from biological samples using octadecylsilyl silica. Prostaglandins 20 (1980) 947-957. SATO, K.; ABE, K.; SEIN0, M.; YASUJIMA, M.; CHIBA, S.; SATO, M.; HARUYAMA, T.; HIwAHIWATARI, TARI, M.; GoTo, T.; TAJIMA, J.; ,J.;TANNO, TARRO,M.; M.;YOSHIIcAGA, YOSHINAIA, K.: K.: Reduced Reduced urinary excretion of
prostaglandin E in essential hypertension. Prostaglandins, Leukotiienes Leukotrienes Med. 11 (1983) 189-
in culture. Effect of angiotensin II and arginin-vasopressin. J. Clin. Invest. 71 (1983) 17561764. 1764.
SNOW,M. SNOw, M.H.; H.;PIERCY, PIERCY,D. D.A.; A.;ROBSON, RoBsoR, V.; V.;WILKINSON, WILKINSON, R.: R.: An An investigation investigation into the pathogenesis of 5353 (1977) 87-91. of hypertension hypertensionininacromegaly. acromegaly.Clin. Clin.Sei. Sci.Mol. Mol.Med. Med. (19) 87-91. ZACITARIEvA,S.; S.;IvANOVA, IvANOvA, M.: Humoral factors involved in the regulatiQn of SOMOvA, L.; ZACIIARIEvA, sodium fluid balance in normal man. I. Effect of dietary sodium chloride intake on renal prota-
glandins, vasopressin and renin-angiotensin-aldosterone system. Acta Physiol. Pharmacol. Bulgar. 10 (1984) 21-28. STAhL, R. STAHL, R. A.; A.; JONASSEN, JONASSEN, A. J.; PARAvICINI, PARAVICINI, M.; M.; SCHOLLMAYER, SCHOLLMAYER, P.: Sodium chloride as regu-
lator of renal PGE, production in patients with essential hypertension. KIm. Wochenschr. 60 (1982) 579-581. STRAUCH, G.; STRAUCH, G.; VALLOTON, VALLOTON,M. M.B.; B.;TOUITOU, TouITou, J.;J.;BRICAIRE, BRICAIRE,H.: H.:The The renin-angiotensin-aldosterone renin-angiotensin-aldosterone
system in normotensive and hypertensive patients with acromegaly. N. EngI. J. Med. 287 (1972)
495-799. TAYLOR, A. A.; BARTTER, I. C.: Hypertesion in licorice intoxication, acromegaly and Cushing's syndrome. In: Hypotension, Hypotension, Eds. Eds. GENEST, GENEST, J.; J.; KoIw, KoIw,E.; E.;KUCJ1EL, KUCHEL, O., O., New New York: York: McGrawMcGraw-
Hill Book company 1977, 758-761. SALvETTI, A.; SALVETTI, A.; PEDRINELLI, PEDRINELLI, R.; MAGAGNA, MACAURA, A.; A.; POLI, PoLI, L.; SASSANO, P.; ARZILLI, FF.:- Influence Influence of of
age and sodium intake on plasma renin activity of normal subjects. Nephron. 26 2 (1980) 189-194. TSUNODA, TSUNODA, K.; ABE, K.; GoTo, Goro, T.; T.;YASUJIMA, YASUJIMA, M.; M.; SATO, SATO, M.; M.; OMATA, K.; SEINO, M.; YOSHIYosH!NAGA, K.: Effect of age on the renin-angiotensin-aldosterone system in normal subjects: Simul-
taneous measurement of active and inactive renin renin substrate, and aldosterone in plasma. J. Clin. Endocrino!. (1986) 384-388. Endocrinol. Metab. Metab.62 2 (1986) (Accepted 12 February 1990) SABINA ZACITARIEVA, ZACHARIEvA, Institute Author's address: Dr. SABINA Institute of of Endocrinology Endocrinology and and Gerontology, 6, Christo Michailov Bd., 1303 Sofia, Bulgaria Michallov
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197.
