ROBERT FRASER, PH.D., CARLO BERETTA-PICCOLI, M.D., JEHOIADA J. BROWN, M.B., ALISON M. M. CUMMING, R.G.N., ANTHONY F. LEVER, M.B.,

Transcription

1 Respnse f Aldsterne and 18-Hydrxycrticsterne t Angitensin II in Subjects and Patients with Essential Hypertensin, 's Syndrme, and Nntumrus Hyperaldsternism ROBERT FRASER, PH.D., CARLO BERETTA-PICCOLI, M.D., JOIADA J. BROWN, M.B., ALISON M. M. CUMMING, R.G.N., ANTHONY F. LEVER, M.B., PETER A. MASON, PH.D., JAMES J. MORTON, PH.D., AND J. IAN S. ROBERTSON, M.B. SUMMARY Dse-respnse curves relating plasma angitensin II (AH) cncentratin during AH infusin t bld pressure (BP), t plasma aldsterne, and t plasma 18-hydrxycrticsterne were cmpared in nrmal subjects and in patients with essential hypertensin, 's syndrme, and nntumrus hyperaldsternism. The BP respnse was steeper than nrmal in patients with 's syndrme and essential hypertensin. Befre infusin, mean plasma aldsterne cncentratin was apprximately fur-fld higher in 's syndrme than in the nrmal grup, while that f 18-hydrxycrticsterne was ninefld higher. Neither increased significantly during AH infusin. In essential hypertensin, bth crticsterids were within the nrmal range, but their respnses t AH infusin were greater than nrmal. In the three subjects with nntumrus hyperaldsternism, plasma aldsterne and 18-hydrxycrticsterne cncentratins were raised, and their respnses t AH infusin resembled thse fund in essential hypertensin and were different frm thse fund in 's syndrme. This suggests that nntumrus hyperaldsternism is nt a rariant f 's syndrme. In the respnse t AH and in ther ways, it is indistinguishable frm essential hypertensin. (Hypertensin 3 (supp I): I-87-I-92, 1981) KEY WORDS aldsterne angitensin II 18-hydrxycrticsterne essential hypertensin nrmal subjects 's syndrme nntumrus hyperaldsternism ALTHOUGH many interacting factrs, a benign adrencrtical adenma ('s syndrme), ntably ACTH, sdium, and ptassium, and hyperaldsternism assciated with bilateral determine the secretin rate and plasma micrndular hyperplasia f the adrenal crtex (nncncentratin f aldsterne in humans, angitensin tumrus hyperaldsternism). 2 Data n the behavir II (All) is prbably the mst imprtant. Angitensin f 18-hydrxycrticsterne in plasma in these II als raises the plasma cncentratins f 18- categries are sparse. The present study cmpares the hydrxycrticsterne, the prbable immediate pre- effect f All infusin n plasma cncentratins f cursr f aldsterne, but is unimprtant in cn- aldsterne and 18-hydrxycrticsterne in grups trlling the plasma levels f ther crticsterids. In f subjects with these frms f hypertensin t its nrmal subjects, the relatinship between plasma All effect in nrmal subjects, and aldsterne levels can be altered, fr example, by sdium depletin r lading: the effect n plasma 18- hydrxycrticsterne cncentratin is less clear but may als change in this way (see review 1). Methds The All: aldsterne relatinship may differ frm All subjects were studied under identical cnditins nrmal in sme types f hypertensin, including essen-, n a metablic ward. Fr 5 t 6 days befre the study, tial hypertensin, primary hyperaldsternism due t they ate a fixed diet cntaining between 145 and 155 meq sdium and between 50 and 80 meq ptassium daily. Angitensin II (Hypertensin, Ciba) was infused Frm the Medical Research Cuncil, Bld Pressure Unit, accrding t techniques already published, 8 in 5% dex- Western Infirmary, Glasgw, Sctland. trse (5 ml hr 1 ) at successive rates f 0.5, 1.0, 2.0, 4.0, Present address fr Dr. Beretta-Piccli: Medizinische Pliklinik, anc 8 0 ng kg" 1 mirr 1, each rate being cntinued fr 1 University f Berne Berne^ Switzerland. h fc bj t recdved nly three rates depend- Address fr reprints: Dr. Rbert Fraser, Medical Research "»» i^uvu au j J r Cuncil, Bld Pressure Unit, Western Infirmary, Glasgw Gil ln 8 n the basal BP - Bld samples were taken at the 6NT, Sctland. end f each perid, and BP was measured aut- 1-87

