Effects of Five Per Cent Dextrose-Water Infusions in Normal and Hypertensive Man

Transcription

1 Effects of Five Per Cent Dextrose-Wter Infusions in Norml nd Hypertensive Mn Evidence for Incresed Proximl nd Distl Tubulr Sodium Rejection by Hypertensive Ptients nd Its Reltion to Renl Hemodynmics By PAUL J. CANNON, M.D. Downloded from by on July 26, 218 SUMMARY During infusions of 5% dextrose in wter urinry sodium excretion nd the renl tubulr rejection of filtered sodium (E/F N %) were significntly higher in hypertensive thn in normotensive subjects. Incresed E/F N % did not result from ltertions in plsm sodium, in filtered sodium, or from n osmotic diuresis. Frctionl sodium rebsorption in proximl (isosmotic) portions of the nephron ws diminished in the hypertensive ptients. Free wter forrntion (CH2) rose with incresed "distl" sodium delivery (V) in both groups; however, frctionl sodium rebsorption in the "distl" nephron ws significntly impired in the hypertensive ptients nd urinry osmollity ws incresed. Men rteril blood pressure nd E/F N % were relted in curviliner fshion in the 31 studies, nd there ws direct reltion between E/F N % nd the mgnitude of renl vsculr resistnce. The dt suggested tht ltertions of renl rteril pressure nd vsculr resistnce in hypertensive disese modify sodium trnsport in proximl nd diluting segments of the nephron nd determine to mjor extent the incresed ntriuresis exhibited by hypertensive subjects during infusions tht expnd extrcellulr fluid volume. Additionl Indexing Words: Sodium excretion Ntriuresis FACTORS tht influence the rte of renl tubulr sodium rebsorption under norml circumstnces hve not been completely clrified. Studies from mny lbortories hve indicted tht the diminished renl tubulr sodium rebsorption developing in response to infusions of sline or Ringer's solution in norml nimls does not result from chnges From the Deprtment of Medicine, College of Physicins nd Surgeons, Columbi University nd the Presbyterin Hospitl, New York, New York. Supported by U.S. Public Helth Service Grnts HE 1182 nd HE Dr. Cnnon is recipient of U.S. Public Helth Service Creer Development Awrd HE 1532 of the Ntionl Hert Institute. Extrcellulr fluid volume expnsion 832 Hypertension in glomerulr filtrtion rte, the filtered lod of sodium, or ldosterone secretion.1 6 To explin this phenomenon of "sline diuresis" ttention hs recently been directed towrd the presence of "third fctor,"7 which my either be "ntriuretic" hormonel 841 or n intrrenl hemodynmic djustment to extrcellulr fluid (ECF) volume expnsion5 11,12 or combintion of both.13 Ptients with rteril hypertension exhibit n exggerted ntriuresis in response to infusions of sline or mnnitol The mechnism limiting tubulr sodium rebsorption in hypertensive more thn in norml subjects during the infusions remins unexplined. It is probbly functionl bnorrnlity rther Circultion, Volume XXXVII, My 1968

2 Downloded from by on July 26, 218 FIVE PER CENT DEXTROSE-WATER INFUSIONS thn the result of structurl dmge to the renl tubules since (1) incresed ntriuresis by hypertensive subjects is mnifest only during the infusions of sline or mnnitol, nd (2) renl slt wsting is not pprent in hypertensive subjects not receiving infusions when they re mintined on norml or low sodium intke.2' 28 The present studies were designed to investigte hemodynmic fctors tht might be involved in the phenomenon of slt rejection in norml nd hypertensive mn during mild degree of expnsion of the extrcellulr fluid volume. To this end renl hemodynmics nd the ntriuretic responses of hypertensive ptients were exmined during rpid infusions of 5% dextrose in wter nd were compred to those of norml nd slt-depleted control subjects. The studies confirm observtions of Ek29 tht n exggerted ntriuresis does occur in hypertensive ptients in response to infusion of 5% dextrose nd wter. In ddition they demonstrte (1) tht in hypertensive ptients during the infusions, sodium rebsorption is impired not only in the proximl tubules but lso in distl "diluting" segments of the nephron, nd (2) tht the degree of sodium rejection is correlted with the men rteril blood pressure nd the renl vsculr resistnce. Methods Thirty-one renl clernce studies were performed in nine norml volunteers nd 18 ptients with essentil hypertension nd one ptient with hypertension cused by n ldosterone-secreting denom. Ech of the hypertensive subjects nd six control subjects prior to study received diet contining 4 to 6 g of sodium; five studies were performed fter the control subjects hd received low-sodium diet (less thn.875 g of NCl per dy) for 4 to 7 dys. None of the ptients received mediction other thn occsionl bedtime sedtion with brbiturtes. None hd ppilledem or congestive hert filure or blood re nitrogen level bove 26 mg/1 ml. All experiments were performed t the sme erly morning hour with the subjects fsting, resting quietly in bed. Wter diuresis ws induced by orl dministrtion of 5 ml of wter during the hour prior to the infusion nd ws mintined by intrvenous dministrtion of 5% dextrose solution t rte of 15 ml/min in Circultion, Volume XXXVII, My studies nd 9 ml/min in nine studies, held constnt by motor-driven pump. Urine collections were mde nd discrded until stedy stte of mximl urine flow ws chieved. Three or four 1-minute clernce periods were then obtined. Venous blood smples were collected t pproprite intervls through n indwelling needle. Urine ws collected continuously vi n indwelling ctheter. Blood pressure ws mesured from the rm during the clernce periods by stndrd cuff mercury sphygmomnometer. The rtes of glomerulr filtrtion (GFR) nd of effective renl plsm flow (ERPF) were mesured by the dministrtion of inulin or14cinulin nd pr-minohippuric cid (PAH). Adequte priming doses were given intrvenously; then these substnces were dded to the 5% dextrose infusion in mounts to mintin constnt plsm concentrtions. PAH ws dded to the sustining infusion immeditely before use to void the depression in PAH extrction tht cn occur when PAH nd dextrose re incubted together for severl hours.3 Plsm nd urine smples were nlyzed for inulin by the nthrone method,31 for 14C-inulin by the method of Cotlove,32 nd for PAH by the method of Smith.33 Sodium nd potssium concentrtions in plsm nd urine were mesured by n Instrumenttion Assocites flme photometer. Chloride concentrtions were mesured by potentiometric titrtion with the Cotlove chloridometer. Urine nd plsm totl-solute concentrtions were mesured with n Advnced Instruments osmometer. Clcultions: Men rteril blood pressure ws clculted s the verge of systolic nd distolic pressures in millimeters of mercury. Effective renl blood flow ws clculted s the clernce of PAH divided by 1 - hct nd ws expressed in milliliters per minute. Renl vsculr resistnce ws clculted by dividing effective renl blood flow by the men rteril blood pressure nd ws reported in rbitrry resistnce units (RU). The glomerulr filtrtion rte ws estimted from the clernce of inulin (CIN) nd expressed in milliliters per minute. Osmolr nd free wter clernces were clculted in the mnner described by Smith:33 COSm =UOSm V/POSM; CH2= V -UOSm V/Posm, where V is the urine flow in milliliters per minute nd Uosm nd Posm re the solute concentrtions of urine nd plsm in milliosmoles per kilogrm of wter. Filtered solute lod ws clculted s the osmollity of plsm in micro-osmoles per milligrm. H2 X CIN in milliliters per minute ws expressed s micro-osmoles per minute. The percentge of the urinry solute concentrtion due to slt ws clculted by the formul: UNmEq/L + UclmEq/L + UosmmOsnM/kg H2 x 1.

