Importance of the renin system for determining blood pressure fall with acute salt restriction in hypertensive and normotensive whites

Hypertensive (n=93) and normotensive (n=39) white individuals were given a high sodium intake of approximately 350 mmol/d for 5 days followed by a low sodium intake of 10 to 20 mmol/d for 5 days. With this acute and large reduction in salt intake, no significant change was seen in blood pressure in the normotensive individuals, but blood pressure decreased in the hypertensive individuals. Compared with normotensive subjects, hypertensive patients had a 7/7-mm Hg greater fall in blood pressure (P<0.05 for systolic and P<0.01 for diastolic, adjusted for age), with similar changes in urinary sodium excretion. From the high-salt to low-salt diet, plasma renin activity rose from 0.90 to 5.99 ng. mL(-1). h(-1) in normotensives, whereas in hypertensives it rose from 0.73 to only 3.14 ng. mL(-1). h(-1) (P<0.05 between hypertensives and normotensives). Plasma aldosterone rose by 1396 pmol/L in normotensive subjects and by 511 pmol/L in hypertensive patients (P<0.05). Significant inverse correlations were obtained for all subjects between the fall in blood pressure from the high-salt to low-salt diet and the rise in plasma renin activity and aldosterone that occurred in addition to the absolute level on the low-salt diet. These results demonstrate that the larger fall in blood pressure with an acute reduction in salt intake in hypertensives compared with normotensives is, at least in part, due to a less-responsive renin-angiotensin-aldosterone system in the hypertensive patients.     

Urinary Excretion of Renal Prostaglandins,Kallikrein, Vasopressin and Aldosterone in Essential Hypertension

To assess the relationship between pressor and depressor factors in essential hypertension, the urinary excretion rates of prostaglandins E2 and F2α, kallikrein, vasopressin and aldosterone were compared between 53 untreated hypertensive patients and 53 age- and sex-matched normotensive controls. Mean basal levels of plasma renin activity and of urinary prostaglandins, vasopressin and aldosterone were similar in both groups, but urinary kallikrein was significantly lower in the hypertensive patients. A weak relationship was found in the hypertensives between diastolic blood pressure, and vasopressin or aldosterone, and between vasopressin and prostaglandin E2, and in the normotensives between vasopressin and prostaglandin F2α. In conclusion, these results do not provide evidence for an important imbalance between pressor and depressor factors in essential hypertension, as reflected by the urinary excretion of the major humoral factors and hormones involved in the regulation of blood pressure.     

Beta-adrenergic regulation of circadian rhythmicity of the renin-angiotensin-aldosterone system in five subtypes of essential hypertension

The possible implication of the beta-sympathoadrenergic system in regulating the rhythmicity of the renin-angiotensin-aldosterone system (RAAS) was studied in ten normotensive volunteers and in thirty-nine essential hypertensive patients. The study was carried out by simultaneous radioimmunological measurements of diurnal levels of plasma renin and aldosterone before and during acute oral medication of beta-adrenoceptors with propranolol. Acute beta-blockade was seen to blunt the circadian periodicity of plasma renin and aldosterone in normotensives and in hypertensives with normal or high renin patterns. Conversely propranolol was seen to be ineffective in low-renin patients. The disappearance of the circadian rhythms under beta-adrenoceptor blockade tends to suggest the existence of a beta-adrenergic control of RAAS cyclicity in normal condition, as well as in normal or high renin essential hypertension. The inefficacy of propranolol in hyporeninemic hypertensives is consistent with the hypothesis that low-renin essemtoa; juertemsopm os a state in which the sympatho beta-adrenergic mechanism controlling the function of RAAS has no biologic time structure.     

Is there a relation between the renin-angiotensin-aldosterone system and vasopressin secretion in essential hypertension?