2 1-88 PATHOPHYSIOLOGY OF HYPERTEION SUPP I, HYPERTEION, VOL 3, N 3, MAY-JUNE, 1981 matically (Bsmat) at 10-minute intervals. Plasma cncentratins f All 4 and aldsterne 6 were measured by radiimmunassay and 18-hydrxycrticsterne" and crtisl 7 by gas-liquid chrmatgraphy. Ttal bdy clearance f infused All was calculated by dividing the infused dse min" 1 by the assciated change in plasma cncentratin and using the mean fr the three infusin rates. Details f patients and cntrls are given in table 1. Thse with essential hypertensin had a diastlic BP cnsistently abve 100 mm Hg in the utpatient department, a nrmal intravenus pyelgram, nrmal plasma cncentratins f aldsterne and electrlytes, and nrmal urinary vanilmandelic acid (VMA) excretin. Of the 10 patients, seven had nrmal plasma renin cncentratins; three had lw renin essential hypertensin. 3 The diagnsis f 's syndrme was based n the demnstratin f an adrenal lesin by cmputed tmgraphy and adrenal vengraphy and f a gradient in the adrenal vein bld levels f aldsterne; in five f eight patients, this was cnfirmed by surgery fllwed by histlgical examinatin f the tumr. Nntumrus hyperaldsternism was diagnsed in three patients with high plasma aldsterne in whm n tumr was demnstrable by cmputed tmgraphy and adrenal vengraphy and in whm adrenal vein aldsterne levels did nt indicate a unilateral lesin. All hypertensive subjects were untreated at the time f study r had had treatment withdrawn fr at least ne mnth (bethanidine fr at least 2 days). Cntrl subjects had an arterial pressure cnsistently belw 140/90 mm Hg befre the study. Plasma Angitensln II Results Basal plasma All cncentratin was similar in nrmal subjects and patients with essential hypertensin r nntumrus hyperaldsternism (table 2). It was slightly, but nt significantly, lwer in patients with 's syndrme. Ttal bdy All clearance was als similar in nrmal subjects (5.6 ± 0.4 SEM 1 min" 1 ), in patients with essential hypertensin (6.2 ± min" 1 ) and nntumrus hyperaldsternism (5.2 ±1.1 1 min" 1 ), but slightly lwer (3.7 ± min" 1, p < 0.05) in 's syndrme cmpared with essential hypertensin. Bld Pressure Bld pressure was highest in 's syndrme (table 2, fig. 1). The largest increase f arterial pressure fr a given rise in plasma All was seen in 's syndrme, and the respnse in essential hypertensin was als greater than nrmal. The enhanced pressr respnse in essential hypertensin was nt a cnsequence f lwer All levels befre infusin, since these were similar t thse fund in nrmal subjects. T few data were btained t cmpare the pressr respnse t All in the nntumrus hyperaldsternism grup. 25 _, b ac S 20 T3 O t a I Change In Plasma Angitensln U: pg/ml FIGURE 1. Respnse f bld pressure t angitensin II infusin in nrmal subjects and patients with essential hypertensin and tumerus primary hyperaldsternism. Plasma Aldsterne and Crtisl Basal plasma aldsterne cncentratin (table 2) was slightly but insignificantly higher in patients with essential hypertensin than in nrmal subjects. It was significantly raised in bth nntumrus hyperaldsternism (p < 0.05) and in 's syndrme (p < 0.02). Infusin f All (table 2, figs. 2 and 3) increased plasma aldsterne cncentratin in all grups except in 's syndrme. The dse-respnse curve was steeper than nrmal in patients with essential hypertensin (fig. 2). Fr example, at the 4 ng kg" 1 min" 1 infusin rate, plasma aldsterne cncentratin increased by a mean f 23 ng 100 ml" 1 in essential hypertensin as cmpared with 15 ng 100 ml" 1 in nrmal subjects. This increased respnsiveness can als be illustrated by expressing the changes in plasma aldsterne and All as a rati that was significantly higher (p < 0.05) in essential hypertensive patients (0.62 ±0.12) than in nrmal subjects (0.32 ± 0.06). In the three cases f nntumrus hyperaldsternism, (fig. 2) a psitive respnse f aldsterne t All infusin cmpared t nrmal was btained that resembled that seen in essential hypertensin. Basal plasma crtisl levels were nt significantly different in the fur grups (nrmal, 7.9 ± 0.9 ng 100 ml" 1 ; 's syndrme, 7.0 ±1.3 ^ig 100 ml" 1 ; nntumrus hyperaldsternism, 3.1 ± 2.3 fig 100 ml" 1 ) and were nt significantly altered by All infusin.