SCHASCHMIDT, L. A.; DUNN, M. J.: Prostaglandin synthesis by rat glomerular mesangial cells
J. A. Barth, Leipzig
Institute of Endocrinology and Gerontology (Director: Ass. Prof. Dr. sc. Sc. Med. Med. D. D. Koev), Koev), Medical Academy, Sofia/Bulgaria
S. ZACHARIEVA, ZACHARIEVA,M. M.ANDRFEVA ANDREEVAand andK.K.ANDONOVA AND0N0vA
Summary. The effects of 5 days low sodium diet and diuretic were studied in 7 normotensive acromegalics, 8 hypertensive acromegalics and 12 normal subjects. Plasma renin activity was significantly lower in both groups acromegalics, compared with that of normal subjects. Plasma aldohypertensive acromegaacromegasterone was similar in normotensive normotensive acromegalics acromegalics and andhealthy healthycontrols. controls.The Thehypertensive lics showed increased plasma aldosterone levels and blunted responses of plasma renin activity and lies plasma aldosterone to sodium depletion. Urinary prostaglandin E2 was significantly lower in hyperemive acromegalics before before and and after after sodium sodium depletion in comparison with normal subjects. Urinary enive acromegalics 6-keto prostaglandin F1 and thromboxane B2 were similar in all groups studied. The decreased proproduction of PGE2 could contribute to the development of arterial hypertension in actomegaly.
Key wo words: r ds:Acromegaly Acromegaly--Sodium Sodiumdepletion depletion -- Renin Renin - Prostaglandins
Introduction general Arterial hypertension occurs occurs more more often often in in acromegalic acromegalic patients patientsthan thanin inthe thegeneral population. .The incidence of hypertension in acromegalics has been reported to be about 30% (Karlberg and Ottosson 1982). The reason of this predisposiion to hypertension in acromegalics is not clear, but alteration in the renin-angiotensin-aldosterone system (RAAS) has been suggested (O'Moore, 1973; Snow et al., 1977; Taylor and Bartter, 1977).
Previous studies demonstrated demonstrated aa relationship relationship between between RAAS RAASand andrenal renalprostaglanprostaganclins dins (Freeman (Freeman et al., 1984). On the other hand several lines of evidence evidence suggest suggest that prostaglandin and and thromboxane thromboxane metabolism metabolismmay maybe beinvolved involved in in the abnormalities in prostaglandin pathophysiology of hypertension (Campbell et al., 1982; Sato et al., 1983; Abe et al., 1985). It has been demonstrated demonstrated previously previously the the dependence dependenceof ofrenal renal prostaglandin production on dietary sodium intake (Stahl et al., 1982; Somova et al., 1984). The present study was undertaken to evaluate the effect of chronic sodium depletion on renal prostaglandins and RAAS in normotensive and hypertensive agromegalic patients. Materials and Methods Patients and Controls. Fifteen patients with active acromegaly were studied. Their clinical and biochemical data are summarized in Table 1. The diagnosis of acromegaly was based on clinical features, elevated basal serum serum growth growth hormone hormone (GH), (Gil), levels, lack lack of of GH Gil suppression after oral ad-
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Effect of Sodium Depletion on the ReninAngiotensin-Aldosterone Angiotensi n -Aldosterone System System and Renal Prostaglandins in Acromegalic Patients
ministration of 75 g glucose, sella turcic radiograms and computed tomography. The diagnosis was confirmed in operated patients by the histological examination of the resected adenoma. Seven of the acromegalics (6 females and 1 male, mean age 35.1 ± 5.9 years) were normotensive, and 8 of them (2 females and 6 males, males, mean mean age age 51.1 51.1 ±± 7.9 7.9 years) years)were werehypertensive. hypertensive.Arterial Arterialhypertension hypertension was was defined by repeated blood pressure measurement measurement >> 140/90 140/90 mmHg. mmilg Two Two of of the the hypertensive hypertensive acromegalics had insulin-dependent diabetes mellitus. None of the patients showed clinical or laboacromegalies ratory evidence of congestive heart