Low-pressure receptor activity and exaggerated natriuresis in essential hypertension

Urinary sodium excretion, central hemodynamics, and mean arterial pressure (MAP) were studied in 7 normal subjects and 19 hypertensive patients during both central hypervolemia by water immersion to the neck (NI) and extracellular volume expansion by i.v. saline infusion. During 2-hour NI, 12 out of the 19 hypertensives exhibited a significant fall in MAP (p less than 0.001). Exaggerated natriuresis did not occur in these patients (ns). In the remaining 7 hypertensive patients in whom, during NI, MAP was unchanged, exaggerated natriuresis was found (p less than 0.001). During saline infusion, MAP was either unchanged or increased and exaggerated natriuresis was found in all hypertensive patients (p less than 0.001) previously submitted to NI. Our findings suggest that a high MAP is a major determinant of exaggerated natriuresis in arterial hypertension.     

Role of renal hemodynamics in the exaggerated natriuresis of essential hypertension

Extracellular fluid volume expansion is known to produce exaggerated natriuresis in essential hypertension. In order to assess the role of hemodynamic and intrarenal physical factors upon natriuretic response to central volume expansion, two hour water immersion (WI) experiments were made in six uncomplicated essential hypertensives and six normotensive healthy controls. Before and during WI we measured mean arterial pressure (MAP), urine flow (V/min), sodium (UNaV) and potassium (UKV) excretion, glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and intrarenal (wedged) venous pressure (IRVP). In comparison with normotensive controls, the exaggerated natriuretic response in hypertensives (P less than 0.05 for UNaV during WI) was associated with an enhanced vasodilating response as demonstrated by a greater increase in ERPF (P less than 0.05) and by a more pronounced fall in calculated renal precapillary resistances (P less than 0.05). A more significant increase in IRVP was found in hypertensive group (P less than 0.05). Glomerular filtration rate (GFR) did not change in either group during WI. MAP, unchanged in normotensives, was significantly reduced in hypertensives (P less than 0.05), while remaining in the hypertensive range. These findings suggest that intrarenal physical factors play a major role in determining the exaggerated natriuresis during WI in hypertensive man.     

Circadian rhythm of natriuresis is disturbed in nondipper type of essential hypertension

We examined the circadian rhythm of urinary sodium excretion and the effects of sodium restriction on rhythm in both dipper and nondipper types of essential hypertension. Patients (n = 26) with essential hypertension were maintained on relatively high- (10 to 12 g/d of sodium chloride) and low-sodium (1 to 3 g/d) diets for 1 week each. On the last day of each diet, 24-hour blood pressures (BPs) were measured every 30 minutes noninvasively with an automatic device, and on the last 3 days, urinary samples were collected for both daytime (7:00 AM to 9:30 PM) and nighttime (9:30 PM to 7:00 AM). Eight patients were classified as dippers based on a more than 10% reduction in mean arterial pressure (MAP) from daytime to nighttime on a high-sodium diet, and 18 patients were classified as nondippers. A nocturnal decrease in urinary sodium excretion rate (U(Na)V) on the high-sodium diet was observed in dippers (from 7.5 +/- 2.1 during the day to 5.3 +/- 2.5 mmol/h at night; P < 0.0001), but not in nondippers (6.7 +/- 2.1 v 7.6 +/- 2.3 mmol/h; not significant). In nondippers, the night-day ratio of sodium excretion was significantly reduced from 1.2 +/- 0.4 to 0.8 +/- 0.3 (P < 0.003) by sodium restriction; at the same time, the night-day ratio of MAP was reduced from 0.98 +/- 0.04 to 0.93 +/- 0.05 (P < 0.05). In dippers, the night-day ratios of MAP and U(Na)V were not affected by sodium restriction, and both ratios remained constant at less than 1. Before sodium restriction, the night-day ratio of sodium excretion correlated with that of MAP (r = 0.78; P < 0.0001), whereas there was no significant correlation (r = -0.05) after sodium restriction. These findings showed that the circadian rhythm of renal sodium excretion differed between the two types of essential hypertension. The enhanced nocturnal natriuresis and diminished nocturnal BP fall on a high-sodium diet, recognized in nondippers, were both normalized by sodium restriction, resulting in circadian rhythms with nocturnal dips in U(Na)V and BP.     