3 834 CANNON Tble 1 Electrolyte Excretion During Five Per Cent Dextrose-Wter Infusions in Hypertensive Ptients (Regulr Sodm Diet-5% D/W Infusion i.v. t 15 ml/min) Subject S.M. G.A.R. J.O.N. H.I. B.O.*1 B.O.2 B.O.3 R.O. R.D. P.A. P.A.W. *Conn's BP. Filtrtion CIN CPAH RBF (ml/min) (ml/min) (mllmin) BP (mm Hg) 2/12 18/11 18/18 25/15 23/ / /1 23/ /12 29/ / syndrome 1-initil 2-K + repleted 3-post op Tble 2 Electrolyte Excretion During Five Per Cent Dextrose-Wter Infusions in Hypertensive Ptients (Regulr Sodium Diet-5% D/W Infusion i.v. t 9 ml/min) frction (%) Renl resistnce (RU) UNV (ueq 1min) Downloded from by on July 26, 218 Filtrtion Renl BP CIN CPAH RBF frction resistnce UN&V Subject (mm Hg) (ml min) (ml min) (ml/mmin) (%) (RU) (geq/min) P.E.R. 21/ B.O.O. 25/ D.A.V. 2/ C.H.A. 22/ D.I.A. 23/ L.A.W. 26/ R.I.C. 27/ K.L.A. 235/ W.I.* 23/ *Pt. prtilly restricted N + intke. The excretion of "non-slt" solutes ws clculted by subtrcting the urinry sodium nd chloride excretion rtes in microequivlents per minute from the totl solute excretion in micro-osmoles per minute. In studies performed during mximl wter diuresis frctionl rebsorption of sodium in the proximl tubules nd in distl "diluting" segments of the nephron (scending limb of Henle's loop, distl tubules) ws ssessed indirectly. The "distl sodium lod" ws clculted s UNV,Eq/min + (PN,uEq/ml X CH2 ml/min) nd ws expressed in microequivlents per minute. This vlue is the sum of the mount of sodium tht must hve been rebsorbed in free wter genertion plus the mount simultneously ppering in the urine; it represents the miniml mount of sodium tht must hve been delivered beyond the proximl site of isosmotic rebsorption to the distl segments of the nephron where free wter is generted by selective rebsorption of sodium. The frction of filtered sodium rejected by the proximl tubules ws clculted by dividing the "distl sodium lod" by the filtered sodium lod, nd ws expressed s percentge, tht is, UNV + (PN X CH2O) *-(CIN X PN) X 1. Frctionl rejection of soditim in distl "diluting" segments of the nephron ws estimted by computing the percentge of the "distl sodium lod" excreted in the urine, tht I UN V (UN V + PN X CH2) X 1. Results re reported in the text s men nd stndrd devition (SD). Differences between the mens found in groups of studies were Circultion, Volume XXXVII, My 1968

4 FIVE PER CENT DEXTROSE-WATER INFUSIONS 835 UKV ( ueq min) E/FN (%) Uosm (mosm/ kg H2) UN + UCi Uosm (%) Uosm V ( Osm/min) Cosm (mi/min) CH2O (ml/min) V V (mi/min) Downloded from by on July 26, 218 UKV UKV (ueqimin) E/FN (No) Uosm (MOSM /kg H2) UN + UcI Uosm (%) compred with the Student t test for unpired vribles. Regression lines nd correltion coefficients were clculted ccording to stndrd sttisticl techniques.34 Results The results re presented in tbles 1, 2, nd 3 nd in figures 1 to 7. Ech number in the tbles nd ech point on the grphs represent the men of vlues obtined in one study during three or four 1-minute clernce periods t stedy stte of wter diuresis. Electrolyte Excretion The ptterns of electrolyte excretion exhibited by hypertensive ptients during the Circultion, Volume XXXVII, MY 1968 Uosm V {AOsm /min) Cosm (ml/min) C H2 (ml/min) V (mi/min) dextrose nd wter (D/W) infusions pper in tbles 1 to 3 nd figure 1. Also shown for comprison re the ptterns exhibited by norml nd sodium-depleted control subjects. An exggerted ntriuretic response to 5% D/W infusion ws observed in ll but two of the hypertensive subjects (fig. 1). Urinry sodium excretion in the ptients with elevted blood pressure verged 458 ± 21 IuEq/min, vlue significntly higher thn the men sodium excretion of norml subjects on similr diets who received similr mounts of fluid (15 ml/min), 133 ± 29.tEq/min (P <.1). The urinry sodium excretion of hypertensive ptients who received the infusion