103 patients with mild or moderately severe essential hypertension and 35 healthy normotensive subjects were examined. In all patients examined plasma osmolality, plasma renin activity and plasma level of vasopressin and aldosterone were estimated twice: first after administration of a diet with a sodium chloride content of 100 to 120 mmol/a day and 8 hours recumbency and a second time after 3 days of dietary sodium chloride restriction (20 mmol/a day) and 3-4 hours upright position. In hypertensives independent of the behaviour of the plasma renin activity similar values of the plasma osmolality, the plasma level of vasopressin and the aldosterone level could be established as in healthy persons. In contrast to normals in hypertensive subjects no significant correlation between plasma osmolality or plasma renin activity and plasma level of vasopressin and aldosterone was stated. In spite of normal levels of vasopressin and aldosterone a significant correlation between the plasma level of vasopressin and aldosterone and the systolic blood pressure was found in hypertensive patients. From the results obtained in this study follows that in hypertensive patients the plasma osmolality is only of secondary importance for the secretion of vasopressin and aldosterone and for the plasma renin activity. The importance of plasma vasopressin and aldosterone in the pathogenesis of hypertension seems to be probable but not yet unanimously proved.     

ALDOSTERONE IN SUSTAINED ESSENTIAL HYPERTENSION

Plasma aldosterone (PA), plasma renin activity (PRA), extracellular fluid volume (EFV) and hepatic blood flow were measured in forty-four patients with sustained essential hypertension and compared with forty-two normotensive controls of same age and sex. All patients had inulin clearances within the normal range and balanced sodium intake and urinary output. In hypertensives, PA, PRA, EFV and hepatic blood flow were within normal ranges; the log-ratio PA: PRA was significantly elevated (P < 0·001). In normotensives, a negative relationship was observed between PA and EFV (r= -0·55; P <0·001) while a positive relationship was observed between PA and PRA (=+0·70; P < 0·001). In hypertensives, the two relationships were disrupted or less significant: for a given value of EFV, PA was more elevated in hypertensives than in normotensives; for a given value of PRA, PA was more elevated in hypertensives than in normotensives. The results could not be explained on the basis of a disturbance in hepatic blood flow and/or in the metabolic clearance rate of aldosterone. The study provided evidence that, in patients with sustained essential hypertension and equilibrated sodium balance, there is an excess of plasma aldosterone relative to the levels of extracellular fluid volume and plasma renin activity. The excess is probably related to an abnormality in the adrenal secretion.     

The effect of sodium and potassium loading on urinary kallikrein-like activity in young patients with borderline hypertension

We studied the effects of a potassium supplement on urinary kallikrein excretion in a setting of high sodium intake after sodium deprivation with diuretics in young patients with borderline hypertension. Eleven patients, who took the potassium supplementation during the high sodium diet period, showed lower increments in mean blood pressure with salt loading than 12 patients without the potassium supplementation. In the non-potassium-supplemented patients, urinary kallikrein was increased significantly when plasma renin activity (PRA), plasma aldosterone concentration (PAC), and urinary aldosterone were increased during the diuretic treatment. It was decreased significantly when the other hormones were decreased during the sodium load. During the high sodium diet period, PRA, PAC and urinary aldosterone were greater in the potassium-supplemented patients than in the non-potassium-supplemented ones, but urinary kallikrein excretion was not higher when potassium was supplemented. Thus, the present results did not support the theory that the kallikrein-kinin system may be involved in the natriuretic and antihypertensive effects of potassium. In addition, these finding suggest that some kallikrein-modulating factor(s) may counteract the increased urinary kallikrein excretion with the augmented renin-angiotensin-aldosterone system during salt loading with potassium supplementation.     

