Similar effects of hydrochlorothiazide and spironolactone on plasma renin activity in essential hypertension

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1 Similar effects f hydrchlrthiazide and spirnlactne n plasma renin activity in essential hypertensin Sergi Acchiard, M.D.* Harriet P. Dustan, M.D., Rbert C. Tarazi, M.D. Research Divisin Thiazide diuretics are the mst frequently used antihypertensive drugs. They reduce arterial pressure when used alne and enhance the effectiveness f nndiuretic antihypertensive drugs when used in cmbinatin. They cause sustained reductins f plasma vlume (PV) and elevate plasma renin activity (PRA). 1 Spirnlactne, an aldsterne antagnist, prduces similar effects n arterial pressure, 2 ' 3 plasma vlume, 4 and plasma renin. 3 ' 6 Of the pssible causes f this hyperreninemia, chrnic ligemia seemed mst likely t play a majr rle, because we had fund an inverse relatinship between PV and PRA in nrmal men, in men with untreated essential hypertensin, and in patients with untreated renvascular hypertensin. 7 Hwever, treatment culd bring ther factrs int play, such as decreases in arterial pressure, 8-9 decreases f plasma sdium, 10 and mdificatin f plasma ptassium cncentratin In additin, the pssibility f a direct effect f these drugs n the juxtaglmerular apparatus shuld be cnsidered, because renin release evked by fursemide has been attributed partfy t inhibitin f sdium This study supprted in part by grant HL-6835 frm the Natinal Heart and Lung Institute, PHS. * Present address: Department f Medicine, University f Tennessee, Schl f Medicine, Memphis, Tennessee

2 154 Cleveland Clinic Quarterly Vl. 39, N. 3 transprt by macula densa cells. 13 Such a mechanism is nt s readily accepted in explanatin fr elevatin f PRA prduced by spirnlactne, because this drug is a ptassium-sparing agent, 14 and may have its majr renal effects n tubular cells distal t the macula densa, althugh there is evidence t suggest that it als affects prximal prtins f the nephrn. 15 A grup f hypertensive patients treated with hydrchlrthiazide alne and anther treated nly with spirnlactne prvided an pprtunity t study the effects f these tw diuretics n PRA in regard t changes in arterial pressure, plasma vlume, and plasma sdium and ptassium cncentratins. Methds Twenty-fur patients with essential hypertensin were studied. Ten received hydrchlrthiazide, 12 spirnlactne, and tw received separate curses f each drug. The tw grups were fairly equally matched in age; thse treated with hydrchlrthiazide were between 30 and 63 years and thse treated with spirnlactne were between 35 and 63 years; in bth grups mst patients were between 45 and 55 years f age. Patients with essential hypertensin were selected because renal arterial r parenchymal diseases and primary aldsternism add factrs which culd make the assessment f diuretic-induced changes difficult. All patients had been investigated fr knwn causes f hypertensin by intravenus urgraphy and renal arterigraphy, and by measurement f urinary excretin rates f aldsterne and catechlamines whenever indicated by clinical features r labratry findings. The severity f hypertensive vascular disease had been determined by tests f renal excretry functin, electrcardigraphy, radigraphic measurement f heart size, and grading f retinal arterilar disease. Patients were either untreated r had been withut antihypertensive drugs fr a mnth r lnger befre cntrl measurements. All patients measured brachial arterial pressures at hme twice daily, and weekly averages f supine readings were used t establish pretreatment levels and t assess results f therapy. When arterial pressure had stabilized, treatment was begun. Hydrchlrthiazide was usually given as 25 mg twice daily and spirnlactne, 25 mg fur times daily. In the frmer grup, treatment ranged frm 1 t 36 mnths with 8 f the 13 patients receiving