5 836 Electrolyte Excretion During Five Per Cent Dextrose-Wter Infusions in Norml Subjects CANNON Tble 3 Subject Regulr Sodium B.U. S.M. S.U. S.M.I. P.E. F.R. Low-Sodium Diet-5% D/W S.M. 11/72 S.M.I. 15/6 P.E. 94/64 P.E.T. 1/64 P.E. 98/7 BP CIN CPAH (mm Hg) (ml l min) (ml / min) Diet-5% D/W infusion i.v. t 15 ml/min 128/ / / / / / infusion i.v. t ml/min RBF (ml/min) Filtrtion frction (N) Renl resistnce (RU) UXV (,EqImin) Downloded from by on July 26, 218 UNV ueq/min 8 r- 7 H 6 [ 5 F F. U. OCP V ml/min Figure 1 Sodium excretion of hypertensive ptients nd norml subjects during 5% D/W infusions is plotted ginst the simultneous urinry volume in ech study. An exggerted ntriuresis ws pprent in the hypertensive ptients. In studies performed with D/W infusion rte of 15 ml/min, the sodium excretion rte (UN V) ws higher in the hypertensive (-) thn in the norml (o) subjects, even when the urinry flow rtes (V) were comprble. Vlues from studies of hypertensive ptients receiving D/W t 9 ml/min re indicted by nd from studies of slt-depleted norml subjects re indicted by. of D/W t the slower rte of 9 ml/min ws lso bove norml nd verged ueq/min (P<.2). Men serum sodium concentrtion ws not significntly different in the hypertensive nd norml subjects (139 ± 6 meq/l nd 14 ±4 meq/ L, respectively), nd the men filtered lod of sodium ws somewht lower in the hypertensive group s consequence of lower men glomerulr filtrtion rte (vide infr). Despite this, the frction of filtered sodium excreted in the urine (E/FN (verged % in the hypertensive subjects nd ws significntly higher thn the E/FN of % noted in the control subjects (P <.1). Men E/FN in hypertensive subjects who received the slower infusion ws lso incresed to 3.6 ± 3.4%. Dietry sodium depletion diminished the sodium excretion observed in the control subjects during D/W infusion; in these studies urinry sodium output verged ,uEq/ min, nd there ws corresponding decline in the tubulr rejection frction for sodium to.21 ±.8%. Urinry potssium output ws ,tEq/ min nd 5 ± 11,uEq/min in the two sets of studies of hypertensive ptients, not significntly incresed bove the vlues observed in norml persons on regulr sodium diets, 52 + Circultion, Volume XXXVII, My 1968

6 FIVE PER CENT DEXTROSE-WATER INFUSIONS 837 Uosm UN + UcI UKV E/FN (mosm/kg Uosm Uosm V Cosm CH2 V (,ueqlmin) (%) H2) (%) (,Osm/min) (mllmin) (ml/min) (ml/mmin) Downloded from by on July 26, ueq/min, or fter sodium deprivtion ,iEq/min. Renl Hemodynmics Men rteril blood pressure of the hypertensive ptients ws significntly elevted nd verged 158 ± 19 mm Hg during the 11 studies with 5% D/W t 15 ml/min nd 185 ± mm Hg during the nine studies t 9 ml/min (tbles 1 nd 2). Men blood pressure during MEAN BY mm Hg U8 18 * S. vq * _ ft OA O AA i studies of the control subjects who received norml sodium diets verged 92 ± 5 mm Hg (tble 3). During studies of control subjects fter sodium depletion men rteril blood pressure ws reduced to mm Hg. Glomerulr filtrtion rte of the hypertensive ptients ws reduced; the inulin clernce (CIN) ws 82 ± 28 ml/ min in those who received the more rpid D/W infusions nd 8+2 ml in the other group. In the * * U. A cp O n * *:so o FILT FX % RBF ml /min GFR ml/min Figure 2 The level of men rteril blood pressure during ech study is plotted ginst the renl blood flow (ERBF) in left column, the glomerulr filtrtion rte (CIN) in center column, nd ginst the filtrtion frction (%) in right column. Circultion, Volume XXXVII, My 1968

7 Downloded from by on July 26, control subjects the CIN ws ml/min in those on regulr sodium diets nd ml/min in those who were deprived of sodium. Effective renl blood flow (ERBF) ws lso decresed in the two hypertensive groups, verging ml/min in the former nd ml/min in the ltter. In the control subjects ERBF ws ml/min nd ml/min fter sodium depletion. Among the entire group of studies of norml nd hypertensive ptients there ws n inverse reltionship between the height of men blood pressure nd the effective renl blood flow (fig. 2 left). No directly inverse reltionships between the level of blood pressure nd the glomerulr filtrtion rte or filtrtion frction were pprent however (fig. 2 left, center, nd right). Reltionships Between Slt Excretion nd Solute Lod In order to exmine the possibility tht the incresed tubulr slt rejection by hypertensive subjects might hve resulted from n osmotic diuresis in these ptients, vrious reltionships between sodium excretion nd solute lod were clculted. In the studies of hypertensive ptients nd normotensive control subjects there ws poor correltion between the filtered solute lod nd the rte of urinry sodium excretion (r =.493). Similrly, the correltion between the urinry excretion of solutes exclusive of sodium nd chloride nd the rte of urinry sodium excretion ws lso poor (r -.83). The "nonslt" solute excretion ws clculted per 1 ml of glomerulr filtrtion in both norml nd hypertensive ptients to correct for possible differences in renl mss; this vlue lso did not correlte well with the E/FN% (r=.6468). Incresed Sodium nd Osmolr Concentrtions in Hypertensives (Tble 1) During stedy stte of wter diuresis urinry osmollity verged 92 ± 12 mosm/ L in the hypertensive ptients, vlue significntly higher thn the men osmollity of mosm/l observed in the norml subjects who received the sme mounts of fluid (15 ml/min) (P <.1). Urinry osmollity CANNON ws 152 ± 7 mosm/l in the hypertensive subjects who received the D/W infusion t slower rte, nd ws 58 ± 15 mosm/l during studies of slt-depleted norml subjects. The incresed urinry osmollity of the hypertensive subject ws lrgely due to incresed urinry sodium nd chloride concentrtions. During pek wter diuresis the urinry sodium concentrtion (UN) of the hypertensive ptients verged 38 ± 4 meq/l, vlue significntly higher thn the (UN) of 19 ± 4 meq/l observed in control subjects receiving the sme diet nd similr D/W infusions (15 ml/min) (P <.1). The dt plotted in figure 1 indicte tht hypertensive ptients excreted more sodium per unit volume of urine even when urinry flow rtes were in the sme rnge s those of the norml controls. The percentge of the urinry osmollity due to slt ( UN+ c %) verged % nd %, respectively, in the two groups of hypertensive ptients but only 22+8% in control subjects receiving regulr diets nd 7 + 3% in control subjects fter sodium depletion. Thus the incresed contribution of sodium nd chloride to urinry osmollity in the hypertensive ptient ws highly significnt (P <.1). Ptterns of Solute nd Free Wter Clernce During Wter Diuresis (Tble 1) The urinry flow rte during the rpid dextrose-wter infusion verged ml/min in the hypertensive ptients nd mi/mim in the control subjects. In the hypertensive group the osmolr clernce (C,, ) of 6.2 ± 2. ml/min ws significntly incresed bove tht of norml subjects, ml/min (P <.2). However, there ws no significnt difference in the free wter clernce (CH2O) of the two groups; Cn2o verged ml/min in the ptients with hypertension nd ml/min in the control subjects. In both norml nd hypertensive subjects CH2 nd the urinry flow rte (V) were directly relted (fig. 3); however, less free wter ws Circultion, Volume XXXVII, My 1968