Behavior of the renin-angiotensin-aldosterone system and vasopressin secretion in patients with renovascular hypertension or small kidney

In 11 hypertensive subjects with unilateral and 8 patients with bilateral renal artery stenosis as well as in 7 hypertensive patients with a so-called small kidney and in 33 normotensive subjects the behaviour of the plasma osmolality, plasma aldosterone and vasopressin level (AVP) as well as of the plasma renin activity (PRA) were estimated twice. First after the supply of a normal salted diet (100-120 mmol NaCl/d) and 8 hr overnight recumbency, and a second time after NaCl restriction (20 mmol NaCl/d) for 3 days and 3-4 hr upright position. In hypertensive patients with bilateral renal artery stenosis and with a "small kidney" significantly elevated AVP-levels were found both before and after NaCl-restriction in the diet as compared with normotensives. In contrast to normotensive subjects in hypertensive patients no significant correlation was found between plasma osmolality and AVP levels. No correlation was also found between plasma AVP-levels and blood pressure as well as between AVP-levels and PRA (with the exception of patients with unilateral renal artery stenosis). From the result obtained in this study the existence of a positive feedback mechanism between the renin-angiotensin-aldosterone system and the AVP-secretion and the participation of AVP in the pathogenesis of the hypertension caused by reduced blood supply of the kidneys is questioned.     

The renin-angiotensin-aldosterone system and hypertension in primary hyperparathyroidism

To evaluate the role of the renin-angiotensin-aldosterone system in the hypertension associated with primary hyperparathyroidism, we measured plasma renin activity and aldosterone concentration before and after maneuvers to suppress and stimulate this system in 11 hypertensive patients with primary hyperparathyroidism. We also measured plasma or urinary norepinephrine concentration to examine the role of catecholamines in the hypertension. The results were compared with an age- and race-matched control population. While the mean plasma aldosterone concentrations were normal, the mean plasma renin activity in response to furosemide stimulation was subnormal in subjects with hyperparathyroidism. Plasma or urinary norepinephrine concentrations were within the normal range. Thus a specific abnormality of the renin-angiotensin-aldosterone system or catecholamines could not be identified in these hypertensives with primary hyperparathyroidism.     

The role of the renal kallikrein-kinin system in sodium metabolism in normal and low renin essential hypertension

In order to investigate the pathophysiological role of the renal kallikrein-kinin system in renin subgroups of essential hypertension, the quantity and activity of urinary kallikrein, urinary kinin excretion, and correlations of kallikrein and kinin excretions with renal sodium handling in the renal tubules were studied in 17 normal subjects, 23 patients with normal renin and 12 patients with low renin essential hypertension. Urine samples were collected by the 2-hour clearance method in the early morning. The quantity and activity of urinary kallikrein, and the urinary excretion of kinin were significantly lower in both low and normal renin patients than in normal subjects. Comparing the normal renin and the low renin group, no significant difference was found in the quantity of urinary kallikrein, while the activity of urinary kallikrein and urinary kinin excretion were significantly lower in low renin patients than in normal renin ones. Fractional excretions of sodium (FENa) and inorganic phosphorus (FEP), which reflect renal tubular and proximal tubular sodium reabsorption, respectively, were significantly lower in the low renin patients than in the normal renin ones. A significantly positive correlation was observed between the urinary kallikrein activity or urinary kinin excretion and FENa or FEP in both normal subjects and normal renin patients, but not in low renin patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of aprotinin, a kallikrein inhibitor, on renin release and urinary sodium excretion in mild essential hypertensives

The effects of aprotinin on renin release and renal function were evaluated in 24 male essential hypertensive patients, on unrestricted (n = 17) and on chronic low as well as on high sodium intake. Aprotinin (1 X 10(6) kallikrein inhibitor units) or saline (200 ml) were infused in all patients for 6 h. Blood samples were taken for plasma renin activity (PRA) and 6-h urine collections were obtained for active and inactive kallikrein, sodium and potassium excretion measurement. In patients on unrestricted sodium diet, aprotinin had no effect on blood pressure (BP), glomerular filtration rate, renal plasma flow, urinary sodium and potassium excretion. However, an inverse relationship was found between pretreatment urinary sodium excretion and the per cent reduction of the latter after aprotinin. A significant reduction in urinary sodium excretion was induced by aprotinin in patients on high sodium intake, whereas no change was observed in the same patients when on a low sodium diet. Aprotinin reduced the urinary excretion of active kallikrein by 81% and the active to total kallikrein ratio from 24 to 6%. Infusion of aprotinin induced a significant decline in active renin but did not modify inactive renin levels in patients on unrestricted sodium diet as well as in patients on low or high sodium intake. Our data suggest that the inhibition of kallikrein and/or other serine proteases by aprotinin can interfere with renal release of active renin and also support the hypothesis that the renal kallikrein system exerts a regulatory control on sodium excretion in salt replete hypertensives.     