3 STEROID RESPOE TO ANGIOTEIN IN HYPERTEION/Fraw el al Plasma 18-Hydrxycrtlcsterne Basal plasma 18-hydrxycrticsterne cncentratins were slightly but insignificantly raised in essential hypertensin and nntumrus hyperaldsternism (table 2). Hwever, cncentratins in patients with 's syndrme were markedly (p < 0.01) higher than nrmal. The prprtinate increase was greater fr 18-hydrxycrticsterne (ninefld) than fr aldsterne (furfld). As with aldsterne, plasma 18-hydrxycrticsterne increased in respnse t All infusin in nrmal subjects. In patients with essential hypertensin and nntumrus hyperaldsternism, the respnse was enhanced (figs. 4 and 5) while in 's syndrme TABLE 1. Clinical and Bichemical Characteristics f Subjects and Hypertensive Patients Primary hyperaldsternism Essential Characteristics subjects hypertensin Tumrus Nntumrus Number Sex, M/F Age(yrs) Bdy weight (kg) Bld pressure (mm Hg) Plasma sdium (mmle/liter) Plasma ptassium (mmle/liter) Plasma urea (mmle/liter) Plasma renin cncentratin (active, /ju/ml) 12 9/3 36± ± /77 ± 4/2 140 ± ± ± ±5 10 9/1 42 ± ± /97 ± 5/3 139 ± ± ± ±4 8 2/6 39 ± ± /109 ± 11/7 142 ± ± ± 0.5 8±2 3 1/2 49 ± ± /108 ± 15/9 141 ±1 3.4 ± ± ±2 TABLE 2. Effects f Angitensin II n Bld Pressure, Plasma Aldsterne, and 18-Hydrxycrticsterne in and Hypertensive Subjects (Mean ± SEtf) Angitensin II infusin (ng/kg/min) Preinfusin Plasma Plasma Plasma angitensin II (pg/ml) 17.5 ± ± ± ± 2.4* Mean bld pressure (mm Hg) 86±2 95 ± 3 «0.05) 119±6«0.001) 112 ±10* aldsterne (ng/100 ml) 8.5 ± ± ± 8.8 «0.02) 18.2 ± 2.3* 23.9 ± ± 6.6T 124 ±6 108 ± It 29.6 ± ± hydrxycrtic8terne (ng/100 ml) 7.4 ± ± ± 13.8 «0.01) 60.7 ± ± 3.8* 37.0 ± 27.8t 29.8 ± ± ± 5.6? 100 ±3 130 ±8 105 ± ± ± ± ± ± ± 13.6T 38.2 ± ± ± ± 9.3* 91 ±3 107 ± 3 «0.01) 138 ± 6 «0.001) 120 ±8* 17.2 ± ± 2.3 «0.01) 25.5 ± 3.3 (0.05) 39.3 ± 6.3* 13.9 ± ± 5.5 «0.01) 66.4 ± 20.4 «0.01) 51.0 ± 17.9* 77.5 ± ± J 98 ±7 115±3(<0.01) 155J 23.9 ± ± 2.9 «0.02) ± ± 5.6 (0.02) 44* ± $ 105 ± ± J 31.2 ±2.6 51t = nrmal subjects; = essential hypertensin; = 's syndrme; = nntumrus primary aldsternism. Figures in parenthesis are prbability values frm cmparisn with the nrmal grup by Students t. Where n value is given, p > *n = 3. T }n = l.