8 FIVE PER CENT DEXTROSE-WATER INFUSIONS 839 Downloded from by on July 26, F 18. F CH2 14. ml/min 1. F 6. F 2. l V ml/min Figure 3 In studies performed during pek wter diuresis (D/W t 15 ml/min) the urinry flow rte (V) is plotted ginst the simultneous free wter clernce (CH2). In both hypertensive nd norml subjects, CH2 incresed s the urinry flowv rte V rose. Less free wter (CH2) ws formed t ech level of V in the hypertensive group. excreted per unit of urine flow in the hypertensive thn in the norml subjects (fig. 3). Although not shown, the reltionship between CH2 nd V remined unchnged when the vlues in both groups were clculted per 1 ml of glomerulr filtrte. Frctionl Sodium Rejection in the Proximl (Isosmotic) nd Distl (Diluting) Portions of the Nephron The frction of filtered sodium rejected from portions of the nephron, where rebsorption is isosmotic (proximl tubules), hs been clculted for ech study during pek wter diuresis (see Methods). The men "proximl" sodium rejection observed during the rpid D/W infusions in the hypertensive ptients verged 17.9 ± 5.4% of the filtered sodium lod, vlue tht ws higher thn the % observed in the norml group (P <.5). Men "proximl" rejection ws not significntly reduced in the control subjects fter sodium depletion, % (P <.2). The frction of the "distl" sodium lod excreted during the infusions ws lso clculted for ech study (see Methods). The percentge of the "distl sodium lod" tht escped rebsorption in the diluting segments of the nephron verged % in the Circultion, Volume XXXVII, My DISTAL No REJECTION 3. r 25. F 2. t 15. F 1 t- 5.. * L An " DISTAL No LOAD".uEq/min Figure 4 The mount of sodium tht ws delivered beyond sites of isosmotic (proximl) rebsorption ws clculted for ech study during pek wter diuresis (UN V + PN X C, 2 ). This "distl sodium lod" is plotted ginst the percentge of the distl sodium lod excreted in the urine-"distl rejection frction %." At comprble levels of delivery of sodium to diluting segments of the nephron, the distl rejection frction ws significntly elevted in the hypertensive ptients (P <.1). hypertensive ptients, vlue signfficntly bove the % found in the norml subjects (P <.1). Distl sodium rebsorption ws incresed by slt depletion in the control subjects; the frction of the distl sodium lod tht escped rebsorption in the diluting segments ws only % in these studies. In figure 4 the mount of sodium delivered beyond the sites of isosmotic (proximl) rebsorption in studies of hypertensive nd norml subjects is plotted ginst the percentge of this "distl sodium lod" tht escped rebsorption in the diluting segments. In the hypertensive ptients the mounts of sodium presented to the diluting segments of the nephron were s lrge s or lrger thn those in norml subjects. Nevertheless, despite comprble or incresed sodium delivery to the distl nephron, the percentge of the "distl sodium lod" tht escped

9 Downloded from by on July 26, MEAN B.P. mm.hg 22[ F cp so **. U. X : E/F No% Figure Reltionship of renl tubulr sodium rejection to men rteril blood pressure in hypertensive ptients nd norml subjects during 5% dextrose-wter infusions. In the 31 studies there ws curviliner positive correltion between the mount of filtered sodium tht escped tubulr rebsorption (E/FN%) nd the men rteril blood pressure. tubulr rebsorption in the diluting segments ws incresed in the hypertensive ptients. Reltion of Renl Tubulr Rejection of Sodium to Men Arteril Blood Pressure nd to Renl Vsculr Resistnce In the 31 studies of norml nd hypertensive subjects there ws curviliner positive correltion between the men rteril blood pressure nd the frction of filtered sodium excreted in the urine (fig. 5). Renl vsculr resistnce (BP/ERBF) ws elevted in the hypertensive ptients nd verged RU in those who received the rpid infusions nd in those receiving D/W t 9 ml/min; renl vsculr resistnce verged 7.13+±1.37 RU in control subjects on regulr diets nd RU in those who hd been deprived of sodium. The mgnitude of the renl vsculr resistnce bore direct liner reltionship to the E/FN% observed during the D/W infusions (r = CANNON.8226, fig. 6). Lesser degrees of correltion were found when glomerulr filtrte rte nd renl blood flow were relted to E/FN% (r=.6938, r =.7298). Reltion of Renl Tubulr Rejection of Sodium to Renl Tubulr Rejection of Solute nd of Wter The frction of filtered sodium tht ppered in the urine during the dextrosewter infusions is plotted ginst the frction of filtered solute tht simultneously ppered in the urine in figure 7 left; liner reltionship with correltion coefficient of.9486 ws obtined. In figure 7 right, dt from 22 studies during pek wter diuresis (D/W infusion t 15 ml/min) re plotted; the rejection of filtered sodium by the renl tubules (E/FN%) in these studies ws directly relted to the frction of filtered wter simultneously rejected by the tubules (V/GFR%), with correltion coefficient of.957. Discussion The present study indictes tht hypertensive ptients exhibit n exggerted ntriuresis in response to n intrvenous infusion of 5% RENAL 4 RESISTANCE R.U. 3j *.. I I I E/F N% Figure 6 Reltionship of renl tubulr sodium rejection (E/FNO%) to the renl vsculr resistnce (men BP/ERBF) in rbitrry resistnce units, R.U. There ws liner positive correltion between the E/FN% nd the renl vsculr resistnce; r Circltion, Volume XXXVII, My 1968