failure, renal failure, or liver diseases. The The group group of of normal normal subjects subjects consisted consisted of of 12 12 healthy healthy volunteers volunteers (7 (7 females females and and 55 males, males, mean mean age 33.5 ± 1.2 years). The normal subjects were without evidence of renal disease or hypertension according to the routine examinations in the clinic. Previous antihypertensive therapy was discontinued for 10 days in hypertensive acromegalics. All subjects gave informed consent to participation in the study. The investigations were performed ni accordance with the principles of the Declaration of Helsinki. biochemical data data in in patients patients with with acromegaly acromegaly Table 1 Clinical and biochemical
Patients
Sex Sex
Age Age
Basal GH Gil
Previous therapy
(mIU/l) Normotensive acromegalics 25 1 F 45 F 2 3
M
4 5 6
FF F F F
7
36 39 35 30 39
80 55 80
-
45 65
-
30 60
Hypertensive acromegalics 1
2
3 4 5 6 7
8
M M M
F F M M M
45 57 60 53 41 58 55 40
5S 5S
75 Th 60 0 70 42 53 75 32 80
-
R+S R
-
S5
S - Surgery; R - Radiotherapy Study Protocol. To evaluate the effect of low sodium intake, sodium chloride was restricted in the diet to 1 g/24 h (by not adding salt in the food and avoiding food known to be loaded with sodium), for 5 days, and 40 mg Furosemide was given daily orally. Prior and at the end of low sodium diet blood pressure was measured and blood was taken for for the the determination determination of of plasma plasma renin renin activity activity (PRA), (PRA), plasma plasma aldosterone aldosterone (PA), (PA), serum serum electrolytes electrolytes and osmolality. The 24 h urine urinc was collected at the same time. Measurements were made in the morning after an overnight overnight fast. fast. PRA was determined by radioimmunoassay (RIA), using the commercially available Angiotensin I kit (Pharmacia Diagnostics, Uppsala, Sweden). PA was estimated by RIA, using commercial (6kits by SORIN Biomedica, Italy. Urinary prostaglandin E2 (PGE2), 6-keto prostaglandin F1 (6.
keto PGF1) and thromboxane B2 (TXB2) (TXB,) were weremeasured measuredby byRIA RIA(Dray (Drayetetal., al.,1975), 1975),using usingantibodies antibodies PGE.2),commercial commercialkits kits and tracers supplied by Institut Pasteur, France (for the determination of PGE2), by Amersham, England (for the determination of 6-keto PGF1) and commercial kits by Hungarian
Downloaded by: National University of Singapore. Copyrighted material.
Endocrinol. 96 (1990) 2 Exp. Clin. Endocrino!.
214
S. Zoauuv et al., Sodium Depletion and Prostaglandins in Acromegaly
215
Academy of Science (for the determination of TXB). Sep Pak C columns (Waters Associates) were used for the urine extractions (Powell, 1980). All samples from the same subject were assayed in a single run to minimize the influence of inter-assay variations. The results were presented as mean ± SEM. Student's paired and non paired t-tests were used for statistical evaluation of the results. A p-value of 0.05 or lcss was considered statistically signif icant.
Results The results are presented on Table 2.
A crome g a lic Patients. The normotensive acromegalics showed significantly increased systolic blood pressure and significantly reduced PRA in comparison with normal subjects prior to the low sodium diet. Diastolic blood pressure was significantly increased and urinary potassium was significantly reduced as compared to the normal subjects after sodium depletion. A low sodium intake reduced significantly systolic blood pressure and urinary sodium,
and induced a significant increase in PRA, PA and urinary PGE2. Serum and urinary potassium, serum and urinary osmolality, serum sodium, urinary 6-keto PGF1 and TXB2 did not change significantly after sodium depletion. The hypertensive acromegalics showed significantly elevated systolic and diastolic blood pressure in comparison with normal subjects and normotensive acromegalics. Serum and urinary potassium, PRA and urinary PGE2 were significantly reduced, while PA was significantly elevated in comparison with normal subjects.