4 1-90 PATHOPHYSIOLOGY OF HYPERTEION SUPP I, HYPERTEION, VOL 3, N 3, MAY-JUNE, , 70 -, 50 - E ~ 60 S t c Essential Hypertensi.i 30 " 20 - Essential Hypertensin 20 " 10 i 20 i Plasma Angitensin II pg/ml Plasma Angitensin II pg/ ml FIGURE 2. Respnse f plasma aldsterne t angitensin II infusin in nrmal subjects and patients with essential hypertensin and nntumrus hyperaldsternism. S t 3 E in 3 Tumrus Plasma Angitensin II pg/ml FIGURE 3. Respnse f plasma aldsterne t angitensin II infusin in patients with 's syndrme. FIGURE 4. Respnse f plasma 18-hydrxycrticsterne t angitensin II infusin in patients with essential hyperten- it was subnrmal (fig. 6). Angitensin II infused at a rate f 4 ng kg" 1 min" 1 raised plasma 18-hydrxycrticsterne cncentratin by a mean f 23 ng 100 ml' 1 in the essential hypertensin grup, but nly 15 ng 100 ml" 1 in the nrmal subjects. The rati f the changes in plasma 18-hydrxycrticsterne and All (see abve) was als higher (p < 0.001) in essential hypertensin (0.68 ± 0.12) than nrmal (0.31 ± 0.05). Discussin Bld Pressure Respnse Angitensin II infusin increased BP in a dsedependent manner in all grups. The rise was greatest in 's syndrme, but was als greater than nrmal in essential hypertensin. These differences are unlikely t be explained by differences in All metablism amng grups since similar infusin rates prduced similar plasma cncentratins and because, in cntrast t ne previus study," angitensin clearance rates were als nt very different frm nrmal. A number f pssible mechanisms have been suggested t accunt fr changes in pressr sensitivity t All. 9 Amng these is the "ccupancy thery," which pstulates that at lw plasma levels f All, such as c-

5 STEROID RESPOE TO ANGIOTEIN IN HYPERTEION/Fmsw el al _. 70 " S 60 e Tumrus 50 " 50 " " > R x Plasma Angttenain n pg/ ml FIGURE 5. Respnse f plasma 18-hydrxycrticsterne t angitensin II infusin in nntumrus hyperaldsternism. cur fr example in sdium-laded subjects, prprtinately large numbers f smth muscle receptrs are free and available fr stimulatin. n< " Hwever, this cannt accunt fr the difference between nrmal and essential hypertensin here where basal ctapeptide levels were similar. Plasma Angitensin II pg/ ml FIGURE 6. Respnse f plasma 18-hydrxycrticsterne t angitensin II infusin in patients with 's syndrme. Aldsterne and 18-Hydrxycrticsterne Previusly reprted ratis f the plasma cncentratins f 18-hydrxycrticsterne and aldsterne in nrmal subjects lie between 1 and 2. The rati is increased during sdium depletin. 1 Schamberlan et al. 12 reprted higher ratis. In ur current study, the rati was apprximately 1 fr nrmal subjects and fr patients with essential hypertensin. In nntumrus hyperaldsternism, the rati was similar t that fund in these grups while that in 's syndrme, as als reprted by Biglieri and Schamberlan, 18 was higher at 2.3. In agreement with previus studies in nrmal subjects, 1 All infusin prvked parallel dse-dependent increases in the plasma cncentratins f aldsterne and 18-hydrxycrticsterne, but failed t d s in subjects with 's syndrme. Indeed, in sme studies All infusin may even have a mildly inhibitry effect n plasma aldsterne. 14 Explanatins f this pr respnse, which is well dcumented, 16 include the autnmus nature f the tumr secretin and a failure f exgenus All t penetrate the sterid-secreting tissue. Neither explanatin seems likely, hwever, since infusin f ACTH causes a brisk increase in aldsterne, ften greater than that btained in nrmal subjects. 