10 FIVE PER CENT DEXTROSE-WATER INFUSIONS E/FNo% 6 5 _ E/FN % 6. Downloded from by on July 26, U n O. 4* E/F osm % Figure oo l o V GFR% During 5% dextrose-wter infusions in hypertensive ptients there ws direct reltionship between the tubulr rejection of filtered sodium (E/FNO%) nd the tubulr rejection of filtered solute (E/F'osm%) r= In studies performed during stedy stte of wter diuresis (D/W t 15 ml/min), the tubulr rejection, of filtered sodium ws lso directly relted to the tubulr rejection of filtered wter (V/GFR%); r =.957. dextrose nd wter. This finding confirms report by Ek,29 who in 1955 reported incresed sodium excretion by hypertensive ptients in response to infusions of 5% D/W, but differs from observtions of Hollnder'35 nd Steinmetz nd ssocites,36 who did not observe incresed ntriuresis in hypertensive ptients during infusions of 3.5% nd 2.5% glucose in wter. As will be discussed subsequently, differences in the degree of extrcellulr fluid expnsion produced by the infusions* nd in the renl hemodynmics *Undoubtedly both intrcellulr nd extrcellulr fluid comprtments incresed s glucose present in the 5% D/W ws metbolized by the body. However, since the infusions were rpid, the rte of glucose intke probbly exceeded the rte of its metbolism s suggested by n occsionl trce of glycosuri. Hence greter expnsion of the extrcellulr fluid comprtment ws probbly present throughout the studies. Circultion, Volume XXXVII, My 1968 vrt IE of the ptients studied my ccount for the discrepncy between the vrious reports. The incresed urinry sodium excretion exhibited by the hypertensive ptients in the present studies did not result from lrger increses in the filtered lod of sodium in response to 5% D/W becuse (1) men serum sodium concentrtion of the hypertensive ptients during diuresis ws not significntly elevted bove tht of the control subjects, nd (2) men glomerulr filtrtion rte ws lower in ptients with incresed blood pressure. Since the frction of filtered sodium excreted by the hypertensive subjects ws significntly incresed bove tht of the control subjects, the dt indicte tht renl tubulr sodium rebsorption ws reduced in the ptients with rteril hypertension during the D/W infusions. In the study of Ek,29 the possibility tht incresed ntriuresis in ptients with hypertension resulted from concomitnt glucose

11 Downloded from by on July 26, osmotic diuresis ws not rigidly excluded. It seems most unlikely tht n osmotic diuresis ccounted for the impired renl tubulr sodium rebsorption observed in hypertensive ptients in the present studies for severl resons: (1) there ws poor correltion between the filtered osmotic lod nd the rejection frction of sodium, (2) incresed tubulr rejection of filtered sodium ws pprent in individul hypertensive subjects who exhibited rtes of glomerulr filtrtion tht equled or exceeded those of individul control subjects (tble 1), (3) the percentge of the urinry osmollity due to sodium nd chloride ws incresed more thn twofold bove norml in the hypertensive ptients, nd (4) there ws poor correltion between the excretion rte of solutes other thn sodium nd chloride nd the urinry sodium output. It lso seems unlikely tht n osmotic diuresis of functioning residul nephrons ccounts for the incresed E/FN% of hypertensive ptients during D/W loding, even though such mechnism my explin in prt the incresed sodium rejection observed in uremic ptients7: First, none of the hypertensive ptients subjected to D/W infusion hd blood ure nitrogen greter thn 25 mg%; with only few exceptions they exhibited only moderte reductions of glomerulr filtrtion. Second, during n osmotic diuresis of residul nephrons, liner correltion would be nticipted between the excretion of solutes other thn sodium nd chloride clculted per 1 ml of glomerulr filtrtion nd the frction of filtered sodium tht escped rebsorption; the bsence of such correltion in the present study tends to mke this mechnism n unlikely cuse for incresed slt rejection by the hypertensive ptients. From n nlysis of the ptterns of solute nd free wter clernce tht ccompny tubulr slt rejection during wter diuresis, one my scertin whether impired tubulr sodium trnsport occurred in portions of the nephron where rebsorption is isosmotic (proximl tubules) or in more distl portions CANNON of the nephron where osmoticlly free wter is generted by the selective rebsorption of sodium (loops of Henle, distl tubules). The finding tht the "proximl" sodium rejection frction ws incresed in hypertensive ptients (P <.5) suggests tht some of the incresed sodium rejection induced by D/W infusion in the hypertensive group my hve occurred in the proximl tubules. This interprettion is consistent with the report of Metzger nd ssocites,37 who found tht CH2/GFR per unit Cosm/GFR ws incresed in hypertensive ptients during orl wter lods. In niml studies extrcellulr volume expnsion by infusion of sline or Ringer's solution hs been demonstrted to depress proximl tubulr rebsorption in rts'3' 38, 39 nd dogs4 by mechnism independent of glomerulr filtrtion rte, plsm protein concentrtion, ldosterone ctivity, or ntidiuretic hormone.4' Tht extrcellulr fluid (ECF) expnsion with dilute dextrose solutions cn produce similr effect on proximl slt rebsorption in nimls is supported by observtions of Mrtino nd Erley42; these investigtors noted depressed frctionl rebsorption of sodium in the proximl tubules of dogs with diuretic-induced blockde of distl tubulr sodium rebsorption during rpid infusions of distilled wter or dilute solutions of glucose. To ssess ccurtely sodium rebsorption in "distl" segments of the nephron it is necessry to consider both the delivery of sodium to the diluting sites nd lso the intrinsic chrcteristics of sodium rebsorption in these res.43 Since little wter escpes from the distl segments t high rtes of wter diuresis, the urinry flow rte, V, ws tken s n pproximtion of the mount of sodium-contining fluid reching the diluting segments, nd CH2 ws tken s n pproximtion of selective sodium rebsorption in these res.* As delivery of sodium-contining *Although C,1,2 ctully represents the mount of free wter generted in the scending limb nd distl tubules minus ny bck diffusion of wter tht occurs in the distl tubule nd collecting duct, it is Circultion, Volume XXXVII, My 1968