treatment fr 4 mnths r lnger. The 14 patients given spirnlactne were treated fr perids f 1 t 12 mnths, and 8 f the 14 received the drug 3 r mre mnths befre the bservatins reprted here were made. Plasma vlume, plasma renin activity, and serum sdium and ptassium cncentratins were measured befre treatment and several times during treatment. The last results btained, representing effects f the lngest term f treatment, were used fr this analysis. All measurements were made in the mrning after supine rest fr 30 t 45 minutes frm bld samples btained withut stasis. Plasma vlume was calculated frm the vlume f distributin f 2.5 fic f 125 I r 5 xc f 131 I human serum albumin, as previusly reprted. 16 Plasma renin activity was estimated using a mdified Pickens methd 7-17 and expressed as nan-

3 Winter 1972 Effects f hydrchlrthiazide and spirnlactne 155 grams f angitensin/ml/4 hr f incubatin. Serum sdium and ptassium cncentratins were measured by lithium internal standard flame phtmetry. Statistical analyses were perfrmed using cnventinal methds fr calculating the significance f standard t tests and crrelatin cefficients. 18 Results Befre treatment there were n significant differences between the tw grups in regard t arterial pressure, plasma vlume, plasma renin activity, and serum sdium and ptassium cncentratins (Table 1). With the exceptin f arterial pressure, mean values fr each grup were within nrmal ranges. Use f averages, hwever, bscures the hetergeneity within the grups, particularly in regard t plasma vlume and plasma renin activity. Fr plasma vlume ur nrmal value fr men is 18.7 ml/cm f height with a range frm 14.7 t 22 ml/cm representing the mean ± tw standard deviatins; fr wmen, the mean is 15.3 ml/cm and range, 11.9 t 18.7 ml/cm. 15 Thus, with the exceptin f three patients (Ns. 1, 10, and 17), plasma vlume was nrmal, but characteristic f essential hypertensives, 19 sme had values in the lwer part f the nrmal range and sme in the upper. In regard t plasma renin activity, althugh the mean values were nt significantly different frm ur previus findings in hypertensive patients, 7 in 8 f the 9 wmen and 11 f the 15 men PRA was less in essential hypertensin than the previusly reprted means. Als in cntrast t that earlier experience, n crrelatin was fund between PV and PRA. Serum ptassium cncentratin was 3.5 meq/liter r higher except in the ne instance f 3.3 meq/liter (N. 24). The cncurrent finding f lw plasma renin activity suggested the pssibility f primary aldsternism, but the reduced plasma vlume was against this pssibility and subsequently, urinary aldsterne was fund t be nrmal. Treatment with hydrchlrthiazide r spirnlactne prduced significant effects. In bth grups arterial pressure, plasma vlume, and serum sdium were similarly reduced and plasma renin activity was similarly elevated (p <.001 fr a cmparisn f each measurement with its cntrl value). Only in regard t serum ptassium were the effects prduced by the tw diuretics different, with hydrchlrthiazide treatment reducing its cncentratin and spirnlactne elevating it. As fr cntrl data, grup means during treatment bscured variatins in respnses. Whereas, withut exceptin, plasma renin activity was elevated and, with nly ne exceptin (N. 2, spirnlactne treatment), serum sdium cncentratin was reduced. Nt all patients had a significant lwering f arterial pressure and in five, (Ns. 1, 3, 7, 20 and 22), plasma vlume changed less than 1.0 ml/cm. T assess the relative imprtance f these changes in plasma vlume, serum sdium cncentratins and arterial bld pressure as determinants f renin activity elevatins, crrelatin cefficients (r) were calculated (Table 2). N relatinship was fund between percentile decreases f arterial pressure and increases f plasma renin. In regard t plasma vlume, when data