16 Exgenus All inhibits ACTH in nrmal subjects. 1 ' In a recent study, 14 infusin f ACTH at a lw, cnstant rate restred the respnse f aldsterne t simultaneusly-infused All in 's syndrme. This suggests that the pr respnse t angitensin alne may have been due t inhibitin f the endgenus ACTH secretin n which aldstcrne is abnrmally dependent. Pr 18- hydrxycrticsterne respnses prbably have the same explanatin. In additin, fewer All receptrs may be present in the adenma tissue. 17 In patients with essential hypertensin, plasma aldsterne cncentratin was mre sensitive t infused All than in nrmal subjects, cnfirming several previus studies, 1 - " ' and plasma 18-hydrxycrticsterne levels shwed the same difference frm nrmal. In bth grups, hwever, there was a clse psitive crrelatin between sterid and ctapeptide levels, suggesting that the mechanism f the effect was

6 1-92 PATHOPHYSIOLOGY OF HYPERTEION SUPP I, HYPERTEION, VOL 3, N 3, MAY-JUNE, 1981 similar but exaggerated in essential hypertensin. In thery, increased respnse culd be due t an increase in the number r the affinity f adrencrtical angitensin receptrs. These can change independently. 20 There is sme evidence f altered affinity in essential hypertensin. 51 Distinctin Between Tumrus and Nntumrus Hyperaldsternlsm Althugh nly three cases f nntumrus hyperaldsternism were studied, the pattern f respnse t angitensin mre clsely resembled that seen in essential hypertensin than in 's syndrme. Other similarities f essential hypertensin and nntumrus hyperaldsternism have been discussed elsewhere. 2 ' M Fr example, while bth All and aldsterne levels remain within the nrmal range, in bth cnditins the aldsterne level assciated with a given All cncentratin is higher than in nrmal subjects: that is, All is lw relative t aldsterne. In this respect, the cncentratins resemble thse in 's syndrme, althugh the mechanism is clearly different Reflecting this, the crrelatin between basal All and aldsterne values is negative in 's syndrme and psitive in bth nrmal subjects and patients with essential hypertensin. A psitive crrelatin als exists between the tw variables in nntumrus hyperaldsternism, again calling int questin the "primary" nature f this disease. Demnstratin f adrencrtical micrndular hyperplasia in sme patients with essential hypertensin increases dubt as t the relevance f the pathlgy t hypertensin. 28 We suggest that nntumrus hyperaldsternism is nt a variant f 's syndrme, but is indistinguishable frm essential hypertensin frm which it has been wrngly separated. References 1. Fraser R, Brwn JJ, Lever AF, Masn PA, Rbertsn JIS: Cntrl f aldsterne secretin. Clin Sci 56: 389, Davies DL, Beevers DG, Brwn JJ, dimming AMM, Fraser R, Lever AF, Masn PA, Mrtn JJ, Rbertsn JIS, Tree M: Aldsterne and its stimuli in nrmal and hypertensive man: are essential hypertensin and primary hyperaldsternism withut tumur the same cnditin? J Endcr 81: 79P, Oelkers W, Brwn JJ, Fraser R, Lever AF, Mrtn JJ, Rbertsn JIS: Sensitizatin f the adrenal crtex t angitensin II in sdium deplete man. Circ Res 34: 69, Mrtn JJ, Semple PF, Waite MA, Brwn JJ, Lever AF, Rbertsn JIS: Assay f vasactive peptides. Angitensin I and II. In Hrmnes in Bld, edited by Antniades HN. Cambridge, Mass: Harvard University Press, 1976, p Fraser R, Guest S, Yung J: A cmparisn f duble istpe derivative and radiimmunlgical estimatin f plasma aldsterne cncentratin in man. Clin Sci Ml Med 45: 411, Wilsn