Effects of Five Per Cent Dextrose-WaterInfusions in Normal and Hypertensive Man
Evidence for Increased Proximal and Distal TubularSodium Rejection by Hypertensive Patientsand Its Relation to Renal Hemodynamics
By PAUL J. CANNON, M.D.
SUMMARYDuring infusions of 5% dextrose in water urinary sodium excretion and the renal
tubular rejection of filtered sodium (E/F Na %) were significantly higher in hyperten-sive than in normotensive subjects. Increased E/F Na % did not result from alterationsin plasma sodium, in filtered sodium, or from an osmotic diuresis.
Fractional sodium reabsorption in proximal (isosmotic) portions of the nephron wasdiminished in the hypertensive patients. Free water forrnation (CH20) rose with in-creased "distal" sodium delivery (V) in both groups; however, fractional sodiumreabsorption in the "distal" nephron was significantly impaired in the hypertensivepatients and urinary osmolality was increased.Mean arterial blood pressure and E/F Na % were related in curvilinear fashion
in the 31 studies, and there was a direct relation between E/F Na % and the mag-nitude of renal vascular resistance. The data suggested that alterations of renalarterial pressure and vascular resistance in hypertensive disease modify sodiumtransport in proximal and diluting segments of the nephron and determine to amajor extent the increased natriuresis exhibited by hypertensive subjects during in-fusions that expand extracellular fluid volume.
Additional Indexing Words:Sodium excretion Extracellular fluid volume expansionNatriuresis
FACTORS that influence the rate of renaltubular sodium reabsorption under nor-
mal circumstances have not been completelyclarified. Studies from many laboratories haveindicated that the diminished renal tubularsodium reabsorption developing in responseto infusions of saline or Ringer's solution innormal animals does not result from changes
From the Department of Medicine, College ofPhysicians and Surgeons, Columbia University andthe Presbyterian Hospital, New York, New York.
Supported by U.S. Public Health Service GrantsHE 10182 and HE 05741.
Dr. Cannon is a recipient of U.S. Public HealthService Career Development Award HE 15032 of theNational Heart Institute.
in glomerular filtration rate, the filtered loadof sodium, or aldosterone secretion.1 6 Toexplain this phenomenon of "saline diuresis"attention has recently been directed towardthe presence of a "third factor,"7 which mayeither be a "natriuretic" hormonel 8410 or anintrarenal hemodynamic adjustment to extra-cellular fluid (ECF) volume expansion5 11,12or a combination of both.13
Patients with arterial hypertension exhibitan exaggerated natriuresis in response to in-fusions of saline or mannitol.14-27 The mech-anism limiting tubular sodium reabsorptionin hypertensive more than in normal subjectsduring the infusions remains unexplained. Itis probably a functional abnorrnality rather
Circulation, Volume XXXVII, May 1968
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FIVE PER CENT DEXTROSE-WATER INFUSIONS
than the result of structural damage to therenal tubules since (1) increased natriuresisby hypertensive subjects is manifest only dur-ing the infusions of saline or mannitol, and(2) renal salt wasting is not apparent inhypertensive subjects not receiving infusionswhen they are maintained on a normal or lowsodium intake.2' 28The present studies were designed to inves-
tigate hemodynamic factors that might beinvolved in the phenomenon of salt rejectionin normal and hypertensive man during amild degree of expansion of the extracellularfluid volume. To this end renal hemodynamicsand the natriuretic responses of hypertensivepatients were examined during rapid infu-sions of 5% dextrose in water and were com-pared to those of normal and salt-depletedcontrol subjects. The studies confirm observa-tions of Ek29 that an exaggerated natriuresisdoes occur in hypertensive patients in responseto infusion of 5% dextrose and water. In addi-tion they demonstrate (1) that in hypertensivepatients during the infusions, sodium reabsorp-tion is impaired not only in the proximaltubules but also in distal "diluting" segmentsof the nephron, and (2) that the degree ofsodium rejection is correlated with the meanarterial blood pressure and the renal vas-cular resistance.
MethodsThirty-one renal clearance studies were per-
formed in nine normal volunteers and 18 patientswith essential hypertension and one patient withhypertension caused by an aldosterone-secretingadenoma. Each of the hypertensive subjects andsix control subjects prior to study received a dietcontaining 4 to 6 g of sodium; five studies wereperformed after the control subjects had re-ceived a low-sodium diet (less than 0.875 g ofNaCl per day) for 4 to 7 days. None of thepatients received medication other than occa-sional bedtime sedation with barbiturates. Nonehad papilledema or congestive heart failure ora blood area nitrogen level above 26 mg/100 ml.