12 Downloded from by on July 26, 218 FIVE PER CENT DEXTROSE-WATER INFUSIONS fluid to the diluting segments incresed in both the normls nd hypertensives, C192 lso incresed (fig. 3). Thus during the D/W lod complete inhibition of distl sodium rebsorption ws not pprent in either group of subjects, nor ws trnsfer mximum for distl sodium trnsport demonstrted over the rnge of distl delivery chieved in these studies. However, frctionl sodium rebsorption in diluting segments of the nephron ws depressed in the hypertensives during the D/W infusions. Nineteen per cent of the "distl sodium lod" of the hypertensive ptients ws excreted in the urine wheres only 7% of the "distl sodium lod" escped rebsorption in the norml subjects on regulr diets, nd only 2% in normls fter sodium depletion. The difference between hypertensive nd norml subjects in frctionl rejection of the sodium delivered to the distl nephron ws highly significnt (P <.1) nd ws proportionlly greter thn the increse in "proximl" rejection found in hypertensive ptients during the sme infusions. Micropuncture studies in norml rts3 38, 39 nd dogs4 hve indicted tht the mrked depression of frctionl sodium rebsorption tht occurs in the proximl tubules during ECF volume expnsion with sline is ccompnied by much smller chnge in sodium excretion, becuse there occurs simultneously n incresed rebsorption of sodium in the distl nephron, prticulrly in the loops of Henle. The present finding tht the frctionl "distl" sodium rebsorption ws reduced 12% below norml in hypertensive ptients during 5% D/W infusion suggests tht reduced distl tubulr sodium trnsport my explin to mjor extent why hypertensive ptients excrete more sodium thn norml subjects in response to infusions tht expnd extrcellulr fluid volume. uinlikely tht bck diffusion of wter ws significntly diminished in hypertensive ptients with incresed urinry flow rtes, since (Uos, ) ws incresed, not decresed, in those ptients. Circultion, Volume XXXVII, My Other dt lso indicte tht urinry dilution ws ltered in the hypertensive ptients during the (15 ml/min) D/W infusions: (1) men Uosm nd UN were higher in the hypertensive thn in the norml subjects; (2) men CH2/GFR per Cosm/GFR ws lower in the hypertensive ptients; (3) slightly less CH12 ws formed by hypertensive ptients t ny given urinry flow rte (fig. 3); nd (4) t comprble levels of "distl sodium lod," the hypertensive ptients exhibited greter "distl" tubulr sodium rejection (fig. 4) nd were unble to lower UO,m nd UN to the levels ttined by norml subjects. Whether the ltered urinry dilution nd the reduced frctionl "distl" sodium rebsorption demonstrted in hypertensive ptients during the D/W infusions occurred in the loop of Henle or in the "corticy' diluting segment43 or in both sites cnnot be scertined from the present studies. However, reductions in urinry concentrting bility in dehydrted hypertensive ptients hve been reported by other investigtors.'7 4' 45 Moreover, Bucklew, Rmirez, nd Goldberg46 hve recently found reduced TCH1,, per unit Cos1 during the ntriuresis induced by hypertonic sline in ntidiuretic hypertensive ptients. Together with the present findings the ccumulted observtions suggest tht t lest some of the impired urinry dilution nd 'distl" sodium rejection observed in hypertensive ptients during ECF volume expnsion results from defect in sodium rebsorption in the scending limb of the loop of Henle. The curviliner positive correltion between the level of men rteril blood pressure nd tubulr sodium rejection observed in the norml nd hypertensive subjects during the D/W infusions (fig. 5) suggests tht renl rteril pressure is in some wy involved in the mechnism for incresed sodium rejection by the ltter group. Rough correltions between the mgnitude of ntriuresis nd the height of blood pressure hve been reported in severl studies of hypertensive ptients receiving sline lods.' In