Renin inhibitors in hypertension

The renin-angiotensin system (RAS) is an important modulator of blood pressure and fluid balance. The clinical success of angiotensin converting enzyme inhibitors (ACEIs) in the treatment of hypertension has stimulated the search for antagonists of renin. Because renin is highly specific for its substrate, angiotensinogen, renin inhibitors may emerge as clinically preferable alternatives to ACEIs, which affect multiple biological systems, including bradykinin and prostaglandin metabolism. Recent advances in renin inhibitor chemistry have produced highly specific and potent, transition-state analogs of angiotensinogen. Several compounds (e.g., enalkiren, ditekiren, CGP 38560A, and RO 42-5892) have been tested in man. These renin inhibitors produce dose-dependent decreases in plasma renin activity (PRA) which are dissociated from the dose-dependent decreases in blood pressure (BP). Potential explanations for this dissociation include methodologic errors in PRA assays and alternate sites or mechanisms of drug action, including inhibition of noncirculating tissue renin. A prolonged hypotensive effect is seen following single doses of enalkiren and RO 42-5892, and repeated dosing with enalkiren results in sustained hypotensive effect without tachyphylaxis. Renin inhibitors can reduce blood pressure irrespective of baseline renin status and sodium balance. However, high-renin patients generally respond more vigorously, and the hypotensive response is enhanced by sodium depletion. In general, renin inhibitors have been safe and well tolerated in limited clinical studies. New generation renin inhibitors with higher potency and greater oral bioavailability may join the antihypertensive armamentarium.     

Renin and blood volume in chronic renal failure: a comparison with essential hypertension

Sixty-five patients with advanced chronic renal failure (CRF) but a normal extracellular fluid volume (ECFV), including 31 dialysis patients, were studied. Plasma volume, blood volume (BV), plasma renin activity (PRA), and mean arterial pressure were measured to examine whether hypertension (when present) is renin dependent, or whether it is related to an abnormal distribution of ECFV between the intra- and extravascular spaces. PRA was higher in dialysis than nondialysis patients, but the incidence of hypertension was the same. In both groups hypertensive patients with normal PRA and normotensive patients with elevated PRA were present. The patients were compared to 65 patients with essential hypertension (EH) and 56 normals. The BV and BV-to-interstitial fluid volume ratio were similar in these groups. We found no decreased BV in patients with EH as has previously been reported by others, possibly because we used an appropriate normalization index and matched control groups. In sum, hypertension in CRF patients with a normal ECFV cannot always be explained by elevated renin levels. In this respect, CRF patients resemble patients with EH. An abnormal extracellular fluid distribution does not seem to be involved in the maintenance of hypertension.     

Potassium chloride lowers blood pressure and causes natriuresis in older patients with hypertension.

Epidemiologic surveys, experimental studies in animals, and clinical trials in young and middle-aged patients with hypertension indicate that dietary potassium lowers blood pressure. The mechanism of the antihypertensive effect is not well defined. Variations in serum potassium within the physiologic range may directly affect vascular smooth muscle tone. Potassium may also influence the regulation of blood pressure through effects on sodium handling, aldosterone secretion, the renin/angiotensin system, renal kallikrein, eicosanoids, and atrial natriuretic peptide. This study was undertaken to confirm the blood pressure-lowering effect of potassium in older patients and to determine the mechanism of the antihypertensive effect. Twenty-two patients greater than or equal to 60 yr of age were admitted to a Clinical Research Unit for 8 days after a 2-wk period free of antihypertensive medication. Patients were placed on an isocaloric diet containing 200 mmol/day of Na+, 70 mmol/day of K+, and 500 mg/day of Ca2+ and were treated in a randomized, double-blinded manner with either potassium chloride (120 mmol/day) or placebo. After 4 days, patients were crossed over to the alternate treatment. Systolic blood pressure decreased 8.6 mm Hg (95% confidence interval -14.6, -2.6), and diastolic blood pressure decreased 4.0 mm Hg (-6.9, -1.0) during potassium chloride supplementation. There was no significant change in blood pressure during treatment with placebo. Serum K+ was 3.9 +/- 0.1 mmol/L after 3 days of placebo and 4.3 +/- 0.1 after 4 days of potassium chloride (P less than 0.002). Urinary sodium excretion averaged 192 +/- 11 mmol/day after placebo and 221 +/- 8 after potassium treatment (P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exaggerated natriuresis in ACTH hypertension in sheep.

