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Kidney International, Vol. 8 (1975), p. 42—47

Altered volume regulation in sustained essential : A hemodynamic study

MICHEL E. SAFAR, GERARD M. LONDON, YVES A. WEIss and PAUL L. MILLIEZ

Hemodynamic Laboratory, Hypertension Research Center, Hospital Broussais,Paris, France

Altered blood volume regulation in sustained essential hyper- sion normale comme système de réfèrence, une evaluation quan- tension: A hemodynamic study. Cardiac and renal titative du trouble de Ia regulation volCmique des hypertendus and total blood volume were determined in 28 normal subjects est proposee. Chez ces patients, Ia valeur de Ia résistance pen- and 60 patients with untreated essential well-established hyper- pherique correspond a deux valeurs du volume sanguin: Ia tension. Endogenous creatinine clearance was within normal valeur mesurée et Ia valeur theorique, extrapolée a partir de Ia ranges and sodium intake was 110 mEq/day. A significant courbe normale. La difference entre ces deux valeurs est appelée negative volume-resistance relationship was observed both in "variation relative en volume sanguin" et utilisée comme normal subjects (P< 0.005) and hypertensive patients (P< 0.001). modéle mathématique. Chez les hypertendus, Ic volume sanguin In comparison with the normal curve, the hypertensive curve has mesuré est rCduit (P< 0,001) alors que Ia "variation relative en two characteristics: 1) the curve was reset on the right-hand side volume sanguin" augmente (P< 0,001). Cette "augmentation and, 2) the slope was significantly shallower, indicating a reduced relative" est correlée directement avec Ia pression artérielle dia- ability to decrease the volume per unit rise in resistance. By stolique (r=0,64; P <0,00001) et inversement avec Ic debit renal using the normal curve as a reference system, a quantitative (r= —0,54; P< 0,0001) et Ia clearance de Ia crCatinine. De telles evaluation of the blood volume disturbance was proposed. In correlations ne sont pas constatées avec le volume sanguin hypertensives, the value of the total peripheral resistance could mesurè. Cette étude montre que l'hypertensiori permanente correspond to two different values of the total blood volume: essentielle est liée a une augmentation du volume sanguin rela- the real value and the theoretical value extrapolated from the tive a Ia capacité du système circulatoire et, confirmant Ia normal curve. The difference between the two values was called thèorie de Guyton, suggCre que Ic rein est nécessairement im- "relative variation in blood volume" and was used as a mathe- plique dans Ic mécanisme d'élévation de Ia pression artCnielle. matical model. In hypertensives, the real blood volume was significantly reduced (P< 0.001) while a significant "relative in- crease" in total blood volume was observed (P<0.001). This Abnormalities of total blood volume [1—5]havebeen "relative increase" was directly correlated with the diastolic commonly observed in arterial hypertension and they arterial pressure (r 0.64; P <0.00001) and was inversely related often have been related to the level of arterial blood to the renal blood flow (r= —0.54; P <0.0001) and the creatinine clearance. Such correlations were not observed with the real pressure [6—9].Thisassumption is not surprising be- blood volume. In agreement with Guyton's theory, this study cause pressure might partly reflect a relationship be- highly suggests that sustained hypertension is related to an in- tween the capacity of the arterial system and the crease in blood volume relative to the capacity of the and that a renal defect is necessary for the volume it contains, as well as the usually considered elevation mechanism. variables of inflow pressure and outflow resistance. Recently, a negative relationship between blood Regulation du volume sanguin dans l'hypertension essentielle volume and total peripheral resistance was described permanente: Etude hemodynamique. Les paramétres hémo- dynamiques cardiaques et rénaux ainsi que le volume sanguin, in normal subjects [4] and patients with essential sont mesurés chez 28 sujets normaux et 60 patients présentant hypertension, renal arterial disease and primary aldo- une hypertension artérielle permanente et essentielle. La clear- steronism [4 ,1O—141. This correlation suggested that a ance de Ia crèatinineest normale et l'apport sodé est de 110 mEq par jour. II a èté trouvé chez les sujets normaux (P<0,005) et negative feedback mechanism between resistance and chez les hypertendus (P< 0,001) une correlation linéaire negative volume might exist. This mechanism could operate et hautement significative entre volume sanguin et résistance differently in normotensive and hypertensive subjects, périphérique totale. La droite de regression des hypertendus comparée a la droite normale est déplacée vers Ia droite. Dc plus, resulting in the latter group from an inappropriate sa pente est nettement diminuée. En utilisant Ia droite de régres- blood volume for the resistance level. Since the de- pendence on resistance of intravascular volume as a function of the integrity of the was never in- Received for publication December 9, 1974; and in revised form February 18, 1975. vestigated, such a study would be of major interest. © 1975, by the International Society of Nephrology. The purpose of the present report is 1)toestablish

