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1. In basal conditions, plasma arterial prostaglandin (PG) E2 was significantly increased in borderline hypertensive patients (BH) (28.5 +/- 6.7 pg/ml) in comparison with sustained essential hypertensive patients (EH) (11.6 +/- 3.2 pg/ml) and in comparison with control normotensive subjects (NTS) (5.8 +/- 1.4 pg/ml). 2. Plasma arterial PGE2 was positively significantly correlated with cardiac index and negatively significantly correlated with total peripheral resistance in basal conditions. 3. Indomethacin induced more pronounced haemodynamic changes in borderline than in sustained hypertensive patients, with a significant increase in arterial blood pressure and total peripheral resistance and a significant decrease in stroke volume and cardiac index. 4. Indomethacin significantly decreased arterial PGE2 in borderline hypertensive patients. The decrease was less important in sustained hypertensive patients. 5. In the overall population, a significant positive correlation between arterial PGE2 concentration and cardiac index was observed before and after indomethacin treatment. 6. The study suggests an important role of PGE2 in the regulation of cardiac output (positive inotropic effect) and blood pressure of essential hypertensive patients.

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Three groups of women underwent water loading tests: normal subjects, idiopathic oedema patients who had taken no medication for at least 3 months, and a second oedema group with recent diuretic intake. Idiopathic oedema in drug-free patients was characterized by an abnormal capillary permeability, lower basal protein values, a dramatic drop in urinary output in the upright position due to reduced glomerular filtration, enhanced reabsorption of sodium and water and stimulation of aldosterone and antidiuretic hormone (AVP) secretions. In these idiopathic oedema cases, osmolar AVP regulation was disrupted but AVP control by plasma volume was maintained. In the basal state, patients with recent diuretic intake were characterized by a gain in body weight and by depletion of plasma volume and plasma potassium. In these subjects, urinary output in the upright posture was as insufficient as in drug-free patients but was due to higher sodium reabsorption. Renal insensitivity to AVP action was also observed. Osmolar regulation and volume regulation of AVP were both disrupted in these cases with recent diuretic intake.

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Guanfacine kinetics were studied in 19 patients with hypertension after single and repeated oral doses. The single-dose study was performed in two homogeneous groups who received 2 mg (n = 9) and 4 mg (n = 10). The plasma concentrations were fitted in a two-compartment open model with first-order absorption. After a lag time of 0.8 hr, the absorption occurred rapidly (t 1/2 congruent to 0.53 hr). The fast and slow elimination phases occurred with t 1/2s of 2 and 19 hr. At therapeutic levels the percent of drug in red blood cells (55%) was independent of total drug concentration. Peak plasma levels had small interindividual variations. Comparison of kinetic parameters and AUC at the two doses studied demonstrated that their bioavailability was equal and the kinetics were linear. In a multiple-dosing study, performed in the same subjects, the plasma levels at steady state were in good agreement with the predicted values (p less than 0.001) and proportional to daily dosage. A single method based on four blood samples collected after 24, 28, 32, and 36 hr allows a reasonable prediction of the effective steady-state plasma levels during chronic dosing with guanfacine.

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Intravenous and oral pharmacokinetics of pinlolol were studied in 18 hypertensive patients-9 with normal renal function and 9 with impaired renal function. Analysis of data showed that a linear two-compartment model was suitable to describe the pindolol kinetics. Compared with patients with normal renal function, patients with chronic renal failure exhibited: (1) unchanged transfer rate constants and distribution volumes and (2) decreased total body clearance with decreased renal clearance and unchanged nonrenal clearance. Analysis of oral data by the Loo-Riegelman method showed that the pindolol absorption kinetic was not first order. Compared with patients with normal renal function, patients with chronic renal failure exhibited decreased fraction of dose effectively absorbed and increased initial rate of absorption. The initial rate of absorption was inversely correlated with the creatinine clearance. The study disclosed evidence that absorption was modified in chronic renal failure.