13 Downloded from by on July 26, ddition, vriety of renl perfusion studies hve indicted tht increses of renl rteril blood pressure my increse urinry slt nd wter excretion without ffecting glomerulr filtrtion rte.47a9 In stop-flow studies of Tobin nd ssocites5 the "distl" nephron ws the site of impired sodium rebsorption in rt kidneys tht were perfused with blood t elevted pressures. Although depressed glomerulr filtrtion rte nd renl blood flow were to some extent correlted with incresed E/FN% in the present studies, these correltions were less significnt thn the liner positive reltionship between the degree of tubulr sodium rejection nd the clculted renl vsculr resistnce (fig. 6). This finding is similr to the direct correltion between slt rejection nd renl vsculr resistnce noted by Cottier, Weller, nd Hoobler24 in group of hypertensive ptients given sline infusions. Renl vsculr resistnce is numericl expression of the intensity of hypertensive renovsculr disese; these observtions therefore suggest tht ltertions of renl pressure nd vsculr resistnce in the kidneys of hypertensive ptients my determine the incresed slt rejection exhibited by these ptients during sline, mnnitol, or 5% D/W infusions. It hs been suggested tht proximl tubulr sodium rebsorption is regulted by ntriuretic hormone of extrrenl' or intrrenl origin.51 Whether greter mounts of postulted ntriuretic hormone re elicited by volume expnsion in ptients with incresed blood pressure nd incresed vsculr resistnce, or whether norml mounts of this substnce elicit greter ntriuresis in hypertensive ptients becuse of bnormlities of renl hemodymics re questions tht wit further study. Alterntively, physicl fctors my influence tubulr sodium trnsport. Erley nd ssocites,5' 12 hve provided evidence to support the hypothesis tht trnsmission of rteril blood pressure long the renl vsculture my ct to inhibit tubulr sodium trnsport, possibly by ltering renl interstitil volume. In the present studies during wter CANNON diuresis the rejection frction of sodium ws directly relted not only to the rejection frction of totl solute (E/FFosm%) but lso to tht of filtered wter (V/ GFR%). Such blnce between the frctionl excretion of sodium nd wter is not chrcteristic of the ction of ny known hormone nd suggests tht the chnges in sodium nd wter output were medited by physicl fctors. Mechnisms whereby the combintion of incresed blood pressure nd incresed renl vsculr resistnce could produce proportionte chnges in the tubulr rejection of filtered sodium, solute, nd wter during ECF expnsion in hypertensive mn remin specultive t this time. It is conceivble however tht (1) medullry wshout secondry to pressure induced increse in medullry blood flow52; (2) incresed pssive bck diffusion of rebsorbed sodium nd wter due to ltered pressure nd resistnce in peritubulr cpillries,12 13, 53 or (3) pressure-induced distortion of the norml reltionship between the quntity of glomerulr filtrte nd tubulr volume, with consequent incresed liner velocity of tubulr flow,54 could contribute to hemodynmiclly medited ntriuresis in these ptients. References 1. MILLS, I. H., DE WARDENER, H. E., HAYTER, C. J., AND CLAPHAM, W. F.: Studies on the fferent mechnism of the sodium diuresis which follows the dministrtion of intrvenous sline in the dog. Clin Sci 21: 259, LEVINSKY, N. G., AND LALONE, R. C.: Mechnism of sodium diuresis fter sline infusion in the dog. J Clin Invest 42: 1261, BLYTHE, W. B., AND WELT, L. G.: Dissocition between filtered lod of sodium nd its rte of excretion in the urine. J Clin Invest 42: 1491, RECTOR, F. C., JR., VAN GIESEN, G., KIIL, F., AND SELDIN, D. W.: Influence of expnsion of extrcellulr volume on tubulr rebsorption of sodium independent of chnges in glomerulr filtrtion rte nd ldosterone ctivity. J Clin Invest 43: 341, EARLEY, L. E., AND FRIEDLER, R. M.: Observtions on the mechnism of decresed tubulr rebsorption of sodium nd wter during sline loding. J Clin Invest 43: 1928, Circultion, Volume XXXVIl, My 1968

14 FIVE PER CENT DEXTROSE-WATER INFUSIONS 845 Downloded from by on July 26, STEIN, R. M., BERCOVITCH, D. D., AND LEVITT1, M. D.: Dul effects of sline loding on renl tubulr sodium rebsorption in the dog. Amer J Physiol 27: 826, BRICKER, N. S.: Control of sodium excretion with norml nd reduced nephron popultions: Pre-eminence of third fctor. Amer J Med 43: 313, JOHNSTON, C. I., AND DAVIS, J. O.: Evidence from cross circultion studies for humorl mechnism in the ntriuresis of sline loding. Proc Soc Exp Biol Med 121: 158, LIcHARDUS, B., AND PEARCE, J. W.: Evidence for humorl ntriuretic fctor relesed by blood volume expnsion. Nture (London) 29: 47, MARTINEZ-MALDONADO, M., KURTZMAN, N. A., RECTOR, F. C., JR., AND SELDIN, D.: Evidence for hormonl inhibitor of proximl tubulr rebsorption. (Abstr.) J Clin Invest 46: 191, EARLEY, L. E., AND FRIEDLER, R. M.: Effects of combined renl vsodilttion nd pressor gents on renl hemodynmics nd the tubulr rebsorption of sline. J Clin Invest 45: 542, EARLEY, L. E., MARTINO, J. A., AND FRIEDLER, R. M.: Fctors ffecting sodium rebsorption by the proximl tubule s determined during blockde of distl sodium rebsorption. J Clin Invest 45: 1668, RECTOR, F. C., JR., SELLMAN, J. D., MARTINEZ- MALDONADO, M., AND SELDIN, D. W.: Mechnism of suppression of proximl tubulr rebsorption by sline infusion. J Clin Invest 46: 47, FARNSWORTH, E. B.: Renl rebsorption of chloride nd phosphte in norml subjects nd in ptients with essentil hypertension. J Clin Invest 35: 897, GREEN, D. M., WEDELL, H. G., WALD, M. H., AND LEARNED, B.: Reltion of wter nd sodium excretion to blood pressure in humn subjects. Circultion 6: 919, BIRCHALL, R., TUTHILL, S. W., JACOBS, W. S., TRAUTTMAN, W. J., JR., AND FINDLEY, T.: Renl excretion of wter, sodium, nd chloride: Comprison of the responses of hypertensive ptients with those of norml subjects, ptients with specific drenl or pituitry defects, nd norml subject primed with vrious hormones. Circultion 7: 258, BRODSKY, W. A., AND GRAUBARTH, H. N.: Excretion of wter nd electrolytes in ptients with essentil hypertension. J Lb Clin Med 41: 43, GREEN, D. M., AND ELLIS, E. J.: Sodium outputblood pressure reltionships nd their modifiction by tretment. Circultion 1: 536, Circultion, Volume XXXVII, My GREEN, D. M., JOHNSON, A. C., BRIDGES, W. C., AND LEHMAN, J. N.: Stges of slt exchnge in essentil hypertension. Circultion 9: 416, THOMPSON, J. E., SILVA, T. F., KINSEY, D., AND SMITHWICK, R. H.: Effect of cute slt lods on the urinry sodium output of normotensive nd hypertensive ptients before nd fter surgery. Circultion 1: 912, COTTIER, P. T., WELLER, J. M., AND HOOBLER, S. W.: Sodium chloride excretion following slt loding in hypertensive subjects. Circultion 18: 196, HOLLANDER, W., AND JUI)SON, W. E., Electrolyte nd wter excretion in rteril hypertension: I. Studies in non mediclly treted subjects with essentil hypertension. J Clin Invest 36: 146, BALDWIN, D. S., BIGGS, A. V., GOLDRING, W., HULET, W. H., AND CHAsIs, H.: Exggerted ntriuresis in essentil hypertension. Amer J Med 24: 893, COTTIER, P., WELLER, J. M., AND HOOBLER, S. W.: Effect of intrvenous sodium chloride lod on renl hemodynmics nd electrolyte excretion in essentil hypertension. Circultion 17: 75, HANENSON, I. B., TAUSSKY, H. H., POLASKY, N., RAUSOHOFF, W., AND MILLER, B. F.: Renl excretion of sodium in rteril hypertension. Circultion 2: 498, PAPPER, S., BELSKY, J. L., AND BLEIFER, K. H.: Response to the dministrtion of n isotonic sodium chloride-lctte solution in ptients with essentil hypertension. J Clin Invest 39: 876, ULRYCH, M., HOFMAN, J., AND HEJL, Z.: Crdic nd renl hyper responsiveness to cute plsm volume expnsion in hypertension. Amer Hert J 68: 193, WESTON, R. E., HELLMAN, L., ESCHER, D. J. W., EDELMAN, I. S., GROSSMAN, J., AND LEITER, L.: Studies on the influence of the low sodium crdic diet nd the Kempner regimen on renl hemodynmics nd electrolyte excretion in hypertensive subjects. J Clin Invest 29: 639, EK, J.: Influence of hevy hydrtion on the renl function in norml nd hypertensive mn. Scnd J Clin Lb Invest 7: (suppl. 19): 1, BALDWIN, D. S., SCHREINER, G. E., BREED, E. S., WESSON, L. G., JR., AND MAXWELL, M. H.: Depression of pprent p-mino hippurte extrction rtio by glucose. J Clin Invest 29: 614, FUHR, J., KACZMARCZYK, J., UND KRiiTTGEN, C.: Eine einfche colorimetrische Methode zur Inulinbestimmung fur Nieren-Clernce-Unter-