Urinary acid-base excretion in normotensives and hypertensives of african origin

Abnormalities in acid-base regulation have previously been reported both in hypertensive humans and animals and a link between abnormalities in renal sodium handling and acid excretion may be particularly important in black hypertensives. The objectives of this study were to compare indices of urinary acid excretion (urinary pH, ammonium and titratable acid excretion) between normotensives and hypertensive people of African origin. Measurements were carried out in 86 black individuals of African origin in a case-control design (19 normotensive; 67 hypertensive). Of these, 17 normotensive and 17 patients with essential hypertension were matched for age, sex and weight. Group comparisons were carried out by unpaired t-tests or two-way analysis of variance and group values are given as means +/- s.d. Urinary pH was significantly higher in the hypertensives both in the unmatched groups and in the matched groups. In the 17 matched pairs: urinary pH in the hypertensive individuals was 6.36 +/- 0.54 and 5.84 +/- 0. 53 in the normotensives, respectively; P = 0.007. Additionally, urinary titratable acidity was significantly lower in the hypertensives than in the normotensives (25.4 +/- 13.7 vs16.7 +/- 10. 7 mmol/24 h; P = 0.047) but there were no significant differences in urinary ammonium excretion. The mechanisms for the apparent reduction in acid excretion in the hypertensives is not clear but these results highlight the possibility that hypertension in blacks is associated with abnormalities of renal sodium and hydrogen exchange with compensatory increases in renal ammonium production.     

Effects of Psychological and Physical Covariates on Plasma Catecholamines in Borderline Hypertensives and Offspring of Hypertensive Parents

The interpretation of plasma catecholamine measurements may be influenced by psychological and physical factors. Therefore, catecholamine concentrations were adjusted for between-subject differences by the following possible confounding factors, i.e. body-mass index, individual maximal physical work capacity, urinary sodium excretion rates and anxiety score. Subjects were 24 borderline essential hypertensives, aged 18–24 years, 50 age-matched normotensive offspring of hypertensive parents and 49 controls with no family history of hypertension studied at rest and during mental stressors (Stroop colour-word conflict test, mental arithmetic). Borderline hypertensives had consistently higher adjusted venous noradrenaline concentrations than control subjects (p<0.05). Adjusted plasma adrenaline concentrations were higher in borderline hypertensive subjects than in offspring of hypertensive parents during supine rest. Despite its limitations, venous plasma noradrenaline concentrations when adjusted for work capacity, body-mass, sodium excretion and anxiety suggest enhanced sympatho-neural activity in young borderline essential hypertensives.     

Differential effects of nifedipine on plasma atrial natriuretic peptide in normal subjects and hypertensive patients.

The physiology of atrial natriuretic peptide (ANP) secretion was studied in normotensive subjects and hypertensive patients both young and old. Basal plasma ANP concentration was least in young normotensives, intermediate in old normotensives and young hypertensives, and highest in old hypertensives. Nifedipine, a known stimulator of ANP secretion, acutely increased plasma ANP in young and old normotensive subjects but not in young hypertensive patients and half of the old hypertensive patients. Increase in serum ANP level in response to nifedipine did not augment its hypotensive effect. However, the increase of aldosterone in response to nifedipine-induced rise in plasma renin activity (PRA) seemed to be suppressed by elevated ANP.     