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The intravenous and oral pharmacokinetics and the hepatic extraction ratio of pindolol were determined in 24 hypertensive patients with normal or impaired renal function. In patients with normal renal function, the total clearance was the sum of equal parts of the renal and nonrenal clearances. The nonrenal clearance was found to be equal to the hepatic clearance directly measured from the hepatic extraction ratio. Compared to patients with normal renal function, patients with chronic renal failure exhibited (i) unchanged K12 and K21 and nonrenal clearances, and (ii) significantly decreased values in half-life of the beta phase, Kel, and total renal clearance. The renal clearance was positively correlated (P less than 0.01) to the creatinine clearance. Bioavailability was significantly reduced (P less than 0.01) in the patients with renal failure. Assuming that the nonrenal clearance was equal to the hepatic clearance, the study provides evidence that, in patients with renal insufficiency, (i) no increased metabolism accompanies the decrease in renal function, and (ii) decreased availability is due to reduced absorption.

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Correlates of plasma renin activity and plasma aldosterone levels with hemodynamic functions were studied in 47 male patients with untreated, permanent essential hypertension. All subjects had a normal creatinine clearance and received a diet of 110 mEq/day of sodium. Supine plasma renin activity was directly correlated with cardiac index (P less than.01) and cardiopulmonary blood volume (P=.01). Percentage changes in plasma renin activity and total peripheral resistance in response to upright position were positively correlated (P less than.001). Supine plasma aldosterone level was directly correlated with stroke index (P less than .001) and negatively correlated with hear rate (P less than .05). No significant correlation of aldosterone level was observed with the other measurements, including plasma renin activity. The study points to the neural sympathetic control of plasma renin activity in essential hypertension and suggests the existence of some interrelationships between aldosterone level and cardiac performance.

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Baroreflex sensitivity and cardiopulmonary blood volume were determined in 95 men, including normotensive and hypertensive subjects with normal renal function and balanced sodium intake and urinary output. Baroreflex sensitivity was estimated by determining the slope of the regression line relating the increase of systolic pressure to the cardiac slowing after transient rises of arterial pressure. A technique of gradual atropinisation was used to evaluate the parasympathetic mediated component of the reflex. With this method, it was possible to calculate the exact atropine dose abolishing the reflex sensitivity. This index was not dependent on age. It was negatively correlated to the diastolic pressure in normotensive patients but not in hypertensive patients. The ratio between the cardiopulmonary and the total blood volume was considered as an index of sympathetic venous tone. This ratio was positively correlated to the diastolic pressure in normotensive patients, but not in hypertensive patients. This study strongly suggests that a precise sympathetic-parasympathetic balance existed in the normotensive patients. This balance was disrupted in the hypertensive patients pointing to abnormalities in the autonomic nervous system of permanently hypertensive patients.

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Blood pressure, renal blood flow, total blood volume (TBV), plasma renin activity, and vascular reactivities to angiotensin and norepinephrine were studied in 48 normotensive subjects and 106 essential, sustained, hypertensive patients with normal renal function, balanced sodium intake, and urinary output. A significant negative pressure-volume relationship was observed in normal subjects. Among the hypertensive patients, some were inside the 95% confidence limits of the normal curve and the others were above, indicating a disturbance in the pressure-volume relationship. A quantitative evaluation of the pressure-volume disturbance was proposed and discussed. The blood pressure of each hypertensive patient corresponded to two different blood volume values: the renal valve and the theoretical value extrapolated from the normal curve. The difference between the two values was called deltaTBV and was positive in hypertensive patients. The deltaTBV value was negatively correlated with the renal blood flow, the creatinine clearance, the plasma renin activity, and the vascular reactivities to angiotensin and norepinephrine (P less than 0.0001). The parameters were not correlated with the real blood volume. This study demonstrates quantitatively a pressure-volume disturbance in essential hypertension. This disturbance is strongly correlated with the renal function and the renin-angiotensin system changes.

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Central hemodynamics were determined in 202 men including 101 normotensive and 101 permanent essential hypertensive patients of the same age. Cardiac output was identical in the two groups while blood pressure and total peripheral resistance were significantly different. Strong differences between the two groups are revealed by a systematic correlation study: (i) correlations of blood pressure (with respectively heart rate and total blood volume) were significant in the normotensive group but not in the hypertensive group; (ii) correlations of cardiac output (with respectively heart rate and total blood volume) were significant in both groups; (iii) correlations of renal blood flow (with respectively cardiac output and blood pressure) were significant in the hypertensive group but not in the normo tensive group. This study provided evidence that the volume and neural pressure controls are impaired in hypertensive patients while the cardiac output control is maintained and, suggested the existence of adaptive mechanisms involving the kidney in the maintenance of normal cardiac output in permanent essential hypertensive patients.