15 Downloded from by on July 26, suchungen bei Stoffwechselgesunden und Dibetikern. Klin Wschr 33: 729, CoTLOvE, E.: C14 inulin method, crboxy-lbeled inulin s trcer for inulin. Fed Proc 14: 32, SMITH, H. W.: Principles of Renl Physiology. New York, Oxford University Press, DIXON, W. J., AND MASSEY, F. J., JR.: Introduction to Sttisticl Anlysis. New York, Mc- Grw-Hill Book Co., HOLLANDER, W.: Effects of intrvenous hydrtion nd pitressin on renl function in subjects with essentil hypertension. Circultion 19: 691, STEINMETZ, P. R., EISINGER, R. P., GOMBOS, E. A., CHASIS, H., AND BALDWIN, D. S.: Excretion of free wter nd solute during mximl wter diuresis in norml nd hypertensive subjects. J Lb Clin Med 64: 238, METZGER, R., VAAMONDE, L., VAAMONDE, C., AND PAPPER, S.: Renl sodium excretion during orl wter loding in hypertensive ptients. (Abstr.) Clin Res 15: 365, LANDWEHR, D. M., AND KLOSE, R. M.: Micropuncture study of sodium in sline loded rts. Proc Int Cong Nephrol 3: 227, HAYSLETT, J. P., KASHGARIAN, M., AND EPSTEIN, F. H.: Chnges in proximl nd distl tubulr rebsorption produced by rpid expnsion of extrcellulr fluid. J Clin Invest 46: 1254, DIRKS, J. H., CIRKSENA, W. J., AND BERLINER, R. W.: Effect of sline infusion on sodium rebsorption by the proximl tubule of the dog. J Clin Invest 44: 116, LEVINSKY, N.: Non ldosterone influences on renl sodium trnsport. Ann NY Acd Sci 139: 295, MARTINO, J. A., AND EARLEY, L. E.: Effects of infusion of wter on renl hemodynmics nd the tubulr rebsorption of sodium. J Clin Invest 46: 1229, SELDIN, D. W., EKNOYAN, G., SuKi, W. N., AND RECTOR, F. C., JR.: Locliztion of diuretic ction from the pttern of wter nd electrolyte excretion. Ann NY Acd Sci 139: 328, DE LEON, A. C., JR., DREIFUS, L. S., AND BELLET, S.: Urinry osmolr concentrtion: A mens CANNON of evluting erly renl function chnges in essentil hypertension. Amer J Med Sci 1: 144, BALDWIN, D. S., GOMBOS, E. A., AND CHUSIS, H.: Urinry concentrting mechnism in essentil hypertension. Amer J Med 38: 864, BUCKALEW, V. M., JR., RAMIREZ, M. A., AND GOLDBERG, M.: Reltionship between exggerted ntriuresis nd renl concentrting defect in hypertensive mn. (Abstr.) Progrm First Annul Meeting Americn Society of Nephrology, Los Angeles, Oct. 1967, p SELKURT, E. E.: Effect of pulse pressure nd men rteril pressure modifiction on renl hemodynmics nd electrolyte nd wter excretion. Circultion 4: 541, SHIPLEY, R. E., AND STUDY, R. S.: Chnges in renl blood flow, extrction of inulin, glomerulr filtrtion rte, tissue pressure nd urine flow with cute ltertions of renl rtery blood pressure. Amer J Physiol 167: 676, McDONALD, S. J., AND DE WARDENER, H. E.: Reltionship between the renl rteril perfusion pressure nd the increse in sodium excretion which occurs during n infusion of sline. Nephron 2: 1, TOBIAN, L., COFFEE, K., FERREIRA, D., AND MEUILI, J.: Effect of renl perfusion on the net trnsport of sodium out of distl tubulr urine s studied with the stop-flow technique. J Clin Invest 43: 118, DAVIS, J. O., HOWARMS, S. S., JOHNSTON, C. 1., AND WRIGHT, F. S.: Renin, sodium-retining nd sodium-excreting hormones nd experimentl renl hypertension. Circultion Reserch 2-21 (suppl. II): II-167, SELKURT, E. E., WOMACK, I., AND DAILEY, W. N.: Mechnism of ntriuresis nd diuresis during elevted renl rteril pressure. Amer J Physiol 29: 95, SWANN, H. G., AND PRINE, J. M.: Reltion of intrrenl pressure to blood pressure nd to perinephric hypertension. (Abstr.) Fed Proc 19: 134, GERTZ, K. H., MANGOS, J. A., BRAUN, G., AND PAGEL, H. D.: On the glomerulr tubulr blnce in the rt kidney. Pfluegers Archiv Ges Physiol 285: 36, Circultion, Volume XXX VII, My 1968