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5 Winter 1972 Effects f hydrchlrthiazide and spirnlactne 157 Table 2. Statistical evaluatin f the relatinships f percentile changes in plasma renin activity t percentile changes in plasma vlume, serum sdium cncentratin, and diastlic arterial pressure Plasma vlume Serum sdium Diastlic bld pressure Treatment grups N. r* P r P r P Hydrchlr n.s n.s n.s. thiazide Spirnlactne < n.s n.s. Bth < n.s. * r = crrelatin cefficient, n. s. nt significant. fr bth grups were cmbined there was a significant relatinship between the percentile decreases and elevatins f plasma renin activity (r = +.461, p <.02) (Fig. 1). Hwever, when data frm each grup were handled separately, a significant assciatin was fund in the spirnlactne-treated grup (r = +.533, p <.05), but nt amng patients receiving hydrchlrthiazide (r = +.474, p < 0.1). In the latter grup, althugh the crrelatin cefficient suggested a relatinship, the grup was t small (n = 12) t represent a statistically significant assciatin. Bth diuretics reduced serum sdium cncentratin. Althugh this reductin was greater in the spirnlactne-treated patients, it was nt significantly different frm the reductin prduced by hydrchlrthiazide. There was n crrelatin between percentile reductin in serum sdium cncentratin and percentile increases in PRA (Table 2) in either grup. Hwever, in the spirnlactne-treated patients, the measured serum sdium cncentratin crrelated inversely and significantly with the actual value fr plasma renin activity (r =.517, p <.05). N assciatin was fund between serum ptassium cncentratin and PRA with either treatment. Discussin Shrt-term experiments in man and in dgs have prvided ample evidence that plasma renin activity is influenced by intravascular vlume, arterial pressure, 8-9 > 22 neural activity, 23 ' 24 and ASSOCIATION OF DIURETIC-INDUCED CHANGES HYDROCHLOROTHIAZIDE SPIRONOLACTONE, PLASMA VOLUME - + % CHANGE 1600 pl % CHANGE -B PRA Fig. 1. Relatinship between rise in PRA and fall in plasma vlume in hypertensive patients during lng-term treatment with hydrchlrthiazide (clsed circles) and spirnlactne (pen circles), crrelatin cefficient (r).461, p <.02.

6 158 Cleveland Clinic Quarterly Vl. 39, N. 3 plasma cncentratins f sdium 10 and ptassium. 11 ' 12 > 25 ' 26 Less well explred is the pssibility that these factrs perate quantitatively during chrnic illnesses and their treatments. In this study, the significant crrelatin between percentile reductins f PV and elevatins f PRA suggests that chrnic ligemia plays an nging rle in renin prductin and release during mnths and years f diuretic treatment. That this is in sme way an effect f ligemia, rather than f the diuretics themselves, is supprted by ur previus finding 7 f an inverse relatinship between intravascular vlume and PRA in nrmal men, men with essential hypertensin, and patients with renvascular hypertensin. A similar suggestin cncerning bld vlume-renin relatinships had cme frm a study f the effects f discntinuing lng-term hydrchlrthiazide treatment. 1 We fund that during the first week withut the diuretic PV rse and elevated levels f PRA decreased t nrmal. Althugh this suggested a suppressin f renin release by intravascular vlume expansin, decrease f PRA culd have reflected merely lack f a direct diuretic-stimulating effect. Hwever, mre recently, we have shwn 27 that during treatment with hydrchlrthiazide r spirnlactne r bth, PRA can be substantially reduced by rapid intravascular vlume expansin with dextran in either 5% glucse r istnic sdium chlride slutins even thugh dextran in glucse decreased serum sdium cncentratin substantially. These results suggest that regardless f any direct renal effects f diuretics n renin prductin and release, intravascular vlume plays a rle in determining the level f plasma renin activity. Hw this perates is nt knwn but pssible explanatins are mdificatin f stretch receptrs in afferent arteriles, 29 f sympathetic vasmtr utflw t the kidneys, 23 and f prximal tubular sdium reabsrptin that wuld determine the amunt f sdium reaching the macula densa. 