Higher urinary albumin excretion is associated with abnormal erythrocyte Na(+)/Li(+) countertransport (SLC) in non-modulating essential hypertensives and offspring of hypertensive parents

Non-modulating is a highly reproducible type of sodium-sensitive hypertension. The aim of this study was to evaluate in non-modulating individuals the erythrocyte sodium-lithium countertransport (SLC) abnormalities, which have been mentioned as a marker of non-modulation, and the association with increased microalbuminuria, as a marker of an early kidney impairment. We measured erythrocyte SLC in 10 normotensives (NT, 28 +/- 4 years), 20 offspring of hypertensive parents being 10 modulating (MHO, 25 +/- 6 years) and 10 non-modulating (NMHO, 26 +/- 5 years), and 23 essential hypertensives being 12 modulating (MHT, 34 +/- 5 years) and 11 non-modulating (NMHT, 32 +/- 4 years). In all the subjects studied, microalbuminuria was determined by duplicate 24-h urine collection by radioimmunoassay. In non-modulating offspring of hypertensive parents and essential hypertensives. SLC was significantly elevated when compared either with normotensives without family history of hypertension, modulating offspring of hypertensive parents or essential hypertensives (P < 0.025). Likewise, 24-h urinary albumin excretion was found higher in non-modulating individuals (essential hypertensives and offspring of hypertensive parents) than in modulating individuals (P < 0.01). In conclusion, non-modulators with higher SLC countertransport sodium transport abnormalities showed higher elimination of microalbuminuria suggesting that non-modulators may have an increased risk for developing cardiovascular morbidity and kidney impairment even in normotensive subjects with familiarity history of hypertension.     

Natriuretic hormones in young hypertensives and in young normotensives with or without a family history of hypertension.

The behavior of plasma atrial natriuretic factor (ANF) and digoxin-like substance (DLS), and the daily urinary excretion of kallikrein (uKK) were evaluated in young hypertensives and in young normotensives with or without a family history of essential hypertension. Each group was also evaluated, separating those with low plasma renin activity from the total sample. The sample group was made up of 75 young males; 31 hypertensives (mean age 22.7 +/- 2.5 years), 28 normotensives with hypertensive heredity (normotensives F+) (mean age 22.2 +/- 1.9 years) and 16 normotensives (mean age 22.0 +/- 2.1 years). An inverse correlation between ANF and PRA was shown in all groups. In hypertensives, ANF was inversely correlated with uKK (r = -0.664, P less than .0001). Plasma ANF (P less than .012) and DLS (P less than .0001) were higher in hypertensives than in normotensives, while uKK excretion was lower (P less than .0001). Plasma levels of DLS were higher in F+ normotensives than in normotensives (P less than .003). Low renin hypertensives showed the lowest uKK excretion (P less than .0001 v normal-high renin hypertensives). Furthermore, low renin hypertensives showed the highest plasma levels of ANF (P less than .0001 v normal high renin hypertensives) and DLS (P less than .012 v normal-high renin hypertensives). Plasma ANF (P less than .0001) was higher, while uKK was lower (P less than .045) in low renin F+ normotensives than in normal-high renin ones. In conclusion, our data indicate that plasma ANF and DLS are elevated since the early phase of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced response of plasma aldosterone to metoclopramide in essential hypertension

Aldosterone responses to posture and the dopamine antagonist, metoclopramide, were studied in seven normotensive controls and 12 patients with essential hypertension. Both groups had similar basal supine plasma renin activity and aldosterone levels. Aldosterone levels of the hypertensive patients were greater than those of the controls 10 min after assuming an upright posture but indistinguishable at 120 min. Metoclopramide induced a peak fourfold increase above basal aldosterone levels in the hypertensive group as compared to a peak twofold increase observed in the normotensive controls. Mean 120-min integrated aldosterone response area for the hypertensives (237 +/- 44 10(-10) mol min/l) was greater (P less than 0.05) than that for normotensive subjects (106 +/- 32 10(-10) mol min/l). Simultaneous cortisol, plasma renin activity, and serum potassium levels were unaffected by metoclopramide. It is concluded that dopaminergic modulation of aldosterone secretion may be altered in essential hypertension.     