42 Altered blood volume regulation in sustained essential hypertension 43 the volume-resistance relationship in normotensive pressure and withdrawal of blood for indicator-dilu- and essential hypertensive patients, 2) to determine in tion curves. was determined with the hypertensive individuals a quantitative index of the use of the Waters cuvette and a densitometer as de- volume-resistance disturbance and 3) to evaluate the scribed previously [5]. Cardiac output was measured role of the kidneys in any observed blood volume ab- at least twice with the subject in the supine position normalities. and was determined by the Stewart-Hamilton method [15]. The reproductibility of the method was 3±2% (± 1 SEM). was expressed in ml mm -1/ Methods m2by correcting for the body surface area. Mean Patients. Sixty male chronic hypertensive patients arterial blood pressure was measured with an elec- and 28 male normal subjects were included in this tronic integrator (Thomson-Telco). Total peripheral study. Patients were considered to have sustained resistance (TPR) was calculated from the following hypertension when the diastolic blood pressure was formula: consistently above 100 mm Hg during the past year. TPR (arbitrary units m2 or kg) = Diagnosis was based on outpatient blood pressure re- MAP/COx 80, cordings. where MAP =meanarterial pressure (mm Hg) and Normotensive and hypertensive subjects were un- CO =cardiacoutput (liters/min/m2 or liters/mm/kg of treated or had discontinued their therapy at least four body wt). weeks before the study. They were hospitalized during Blood volume determinations. 1) Real blood volume. a six-day period and placed on a 110 mEq/day sodium Before the hemodynamic study, total blood volume diet. During hospitalization, sodium intake and output was measured in the recumbent position. It was deter- were equivalent. In hypertensive subjects, extensive in- mined by isotope dilution technique with the use of vestigations included the following: blood and urinary radio-iodinated albumin as previously described [5]. electrolyte and catecholamine determinations, endo- After a control sample was taken, 3 1j.Ci was injected at genous creatinine clearance, timed i.v. urography with zero time; ten minutes later, a sample was taken for dye washout test and/or renal arteriography. All counting. Blood volume was expressed in ml.kg'. patients were felt to have essential hypertension. None 2) Theoretical blood ,volume. A significant resis- had cardiac or neurologic involvement. Mean endo- tance volume relationship was observed in normal genous creatinine clearance was 97±3 ml. mm '. subjects (P <0.005) as previously reported [4]. The cor- 1.73rn-2. Clinical characteristics are listed in Table 1. relation is not dependent on the age (partial correlation Hemodynamic indexes. Hemodynamic indexes were coefficient) and exists even when unnormalized values determined on the third day of hospitalization. At this are used. Fig. I shows the regression line and the 95% time, 48 hypertensive patients had a diastolic blood pressure above 95 mm Hg; 12 patients had values beneath this figure. After an overnight fast, the The relative variation in patients were brought to the hemodynamic laboratory total blood volume in a + hypertensive patient without premedication. A transcutaneous catheter 100 — was inserted via an antecubital vein into the subclavian r— _ U vein for the injection of indocyanine green dye. An E 18-gauge thin-walled needle was also inserted into a 0 brachial artery for the measurement of intra-arterial