30 In regard t intravascular vlume- PRA relatinships, it shuld be mentined that befre treatment an inverse crrelatin was nt fund in these patients as previusly reprted fr essentiaf hypertensin. 7 Since this was a retrspective study f the effects f tw diuretics n PRA, the grup cntained a number f patients with "hypervlemic essential hypertensin" wh, because f either expanded plasma vlume r plasma vlume inapprpriately nrmal fr the height f diastlic arterial pressure, were expected t respnd well t diuretic treatment. 19 Further, PRA was lwer and the range f values mre limited than usually fund in hypertensive patients. 7 Thus, neither plasma vlume nr plasma renin activity was representative fr the spectrum f essential hypertensin. Lng-term interrelatinships f arterial pressure and the renal pressr system remain bscure. In this study we failed t find an assciatin between arterial pressure reductin and increases f PRA. This may indicate that in hypertensive patients s treated, whatever pressure is achieved reflects the sum f the depressr ptential f the drug and the pressr ptential ffered by substantial increases f PRA. In fact, these increases are f a magnitude ften fund in patients with renvascular hypertensin, a cnditin in which we have fund evidence fr a direct relatinship be-

7 Winter 1972 Effects f hydrchlrthiazide and spirnlactne 159 tween severity f hypertensin and peripheral PRA. As yet there is n understanding f the mechanism whereby diuretic drugs lwer arterial pressure, and at the same time raise PRA. There is cnsiderable evidence that plasma sdium cncentratin plays a rle in renin prductin r release r bth, nt nly in animal studies f brief duratin, 31 but als in chrnic illness. 10 In renal perfusin studies in dgs, Nash et al 31 evked renin release by lwering sdium cncentratin and then suppressed it by increasing sdium cncentratin. In regard t these relatinships in chrnic illness, Brwn et al 10 fund an inverse assciatin between serum sdium and renin cncentratins in a large grup f patients with a brad spectrum f hypertensive disrders. The same relatinship was fund between serum sdium cncentratin and PRA btained in ur spirnlactne-treated patients, but nt in thse receiving hydrchlrthiazide. Bth diuretics decreased serum sdium cncentratin and, althugh the spirnlactne decrease was greater, it was nt significantly s. These effects n sdium cncentratin are similar t thse btained by Mrrisn and Sebestyn 32 in a cmparative study f the tw diuretics. They fund, during tw weeks f treatment, that althugh hydrchlrthiazide increased urine vlume mre than spirnlactne, each prduced the same degree f negative sdium balance, and that as a cnsequence spirnlactne treatment was assciated with greater decreases in serum sdium cncentratin. Our failure t find a relatinship between serum sdium and PRA with hydrchlrthiazide administratin is nt readily explainable. Cnsidering the kalipenic effect f this diuretic and the recent demnstratins f an inverse relatinship between serum ptassium cncentratin and renin, 11-12, 25, 26 ne might expect t find that PRA enhancement by hypnatremia wuld be reinfrced by decreases in serum ptassium. Cnversely, the finding f an inverse relatinship between serum sdium cncentratin and PRA during spirnlactne treatment was unexpected since serum ptassium was maintained at levels that culd cnceivably blunt the effects f hypnatremia. Whatever the influence f these plasma electrlyte cncentratins n renin release may be, it seems capable f being ver-ridden by extracellular fluid expansin. As referred t abve, 27 elevated PRA fund during hydrchlrthiazide r spirnlactne treatment r bth culd be quickly suppressed by rapid intravascular vlume expansin whether r nt serum sdium value fell. Als, Newsme and Bartter 33 shwed in experiments f several days' duratin that verhydrating nrmal persns suppressed bth PRA and serum sdium. Further, plasma renin cncentratin has been fund t be nrmal r lw in patients with inapprpriate ADH secretin and marked hypnatremia and high in assciatin with dehydratin and hypernatremia. 