A, Masn PA, Fraser R: Estimatin f 18-hydrxycrticsterne cncentratin in human peripheral plasma by gas liquid chrmatgraphy with electrn capture detectin. J Ster Bichcm 7: 611, Masn PA, Fraser R: Estimatin f aldsterne, 11 dexycrticsterne, 18 hydrxy 11 dexycrticsterne, crticsterne, crtisl and 11 dexycrtisl in human plasma by gas-liquid chrmatgraphy with electrn capture detectin. J Endcr 64: 277, Jhnstn CI, Mendelshn FAO, Dyle AE: Metablism f angitensin II in sdium depletin and hypertensin in humans. Circ Res 30 and 31 (suppl II): , Brwn JJ, Casals-Stenzel J, Cumming AMM, Davies DL, Frascr R, Lever AF, Mrtn JJ, Semple PF, Tree M, Rbertsn JIS: Angitensin II, aldsterne and arterial pressure: a quantitative apprach. Hypertensin 1: 159, Davis JO: The use f blcking agents t define the functins f the renin-angitensin system. Clin Sci Ml Med 48 (suppl 2): 3, Thurstn H, Laragh JH: Prir receptr ccupancy as a determinant f the prcssr activity f infused angitensin II in the rat. Circ Res 36: 113, Schamberlan M, Rse CR, Sebastian A, Biglieri EG: Influence f the renin angitensin system, ptassium and ACTH n plasma levels f 18 hydrxycrticsterne and aldsterne in man. Prc 6th Int Cngr Endcr. In press 13. Biglieri EG, Schamberlan M: The significance f elevated levels f plasma 18 hydrxycrticsterne in patients with primary aldsternism. J Clin Endcr Mctab 49: 87, Fraser R, Masn PA, Yung J: The acute effect f angitensin II n adrenal and anterir pituitary functin in nrmal subjects and subjects with primary hyperaldsternism. Prg Bichem Pharmacl 17: 14, Wenting GJ, Man in't Veld AJ, Derkx FH, Brummelen PV, Schalekamp MADH: ACTH-dependent aldsterne excess due t adrencrtical adenma: a variant f primary hypcraldsternism. J Clin Endcr Metab 46: 326, Semple PF, Buckingham JC, Masn PA, Fraser R: Suppressin f plasma ACTH cncentratin by angitensin II infusin in nrmal humans and in a subject with a sterid 17a hydrxylase defect. Clin Endcr 10: 137, Brwn G, Duglas J, Brav E: Angitensin II receptrs and in vitr aldsterne respnses f aldsterne-prducing adenmas adjacent nn-tumrus tissue and nrmal human adrenal glmerulsa. J Clin Endcr Metab 51: 718, Kisch ES, Dluhy RG,'Williams GH: Enhanced aldsterne respnse t angitensin II in human hypertensin. Circ Res 38: 502, Wisgerhf M, Brwn RD: Increased adrenal sensitivity t angitensin II in lw renin essential hypertensin. J Clin Invest 61: 1456, Catt KJ, Aguilcra G, Cappni A, Fujita K, Schiras A, Fakunding J: Angitensin II receptrs and aldsterne secretin. J Endcr 81: 37P, Williams GH, Hllenberg NK, Mre JJ, Swartz SL, Dluhy RG: The adrenal receptr fr angitensin II is altered in essential hypertensin. J Clin Invest 63: 419, Leading article. Idipathic aldsternism: a diagnstic artifact? Lancet 2: 1221, Cllins RD, Weinberger MH, Dwdy AJ, Nkes GW, Gnzales CM, Luetscher JA: Abnrmally sustained aldsterne secretin during salt lading in patients with varius frms f benign hypertensin: relatin t plasma renin activity. J Clin Invest 49: 1415, Grim C, Winnacker J, Peters T, Gilbert G: Lw renin nrmal aldsterne and hypertensin: circadian rhythm f renin, aldsterne, crtisl and grwth hrmne. J Clin Endcr Metab 39: 247, Re RN, Sanch J, Kliman B, Haber E: The characterizatin f lw renin hypertensin by plasma renin activity and plasma aldsterne cncentratin. J Clin Endcr Metab 46: 189, Lng DL, Esterly JA, Grim CE, Keitzer WF: Pathlgy f the adrenal gland in refractry lw renin hypertensin. Arch Pathl Lab Med 102: 322, 1978