Dipyridamole decreases circulating renin-angiotensin system activity in hypertensive patients.

To study the effect of adenosine on renin release, n = 6 hypertensive patients, while on a constant 80 to 100 mEq/24 h Na+ diet, received oral 150 mg dipyridamole (an adenosine uptake inhibitor) three times daily for 3 days while upright plasma renin activity (PRA) and plasma aldosterone, urinary aldosterone, plasma and urinary Na+,K+, and creatinine clearance were monitored the day before (basal) the first and third day of the treatment and the day after the withdrawal (recovery). As compared to basal and to recovery, dipyridamole significantly decreased PRA, and plasma and urinary aldosterone without affecting plasma and urinary Na+ and K+, creatinine clearance, blood pressure, and heart rate. These data, showing that dipyridamole decreases PRA and aldosterone, confirm also in hypertensives that endogenous adenosine inhibits the circulating renin-angiotensin-aldosterone system.     

Effect of prepuberal gonadectomy upon aldosterone levels in female and male SHR: interaction between blood pressure and kallikrein kinin system

It has been suggested that an abnormal activity of the hypothalamic-pituitary-adrenal-gonadal axis may be implicated in the pathogenesis of spontaneously hypertensive rats (SHR) blood pressure hypertension. However, it is widely known that the kallikrein-kinin system plays a role in blood pressure regulation in this strain, because an inverse relation between blood pressure and urinary kallikrein excretion has been reported. It was of our interest to study how early suppression of sexual hormones affected blood pressure regulation in SHR and urinary kallikrein excretion and to elucidate the involved mechanisms. For these purpose, SH and Wistar-Kyoto (WKY) rats blood pressure, renal function, and hormonal profile were studied after prepuberal gonadectomy starting at 4 weeks of age throughout until the 12th week of age. Results were compared with those of untreated SH and WKY rats of either sex. The response to blocking agents against aldosterone and kallikrein-kinin system also were evaluated. Systolic blood pressure increased progressively in male and female SHR 12 weeks of age. Systolic blood pressure was higher in male than in female SHR, but urinary kallikrein was lower in male SHR. Prepuberal gonadectomy induced a significant decrease in systolic blood pressure in male and in female SHR at 12 weeks of age, accompanied by an increase in urinary kallikrein in male and in female SHR. Plasma aldosterone increased markedly in female and male SHR after gonadectomy. No concurrent changes in plasma renin activity or corticosterone levels were observed. The aldosterone receptor antagonist and the kallikrein inhibitor treatment blunted the blood pressure lowering effect of gonadectomy and diminished urinary kallikrein excretion. Results support the existence of a sexual dimorphism related to hypertension and urinary kallikrein and suggest an interaction among the kallikrein-kinin system, sexual hormones, and mineralocorticoids in the neonatal programming of hypertension.     

The role of atrial natriuretic peptide in natriuresis of fasting.

OBJECTIVE: To examine the relation between plasma atrial natriuretic peptide (ANP) and the natriuresis of fasting. DESIGN: ANP, aldosterone and renin were examined during natriuresis of fasting in 25 obese essential hypertensive patients and nine overweight normotensive subjects placed on a supervised 500-KCal diet composed of 50% carbohydrates, 30% fat and 20% protein, and unlimited salt. Twenty-four-hour urinary electrolytes were measured on days 0, 4, 7 and 10 of the diet. RESULTS: Urinary sodium concentration nearly doubled in the patients on day 4, and increased 1.4-fold in the normotensive controls. Plasma ANP rose nearly threefold in the hypertensives on day 4 and nearly doubled in the normotensives. Patients and controls showed similar patterns of natriuresis and ANP secretion during the diet. CONCLUSIONS: We conclude that there is a clear association between ANP levels and natriuresis of fasting.