35 This study prvides n infrmatin cncerning different direct effects f these tw drugs n the juxtaglmerular apparatus. If there are differences, it seems likely that the similar extrarenal effects n plasma vlume and sdium cncentratin were enugh t bscure them. Vander has prpsed that renin release is reg-

8 160 Cleveland Clinic Quarterly Vl. 39, N. 3 ulated by the amunt f sdium reaching the macula densa area and by the ability f these cells t reabsrb it. He suggests that fursemide and prbably ther chlrthiazide diuretics impair this transprt functin. Since bth ligemia and hypnatremia diminish the filtered sdium lad and thereby influence fractinal sdium reabsrptin by the prximal tubule, 36 this wuld limit the amunt f sdium reaching mre distal prtins f the nephrn, the macula densa, and the area where Na+-K+ exchange is influenced by aldsterne. Thus, as in this study, the ligemic and hypnatremic effects f tw dissimilar diuretics culd s restrict the distal sdium lad as t bscure any difference between a macula densa blckade by hydrchlrthiazide and a mre distal aldsterne antagnism by spirnlactne. Cnsidering the number f factrs nw knwn t stimulate renin release, the number that will prbably be fund related t renin prductin, as well as the cmplexities f the reninrenin substrate reactin, it is unlikely that a clinical study such as this can describe a ne-fr-ne relatinship between a factr releasing renin and PRA. It may be pssible, hwever, that a multifactrial analysis can describe the relative imprtance f each f the varius factrs. Summary Mechanisms whereby plasma renin activity becmes elevated during chrnic treatment with tw dissimilar diuretics, hydrchlrthiazide and spirnlactne, were studied in patients with uncmplicated, essential hypertensin. Twelve patients were given hydrchlrthiazide (50 mg/day) and 14 received spirnlactne (100 mg/day) fr 3 t 11 mnths. Each patient measured his arterial pressure twice daily. Plasma renin activity (PRA), plasma vlume (PV), and serum sdium and ptassium cncentratins were measured befre and several times during treatment. Except that serum ptassium was significantly reduced by hydrchlrthiazide (p <.001) and elevated by spirnlactne (p <.001), effects f the tw diuretics were similar. PRA increased equally; sdium, PV, and bld pressure decreased equally; all changes were significant at p <.001. Fr the tw grups cmbined, increase in PRA crrelated directly with plasma vlume reductin (r = +.461, p <.02), but nt with decrease f arterial pressure r percentile changes in serum sdium and ptassium. Hwever, in spirnlactne-treated patients serum sdium cncentratin and PRA were inversely assciated (r =.517, p <.05). The data suggest that chrnic ligemia is an imprtant determinant f PRA in diuretic-treated patients, and that plasma sdium cncentratin may als be a factr. Acknwledgment We thank Dr. William E. Wagner f Ciba Pharmaceutical C. fr generus supplies f hydrchlrthiazide. References 1. Tarazi RC, Dustan HP, Frhlich ED: Lng-term thiazide therapy in essential hypertensin. Circulatin 41: , Cranstn WI, Juil-Jinsen BE: The effects f spirnlactne and chlrthalidne n arterial pressure. Lancet 1: , Jhnsn LC, Grieble HG: Treatment f