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The smoothing technique is used in this part II to study the cardiac output control in normotensive and hypertensive subjects. It is proved that: 1. cardiac frequency and total blood volume are both determinants of cardiac output in the normotensives; 2. in the hypertensives, blood volume is the main factor, the role of the frequency becomes negligible; 3. at high pressures, the part of the blood volume in the body-weight increases, suggesting an overhydration phenomenon in essential human hypertension.

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A method of data analysis is proposed. Applied to the essential human hypertension study, the method put into evidence broken points in the evolution of certain hemodynamic parameters. These results could not be obtained by classical statistical analysis.

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Cardiac and renal hemodynamics and cardiopulmonary and total blood volume were determined in 202 men, 101 with normotension and 101 of the same age with chronic essential hypertension, normal renal function and balanced sodium intake and urinary output. Cardiac output was identical in the two groups, whereas blood pressure and total peripheral resistance were significantly different. The two groups exhibited strong differences in the correlation study: (1) Correlations of blood pressure with, respectively, heart rate, cardiopulmonary blood volume and total blood volume were significant in the normotensive group but not in the hypertensive group. (2) Correlations of cardiac output with, respectively, heart rate, cardiopulmonary blood volume and total blood volume were significant in both groups. (3) Correlations of renal blood flow with, respectively, cardiac output, blood pressure and total blood volume were significant in the hypertensive group but not in the normotensive group. This study provides evidence that: (1) the volume and neural control of blood pressure are disrupted in hypertension whereas control of cardiac output is maintained; and (2) adaptive mechanisms involving renal function are necessary to the maintenance of normal cardiac output in patients with essential hypertension.

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The pressor-response to norepinephrine was determined in the whole body circulation of 15 normal subjects and 86 untreated essential hypertensive patients. The slope, the threshold-dose and the critical-dose were calculated from the log dose-response curve. In the overall population (101 subjects) a slight correlation (r = +0.20 less than 0.05) was observed between the basal diastolic arterial pressure and the threshold-dose. In contrast, highly significant parabolic correlations (r = +0.46 less than 0.00001) were observed between the diastolic arterial pressure and the slope or the critical dose. When diastolic arterial pressure was above 100 mmHg, the slope increased while the blood pressure increased. This result suggests either a decreased sympathetic tone or an adaptative structural change of the arterial wall. When diastolic arterial pressure was under 100 mmHg, the slope decreased while the blood pressure increased. This observation points to an enhanced sympathetic activity in mild blood pressure.

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The isoproterenol sensitivity (dose-response curve) and the total body clearance of propranolol were measured in 80 men including 15 normal subjects and 65 essential hypertensive patients (20 borderline and 45 permanent hypertensives). The critical dose of isoproterenol was found to be directly correlated to weight (P less than 0.01), age (P less than 0.001), and basal diastolic arterial pressure (P less than 0.001). A partial correlation coefficient study showed that the diastolic arterial pressure was of greater influence than weight and age. The total body clearance of propranolol was inversely related to the basal diastolic arterial pressure (P less than 0.0001) in hypertensive patients. The study provides evidence that the level of basal diastolic arterial pressure could influence the beta-receptor responsiveness and the beta-adrenergic blockade in hypertensive patients.

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Twenty-nine patients with terminal renal failure were treated by periodic hemodialysis for 2 to 18 months. Serial determinations of blood pressure, blood volume, cardiac output, exchangeable sodium and plasma renin activity were performed. Bilateral nephrectomy was performed in 17 patients and followed by a fall in blood pressure. Cardiac index was elevated in all patients but the blood pressure changes were mainly related to resistance changes. In non-nephrectomized patients, mean arterial pressure was directly correlated to plasma volume (P less than 0.0001), exchangeable sodium (P less than 0.01) and plasma renin activity (P less than 0.001). In anephric patients, mean arterial pressure was only directly correlated to plasma volume (P less than o.005). The slope of the curve relating arterial pressure to plasma volume was significantly shallower in nephrectomized than in non-nephrectomized patients, indicating a lower sensitivity of pressure to volume changes. The study provides evidence that, in hypertensive patients with chronic renal failure, the positive pressure-volume relationship is the fundamental cause of the high blood pressure and that the renin-angiotensin system acts mainly by changing the sensitivity of this mechanism.