After sodium depletion systolic and diastolic blood pressure, serum and urinary sodium and urinary osmolality decreased significantly in comparison with basal values. PRA and urinary PGE2 increased significantly. Serum and urinary potassium, serum osmolality, PA, 6-keto PGF1 and TXB2 did not change significantly after sodium depletion. Discussion
Our findings of a decreased PRA, increased PA and blunted response of RAAS to sodium depletion in hypertensive acromegalics confirm the previous reports demonstrating alterations in the RAAS in acromegaly (Strauch et al., 1972; Mantero et al., 1979). The reason that PA in hypertensive acromegalics was increased is not clear. It may be a direct consequence of the effect of GH on the adrenal production of aldosterone. However, in the present study no difference was observed between GH levels of hypertensive acromegalics with increased PA levels and normotensive ones with normal PA levels. The normotensive acromegalics demonstrated low basal PRA, but their PRA and PA responses to sodium depletion were similar to those in normal subjects, suggesting that the alteration in RAAS are functional rather than organic. The interaction between RAAS and prostaglandins have been clearly demonstrated in essential hypertension. To our knowledge there are no data concerning the relationship between these humoral systems in patients with acromegaly.
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Normal Subjects. Sodium depletion induced a significant decrease in systolic blood pressure, serum and urinary sodium. Diastolic blood pressure tended to decrease but without statistical significance. There were no differences in serum and urinary potassium, serum and urinary osmolality after sodium depletion. PRA, PA and urinary PGE2 significantly increased. Urinary 6-keto PGF and TXB2 did not change significantly after sodium depletion.
137.3 ± 0.83*
140.8 ± 1.16
493.5 ± 39.3
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< 0.05; ... p < 0.001 vs normotensive acromegalics.
p < 0.001 vs normal subjects;
478 ± 90.9 492 ± 30.6
415.6 ± 53.7
360.3 ± 83.2 518.9 ± 79.9
316 ± 42.0 427.6 427.6 ± 68.7
382.2 ± 24.4
710 ± 943*
507.56 ±±79.6 507.56 '9.6
996.1 ± 70.7
366.05 ± 43.3
913 ± 87.5
58.2 ± 8.2
338.2 ± 56.2
1070 ± 85.5
46.9 ± 3.6
2.9 54.6 ± 2.9+
108.6 ± 14.2***
285 ± 2.3
1.78 ± 0.33*+++ Ø33*+++ 246.3 ± 32.1 726.5 ± 759***+
850 ±± 72.5 SSO 72.5
948 ± 79.7
46.7 ± 4.8+ 4.8
203.8 ± 16.2
94.4 ± 12.3
289.4 ± 2.8
4.2 ± 0.12++ 0.12+
139.2 139.2 ±± 0.70** 0.70**
95.6 ±± 2.O**++... 2.0**++...
153.8 1.8***... 153.8 ± ± 1.8***+++...
0.87 ± 190.6 ± 26.5 394.5 ± 26.2+ 26.2k
76 ± 7.7
63.3 ± 6.2
193.7 ± 34.7
286.1 ± 1.3
4.2 ± 0.18++ 0.18
144.4 ± 1.28
105 105 ±
165 1.9" 165 ±±1.9+»
3.25 ± 0.38***+++ 0.76 0.76 ±± 0.18+++ 401.4 ± 107.7* 135.55 ± 26.7 1037.1 ± 44*** 516.2 ± 42.9
105 ± 13.9**
198 ± 21.5
288.2 ± 1.6
4.0 ± 0.17
139.6 ± 1.5
141.6 ± 1.7
4.4 ± 0.16
72.8 ± 1.9
117.85 ± 2.8*+
77.1 ± 1.8
125.7 ± 2.8k
Hypertensive Acromegalics (n = 8) Hyportensive Basal Sodium depletion
1.91 ± 0.15 7.8 7.8 ± 0.46*** 99.02 ± 10.9 287.9 ± 30.5** 519.9 ± 44.2 1131. ± 136.3*** 519.9
284.5 ± 1.3
288.2 ± 2.04
4.65 ± 0.07
69.6 ± 2.8
75 ± 2.7
4.78 ± 0.08
105.8 ± 4.0*
116.6 ± 3.4 116.6
NormotensiveAcromegalics Normotnsive Acromegalies (n = 7) Sodium depletion Basal
(M ± SEM); * p < 0.05; ** p < 0.01; *** p < 0.001 vs basal values; + p < 0.05; ++ p < 0.01;
Serum osmolality (mOsm/kg) Urinary sodium (mmol/24 (mmol/24 h) Urinary potassium (mmolJ24 (mmol/24 h) Urinary osmolality (mOsm/24 (mOsm/24 h) h) PRA (ng/ml/h) PA (pg/mI) (pg/ml) Urinary PUE2 (ng/24h) Urinary 6-keto PUF1 (ng/24 h) Urinary TXB2 (ng/24h)
(mmol/1)
Serum potassium
(mmol/l) (mmol/1)