Table1. Clinicalcharacteristics P<0.005 Normal subjects Permanent hypertensives 50,000 100,000 150,000 Patients, N 28 60 Total peripheral resistance Age,yr 34±2 39±1 Weight, kg 66±2 74±P Fig. 1. Volume-resistance relationship in normal subjects (y= Height, cm 169 1 172 1 —0.25 x 103x +99, 69). The regression line is represented with Body surface area, m2 1.76 0.03 1.87 0.02° its 95% confidence limits. Legend: Blood volume is expressed in ml .kg1and total peripheral resistance in arbitrary unit kg Values are± I SEM. of body wt. Note that the correlation exists even with unnormal- bP<0.01 in comparison with normal subjects. ized values. For the definition of the "relative variation in blood P <0,001 in comparison with normal subjects. volume", see text. 44 Safar et a! confidence limits for the normal curve. The normal Table 2. Hemodynamic indexesa curve can be used as a reference system for the hyper- tensive patients. In each hypertensive patient, two Normal subjects Permanent blood volume values can be defined: the real blood hypertensives volume and the theoretical and extrapolated blood volume corresponding to the interception of the total Patients, N 28 60 peripheral resistance with the normal curve. The Sytolic arterial pressure, mmHg 125±2 194±4b difference between the theoretical and the real blood Diastolic arterial volume is called the relative variation in blood pressure,mmHg 72±2 ll9±2b volume (Fig. 1). When the theoretical value is greater , than the real value, there is a relative decrease in blood mmHg 90±2 l47±3L volume. When the theoretical value is less than the rate, beats/mm 1 732 79 2° real value, there is a relative increase in blood volume. Cardiac output, mlmin'm2 3360±109 3164±75 As a matter of fact, these terms point out a variation in mImin1kg 90±4 80±8° blood volume relative to the total peripheral resistance , level. mlm2 46±2 41±1° Renal indexes. Renal blood flow was estimated by mlkg1 1.25±0.06 1.05±0.03d the '311-hippurate clearance (20 PCi) and determined Total peripheral resistance, by using the single-injection method. After a control arbitrary unit m2 2118±256 3652±223b sample was taken the injection was given at time zero arbitrary unitS kg 83292± 3823 152687±5668b and blood samples were collected five times between the 10th and the 20th mm. Radioactivity concentra- Values are 1 SEM. b p<0.0001 in comparison with normal subjects. tions were plotted against time on semilogarithmic P <0.05 in comparison with normal subjects. paper. The calculations were made by using the model dp<0.01 in comparison with normal subjects. of one compartment mamillary system as previously described [16, 17]; the creatinine clearance was deter- mined according to the classical methods reported Table 3. Blood volume determinations elsewhere [18]. Statistical study. Statistical analysis using classical Normal subjects Permanent methods (difference of means, correlations, stepwise hypertensives regressions) [19] were performed. For the correlation Patients, N 28 60 study, each hemodynamic index was expressed per Hematocrit,% 44±1 44±1 kilo of body weight as it was for the blood volume. Total blood volume The protocol was approved by INSERM (Institut (Real value) National de la Sante et de la Recherche Médicale, mlkg' 79±2 70±lb Paris). Informed consent for the investigation was Total blood volume (Theoretical value) obtained from the patients after a detailed description m1kg1 — 61±2 of the procedure. Relative variation in blood volume mlkg' 0.0±1.45 +9±1° Results Values are 1 SEM. Hemodynamic indexes (Table 2). Hypertensive sub- b p<0.001in comparison with normal subjects. jects have a normal cardiac index and an elevated P< 0.0001 in comparison with normal subjects. value for total peripheral resistance (P <0.0001). Heart rate is slightly increased (P <0.05). Blood volume determinations (Table 3). 1) Real normal curve, the hypertensive curve has two charac- blood volume: Whatever unit of measurement is used teristics: a) the curve is reset on the right-hand side and (ml.kg', ml.m2), the real blood volume is signifi- b) the slope is significantly shallower, indicating a re- cantly reduced (P< 0.001). duced ability to decrease the volume per unit rise in 2) Resistance-volume relationship: A significant resistance. Fig. 2 illustrates the hypertensive curve as negative linear correlation (r° —0.42; P<0.001) is compared with the normal curve and reveals two facts: observed in hypertensive subjects. As in normal sub- a) the data representing the normotensive subjects jects, the correlation is not dependent on either age or overlap significantly with those of the hypertensive the normalization process. In comparison with the patients at the lowest levels of resistance and b) 8O% of Altered blood volume regulation in sustained essential hypertension 45