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Cardiac and renal hemodynamics and total blood volume were determined in 28 normal subjects and 60 patients with untreated essential well-established hypertension. Endogenous creatinine clearance was within normal ranges and sodium intake was 110 mEq/day. A significant negative volume-resistance relationship was observed both in normal subjects (P less than 0.005) and hypertensive patients (P less than 0.001). In comparison with the normal curve, the hypertensive curve has two characteristics: 1) the curve was reset on the right-hand side and, 2) the slope was significantly shallower, indicating a reduced ability to decrease the volume per unit rise in resistance. By using the normal curve as a reference system, a quantitative evaluation of the blood volume disturbance was proposed. In hypertensives, the value of the total peripheral resistance could correspond to two different values of the total blood volume: the real value and the theoretical value extrapolated from the normal curve. The difference between the two values was called "relative variation in blood volume" and was used as a mathematical model. In hypertensives, the real blood volume was significantly reduced (P less than 0.001) while a significant "relative increase" in total blood volume was observed (P less than 0.001). This "relative increase" was directly correlated with the diastolic arterial pressure (r=0.064; P less than 0.00001) and was inversely related to the renal blood flow (r=-0.54; P less than 0.0001) and the creatinine clearance. Such correlations were not observed with the real blood volume. In agreement with Guyton's theory, this study highly suggests that sustained hypertension is related to an increase in blood volume relative to the capacity of the circulatory system and that a renal defect is necessary for the blood pressure elevation mechanism.

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1. The changes in plasma volume, haemodynamic variables, plasma renin activity and plasma aldosterone were studied in forty-one hypertensive patients after administration of adrenergic-blocking agents. Four drugs were used: alpha-methyldopa (fourteen patients), guanethidine (ten patients), clonidine (nine patients) and reserpine (eight patients). Drugs were administered orally during 7 days' hospitalization on a normal sodium diet (110 mmol/day). 2. The four drugs had similar effects: a significant decrease in blood pressure, a significant increase in plasma volume and no change in stroke volume. 3. With alpha-methyldopa and guanethidine, heart rate, plasma renin activity and plasma aldosterone were unchanged. 4. With reserpine and clonidine, heart rate and plasma renin activity were significantly decreased, whereas plasma aldosterone did not change significantly. 5. This study suggests that the decrease in plasma renin activity was related to the lowering of the heart rate rather than to sodium retention and that adrenergic-blocking agents can impair the normal relationship between stroke index and plasma volume, between plasma volume and plasma renin activity, and between plasma renin activity and plasma aldosterone.

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Hemodynamic changes in supine and upright position and during exercise were studied in 144 men including 37 normal subjects and 107 patients with borderline hypertension. Borderline hypertensives were classified in 4 groups, according to the basal level of heart rate and stroke index. In the first two groups, stroke index was normal, but heart rate was either decreased (Group I) or elevated (Group II): supine total peripheral resistance was superior (Group I; p less than 0.02) or equal (Group II) to normal values; plasma volume was normal or slightly decreased; hemodynamic response to tilt test closely approximated the normal; impaired adaptation of cardiac index and stroke index to exercise was observed in Group II (p less than 0.001). In the other two groups, stroke index was significantly elevated (p less than 0.0001) but heart rate was either decreased (Group III) or increased (Group IV); supine total peripheral resistance values were decreased (p less than 0.001); plasma volume was equally reduced (p less than 0.001); abnormal percentile increase in diastolic arterial pressure (p less than 0.02; p less than 0.001) and total peripheral resistance during tilt test were observed; during exercise, only the patients of Group IV had an impaired adaptation of cardiac index (p less than 0.001) and total peripheral resistance (p less than 0.02). The study provide evidence that in boderline hypertension i) a high basal level of stroke volume is associated with a reduced plasma volume and an imparied adaptation of total peripheral resistance during tilt, ii) a high basal level of heart rate is associated with an impaired adapatation of cardiac output during exercise, and iii) only patients having an increase in both heart rate and stroke volume exhibited a specific hemodynamic pattern including: reduction of plasma volume, impaired adaptation of cardiac output during exercise, impaired adaptation of total peripheral resistance during tilt and exercise.

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