All experiments were performed at the sameearly morning hour with the subjects fasting,resting quietly in bed. Water diuresis was in-duced by oral administration of 500 ml of waterduring the hour prior to the infusion and wasmaintained by intravenous administration of a5% dextrose solution at a rate of 15 ml/min inCirculation, Volume XXXVII, May 1968
26 studies and 9 ml/min in nine studies, heldconstant by a motor-driven pump. Urine col-lections were made and discarded until a steadystate of maximal urine flow was achieved. Threeor four 10-minute clearance periods were thenobtained.Venous blood samples were collected at appro-
priate intervals through an indwelling needle.Urine was collected continuously via an in-dwelling catheter. Blood pressure was measuredfrom the arm during the clearance periods by astandard cuff mercury sphygmomanometer.The rates of glomerular filtration (GFR) and
of effective renal plasma flow (ERPF) weremeasured by the administration of inulin or14C-inulin and para-aminohippuric acid (PAH). Ade-quate priming doses were given intravenously;then these substances were added to the 5% dex-trose infusion in amounts to maintain constantplasma concentrations. PAH was added to thesustaining infusion immediately before use toavoid the depression in PAH extraction that canoccur when PAH and dextrose are incubatedtogether for several hours.30 Plasma and urinesamples were analyzed for inulin by the anthronemethod,31 for 14C-inulin by the method of Cot-love,32 and for PAH by the method of Smith.33Sodium and potassium concentrations in plasmaand urine were measured by an InstrumentationAssociates flame photometer. Chloride concentra-tions were measured by potentiometric titrationwith the Cotlove chloridometer. Urine and plasmatotal-solute concentrations were measured with anAdvanced Instruments osmometer.
Calculations: Mean arterial blood pressurewas calculated as the average of systolic anddiastolic pressures in millimeters of mercury.Effective renal blood flow was calculated asthe clearance of PAH divided by 1 - hct andwas expressed in milliliters per minute. Renalvascular resistance was calculated by dividingeffective renal blood flow by the mean arterialblood pressure and was reported in arbitraryresistance units (RU). The glomerular filtrationrate was estimated from the clearance of inulin(CIN) and expressed in milliliters per minute.Osmolar and free water clearances were calcu-lated in the manner described by Smith:33COSm =UOSm V/POSM; CH20= V -UOSm V/Posm,where V is the urine flow in milliliters per minuteand Uosm and Posm are the solute concentrationsof urine and plasma in milliosmoles per kilogramof water. Filtered solute load was calculated asthe osmolality of plasma in micro-osmoles permilligram. H20 X CIN in milliliters per minutewas expressed as micro-osmoles per minute. Thepercentage of the urinary solute concentration dueto salt was calculated by the formula:UNamEq/L + UclmEq/L + UosmmOsnM/kgH20 x 100.
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Table 1Electrolyte Excretion During Five Per Cent Dextrose-Water Infusions in Hypertensive Patients (Regular SodmDiet-5% D/W Infusion i.v. at 15 ml/min)BP.
CIN CPAH RBF(ml/min) (ml/min) (mllmin)
*Conn's syndrome 1-initial2-K + repleted3-post op.
Table 2Electrolyte Excretion During Five Per Cent Dextrose-Water Infusions in Hypertensive Patients (Regular SodiumDiet-5% D/W Infusion i.v. at 9 ml/min)
Filtration RenalBP CIN CPAH RBF fraction resistance UN&V
Subject (mm Hg) (ml min) (ml min) (ml/mmin) (%) (RU) (gEq/min)P.E.R.B.O.O.D.A.V.C.H.A.D.I.A.L.A.W.R.I.C.K.L.A.W.I.*
*Pt. partially restricted Na + intake.
The excretion of "non-salt" solutes was calculatedby subtracting the urinary sodium and chlorideexcretion rates in microequivalents per minutefrom the total solute excretion in micro-osmolesper minute.
In studies performed during maximal waterdiuresis fractional reabsorption of sodium in theproximal tubules and in distal "diluting" seg-ments of the nephron (ascending limb of Henle'sloop, distal tubules) was assessed indirectly.The "distal sodium load" was calculated asUNaV ,Eq/min + (PNa ,uEq/ml X CH20 ml/min)and was expressed in microeq