Systolic blood pressure pressure (mgHg) (mgllg) Diastolic blood pressure (mmllg) Serum sodium
Normal Subjects (n = 12) Basal Sodium depletion
Table 22 Changes in investigated parameters after sodium depletion in normal subjects and acromegalic patients
217
The urinary excretion of prostaglandins has been used as a measure of their renal production (Frölich, 1984). In the present study urinary PGE2 increased after sodium depletion in parallel with PRA in all groups studied. The increased excretion of PGE2 could be attributed attributed to tothe theelevated elevatedangiotensin angiotensinIIII(ATT) (All) in these conditions conditions (Stahl (Stahl et et al., 1982), since AIT All stimulates stimulatesPGE2 PGE2synthesis synthesis (Sehaschmidt (Schaschmidt and and Dunn, Dunn, 1983). 1983). Urinary 6-keto PGF1 (stable (stable metabolite metabolite of of prostacyclin) prostacyclin) and and TXB2 TXB2(stable, (stable metabolite of thromboxan A2) were similar in the groups of acromegalics and normal subboute jects. Sodium depletion did not alter urinary excretion of these prostaglandins. Similar results were reported by others (Campbell et al., 1982) in normotensive and hypertensive subjects in which rio changes in in urinary urinary TXB2 TXB2 on on varying varying sodium sodium intake intake was was obobno changes served. Our results suggest that the effect of sodium depletion on blood pressure and electrolyte balance did not involve changes in prostacyclin and TXA2, although it is possible that the urinary excretion of the metabolites could not entirely reflect their renal synthesis. PGE2 and and blunted blunted PGE2 PGE2 response response to tosodium sodiumdepletion depletionininhyperhyperThe reduced urinary PGE2 tensive acromegalics suggest a deficiency of this prostaglandin. It appears unlikely that acromegaly per se would account for the reduced production of PGE2, since normotensive acromegalics showed similar urinary PGE2 to that of normal subjects and intact PGE2 response to sodium depletion. Most studies reported low levels of POE2 PGE2 in patients with essential hypertension (Sato et al., 1983; Abe et al., 195), although others did not confirm these observations observations (Lebel (Lebel and and Grose, Grose, 1982). 1982). Tt It has been suggested that urinary PGE2 excretion may be depressed in older patients with essential hypertension (Mackenzie et al., 1984). The decreased POE2 PGE2 production in hypertensive acromegalics may be
linked to the decreased activity activity of of RAAS RAAS or/and or/and advanced advanced age ageof ofthese thesepatients. patients.Tt It is well known that activity of RAAS decreases with ageing (Salvetti et al., 1980; Tsunada et al., 1986). The decreased production of PGE2 (vasodilatator and natriuretic) may contribute to the development of hypertension in acroniegaly. acrornegaly. However, it is difficult to assess whether the reduced production of PGE2 leads to hypertension, or it is a secondary response to variations of hormonal secretion, blood pressure, or sodium excretion. The results need further evaluation using inhibitors of prostaglandin synthesis. Acknowledgements. This work was supported in part by a grant from CHIMIMPORT PLC. We We thank thanl Prof. Fernand Dray for the supply of the antibodies antibodies and and tracers tracers of of PGE2. POE2.We Wealso also wish to thank Mrs. forher herskilled skilledtechnical technicalassistance assistance and and Mrs. Mrs. Plamena Penkova Mrs. Dimitrina Dimitrina Stomnova Stonova for for for expert expert typing typing of of the the manuscript. manuscript. RoYereneos ReYerenees ABE, K.; TSUN0DA, T5UN0DA, K.; YASUJIMA, M.; CHIBA, S.; SATO, M.; OMATA, K.; KUDO, K.; YosnIYosnl-
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