too. — — — Normal subjects . Hypertensive subjects 90 S 170 80-

C .0 70- 0 E. 60-

50- 150 50000 100,000 50,000 200,000 250,000 300,000 Total peripheral resistance

Fig.2. Volume-resistance relationship in hypertensive patients 5) S (y= —0.07 x 10 3x + 80.4). The hypertensive curve can be com- pared with the normal regression line. The slopes of the re- 5) gression equations defining the two lines are significantly different from each other. Note that 80% of the data represent- ing the hypertensive patients are above the normal curve. 5) 130 . Legend: See Fig. 1. Sn 5.) 0 the data from the hypertensive subjects are above the so . • normal curve. •5 3) Theoretical blood volume: The theoretical mean value is significantly lower (P<0.OOl) than the real 110 r =+0.64 mean value. 4) Relative variation in blood volume: The mean P <0.00001 value is positive and the difference from the normal .' . value is highly significant (P<0.0000l). The relative variation in blood volume is correlated directly with the diastolic arterial pressure (P<0.000l) (Fig. 3). Renal indexes (Table 4). The renal blood flow is I I I slightly decreased (P<0.05). The relative increase in —10 0 +10 +20 +30 +40 +50 blood volume is negatively correlated with renal blood Relative variation in total blood volume flow (P <0.0001) (Fig. 4) and creatinine clearance Fig. 3. Relationshij5 between the relative variation in blood volume (r= —0.55; P<0.00l). No correlation is observed (ml kg-1) and the diastolic arterial pressure (mm Hg) in hyper- between the real blood volume and the renal blood tensive patients. flow or the creatinine clearance. Our study demonstrates that the volume-resistance Discussion mechanism is quite different in normotensive and hy- The present study suggests several comments con- pertensive patients. The hypertensive curve is reset on cerning blood volume regulation in sustained essential the right.hand side and has a diminished slope value, in- hypertension. dicating a decreased ability to reduce the blood volume The volume-resistance relationship in arterial hyper- tension. System analysis [20—23] has emphasized the Table 4. Renal indexes role of the negative volume-pressure (or resistance) feedback mechanism in the long-term control of Normal subjects Permanent arterial blood pressure. The increase in pressure in- hypertensives duces an increase in urinary output and a decrease in Endogenous creatinine blood volume and mean circulatory pressure. This, in clearance turn, reduces the cardiac output and finally the total mlmin'l.73m2 108± 6 97±3 peripheral resistance, thus causing the arterial pres- ml min' kg1 1.78±0.23 1.42±0.05 (N=11) (N=60) sure to return towards the normal level. Although the Renal blood flow mean circulatory pressure cannot be measured in man, mlmin' 1.73 rn2 1567±98 l3l0±69' the negative volume-resistance relationship we have rnlmin1kg' 25±2 19±lb observed in normotensive subjects parallels such a (N=l1) (N=52) mechanism and constitutes a working model in a Valuesare 1 SEM. clinical investigation. b p<0.05 in comparison with normal subjects. 46 Safar et a!