9 Winter 1972 Effects f hydrchlrthiazide and spirnlactne 161 arterial hypertensive disease with diuretics. V. Spirnlactne, an aldsterne antagnist. Arch Intern Med 119: , Dustan HP, Brav EL, Tarazi RC: Vlume dependent essential and sterid hypertensin (submitted fr publicatin). 5. Maebashi M, Yshinaga K: Changes in plasma renin activity after administratin f spirnlactne. Jap Cire J 31: , Jse A, Crut JR, Kaplan NM: Suppressed plasma renin activity in essential hypertensin. Ann Intern Med 72: 9-16, Dustan HP, Tarazi RC, Frhlich ED: Functinal crrelates f plasma renin activity in hypertensive patients. Circulatin 41: , Kanek Y, Ikeda T, Takeda T, et al: Renin release during acute reductin f arterial pressure in nrmtensive subjects and patients with renvascular hypertensin. J Clin Invest 46: , Kuchel O, Fishman LM, Liddle GW, et al: Effect f diazxide n plasma renin activity in hypertensive patients. Ann Intern Med 67: , Brwn JJ, Davies DL, Lever AF, et al: Plasma renin cncentratin in human hypertensin: I. Relatinship between renin, sdium and ptassium. Br Med J 2: , Dluhy RG, Underwd RH, Williams GH: Influence f dietary ptassium n plasma renin activity in nrmal man. J Appl Physil 28: , Brunner HR, Baer L, Sealey JE, et al: The influence f ptassium administratin and f ptassium deprivatin n plasma renin in nrmal and hypertensive subjects. J Clin Invest 49: , Vander AJ, Carlsn J: Mechanism f the effects f fursemide n renin secretin in anesthetized dgs. Circ Res 25: , Kagawa CM, Sturtevant FM, Van Arman CG: Pharmaclgy f a new sterid that blcks salt activity f aldsterne and desxycrticsterne. J Pharmacl Exp Ther 126: , Hierhlzer K, Stlte H: The prximal and distal tubular actin f adrenal sterids n Na reabsrptin. Nephrn 6: , Tarazi RC, Dustan HP, Frhlich ED: Plasma vlume in men with essential hypertensin. N Engl J Med 278: , Pickens PT, Bumpus FM, Llyd AM, et al: Measurement f renin activity in human plasma. Circ Res 17: , Crxtn FE, Cwden DJ: Applied General Statistics. New Yrk: Prentice Hall, Tarazi RC, Dustan HP, Frhlich ED, et al: Plasma vlume and chrnic hypertensin. Relatinship t arterial pressure levels in different hypertensive diseases. Arch Intern Med 125: , Davis JO, Carpenter CCJ, Ayers CR, et al: Evidence fr secretin f an aldsternestimulating hrmne by the kidney. J Clin Invest 40: , Skillman JJ, Lauler DP, Hickler RB, et al: Hemrrhage in nrmal man: Effect n renin, Crtisl, aldsterne, and urine cmpsitin. Ann Surg 166: , Skinner SL, McCubbin JW, Page IH: Renal barceptr cntrl f renin secretin. Science 141: , Bunag RD, Page IH, McCubbin JW: Neural stimulatin f release f renin. Circ Res 19: , Grdn RD, Kuchel O, Liddle GW, et al: Rle f the sympathetic nervus system in regulating renin and aldsterne prductin in man. J Clin Invest 46: , Vander AJ: Direct effects f ptassium n renin secretin and renal functin. Am J Physil 219: , Sealey JE, Clark I, Bull MB, et al: Ptassium balance and the cntrl f renin secretin. J Clin Invest 49: , Hall PM, Dustan HP, Tarazi RC: Suppressin f renin release by intravascular vlume expansin during chrnic diuretic treatment. (Submitted fr publicatin.) 28. Meyer P, Menard J, Papaniclau N, et al: Mechanism f renin release fllwing diuresis in rabbits. Am J Physil 215: , Tbian L: Relatinship f juxtaglmerular apparatus t renin and angitensin. Circulatin 25: , Vander AJ: Cntrl f renin release. Physil Rev 47: , Nash FD, Rstrfer HH, Bailie MD, et al: Renin release: Relatin t renal sdium

10 162 Cleveland Clinic Quarterly Vl. 39, N. 3 lad and dissciatin frm hemdynamic changes. Circ Res 22: , Mrrisn RS, Sebestyen CS: Cntrasting effects f hydrchlrthiazide and spirnlactne. (Abstr). Clin Res 9: 206, Newsme HH, Bartter FC: Plasma renin activity in relatin t serum sdium cncentratin and bdy fluid balance. J Clin Endcrinl 28: , Brwn JJ, Davies DL, Lever AF, et al: Plasma renin in hypertensin and in patient with versecretin f ADH. J Endcrinl 32: v-vii, Grdn RD, Pawsey CGK: Relative effects f serum sdium cncentratin and state f bdy fluid balance n renin secretin. J Clin Endcrinl Metab 32: , Berliner RW, Davidsn DG: Prductin f hypertnic urine in the absence f pituitary antidiuretic hrmne. J Clin Invest 36: , 1957.