r =—0.54 Role of the kidneys in essential hypertension. Guyton P <0.0001 et at (22, 23) have emphasized the role of depressed 0. salt and water clearance by the kidneys in hypertension. •• • The theoretical approach to this problem was based 0 S 0 S . on the concept of "infinite gain" displayed by the body .0 •• fluid control system and its effects on arterial pressure a . U . regulation. It was therefore postulated [23] that the •... kidneys of all hypertensive patients are abnormal since S . they require an elevated pressure to excrete normal amounts of ingested sodium. I I I I I The present study was performed in patients with —10 0 +10 +20 +30 +40 + 50 essential and sustained hypertension whose sodium in- Relative variation in total blood volume take and urinary output were balanced. In addition, Fig. 4.Relationshipbetween the relative variation in blood volume all subjects had endogenous creatinine clearances (ml.kg-1) andthe renal blood flow (ml. mm -kg')in hyper- within normal ranges. In such a steady state, the "rel- tensive patients (semilogarithmic scale). ative variation in blood volume" is negatively corre- lated to the renal blood flow and the creatinine per unit rise in resistance. Such an observation in clearance. This result is in agreement with the theory hypertensive patients reveals the inability of the body of Guyton et at and suggests strongly that a renal fluid control system to help maintain the blood pres- mechanism is necessary in long-term arterial pressure sure within normal ranges. regulation, both in the normal state and in hyper- Meaning of the "relative variation in blood volume" tension. Taking this into consideration, hypertension in hypertensive patients. Analysis of the volume- can be considered to be the consequence of feedback resistance curves has shown that, at each level of total mechanisms resulting from a disorder of a regulatory peripheral resistance, the real blood volume is higher system of renal origin. in hypertensive than in normotensive subjects. This leads to the definition of the "relative variation in blood volume". This procedure can be questionable Acknowledgments because our data are in part based on extrapolated This study was supported by a grant from the values. However, the model we have proposed is con- Institut National de la Sante et de Ia Recherche sistent with common knowledge concerning the nature Médicale (Paris). Ms. Chantal Pillet provided assist- of hydraulic systems: it is impossible to increase the ance. pressure without achieving a volume that is relatively too large for the capacity of the system. Therefore, it Reprint requests to Dr. Michel E. Safar, Clinique Medicale Propedentique, Hopital Broussais, 96, rue Didot, 75014 Paris, is not the purpose of the present study to prove the Cedex 14, France. existence of such a mechanism, but only to provide a quantitative index of such a disturbance in human hypertension. This evaluation can be of major interest References in practical applications. As described previously (1—3, 5, 13), real blood 1. RocuLiN DB, SHOHL T, BLAKEMOE.E WS: Blood volume changes associated with essential hypertension. Gynecol volume is reduced in essential hypertension. However, Obstet 111:569—574, 1960 the present study demonstrates that, although the 2. TIBBLIN G,BERGENTZSD, BJURE J, WILHELMSEN L: Hema- volume is reduced, the reduction is insufficient to re- tocrit, plasma protein, plasma volume and viscosity in early store the blood pressure to normal. The relative in- hypertensive disease. Am Heart J 72:165—176, 1966 crease in blood volume reveals this fact and charac- 3. DUSTAN HP, TARAZI RC, BRAVO EL, DART RA: Plasma terizes the inadequate relationship between blood and extracellular fluid volumes in hypertension. Circ Res 32 (suppl l):73—81, 1973 volume and blood pressure. The direct correlation 4. JuLius S, PASCUAL AV, REILLY K, LONDON R: Abnormali- with the diastolic pressure suggests strongly that the ties of plasma volume in borderline hypertension. Arch high blood pressure in sustained essential hypertension Intern Med 127:116—119, 1971 is volume-dependent. In addition, the relative increase 5. SAI'AR ME, WEIss Y, LEVENSON J, LONDON G, MILLIEZ P: in blood volume can be defined as a volume that is not Hemodynamic study of 85 patients with borderline hyper- tension. AmJ Cardiol 31:315—319, 1973 eliminated by the body, so that a normal blood pres- 6. TARAZI RC, FROHLICH ED, DUSTAN HP: Plasma volume in sure cannot be restored. This assertion implicates the men with essential hypertension. NEng1J Med 278:762—765, existence of a renal mechanism. 1968 Altered blood volume regulation in sustained essential hypertension 47

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