Adrenocorticotrophic hormone (ACTH) administration to sheep (100 IU/day) produces a sustained increase in arterial pressure within 24 h. The effect of ACTH on excretion of an intravenous saline load was tested in 8 adult cross-bred Merino ewes. A significant diuretic response to saline loading was found after 24 h but no increased natriuresis. On days 3 and 6, diuretic and natriuretic responses were both significantly increased. Steroid-induced sodium retention may have abolished the natriuretic effect on day 1.     

Home blood pressure monitoring improves the diagnosis of hypertension in hemodialysis patients

Using interdialytic ambulatory blood pressure (BP) recordings as the reference standard, we compared the performance of routine, standardized and home BP monitoring in 104 predominantly black patients on chronic hemodialysis for at least 3 months. Dialysis unit BP recordings were averaged over 2 weeks and home BP over 1 week. Awake ambulatory BP of > or =135 mmHg systolic or > or =85 mmHg diastolic was taken as evidence of hypertension. Average awake ambulatory BP was 128.1+/-21.6/73.5+/-13.5 mmHg, home BP 141.3+/-21.9/78.7+/-11.9 mmHg, standardized pre-dialysis BP 141.7+/-22.6/74.2+/-13.5 mmHg and post-dialysis 119.9+/-20.5/69.1+/-13.1 mmHg, routine pre-dialysis 145.4+/-21.8/79.0+/-13.1 mmHg and post-dialysis 131.5+/-19.2/72.5+/-11.4 mmHg. Sixty-three percent of the patients had well-controlled BP by ambulatory BP monitoring and isolated diastolic hypertension was rare (3%). The standard deviation of the differences between ambulatory and routine pre-dialysis BP was 17.6 mmHg, routine post-dialysis was 16.1 mmHg, standardized pre-dialysis was 16.4 mmHg, standardized post-dialysis was 14.1 mmHg, and home BP was 14.2 mmHg. The area under receiver operating characteristic curves was similar for home and standardized BP but lower for routine BP. Home systolic BP of > or =150 mmHg averaged over 1 week had the best combination of sensitivity (80%) and specificity (84.1%) in diagnosing systolic hypertension--present in 94% of the hypertensive dialysis patients. Home BP monitoring is similar to standardized recording of BP in hemodialysis patients. A systolic BP threshold of 150 mmHg at home averaged over 1 week serves as a useful predictor of hypertension diagnosed by ambulatory BP monitoring.     

白蛋白尿与高血压患者血压水平的关系

目的 研究我国不同区域高血压患者白蛋白尿与血压水平及体质量指数（BMI）的关系。 方法 在我国5个城市随机抽取5021例明确诊断为高血压的非糖尿病患者,进行两次随机点测尿中的白蛋白/肌酐比值,将尿蛋白的检出率与不同血压水平及BMI进行统计分析。 结果 （1）高血压患者白蛋白尿的检出率,在< 60岁与≥60岁组间差异无统计学意义;高血压病程越长,其检出率越高（P < 0.05）。（2）白蛋白尿检出率与血压水平相关,血压越高,尿蛋白量越高。正常血压、正常高值以及Ⅰ、Ⅱ、Ⅲ级高血压的白蛋白尿检出率分别为26.3%、27.3%、28.7%、31.5%和40.3%。（3）高血压患者血压控制达标（<140/90 mm Hg）与控制不良（≥140/90 mm Hg）的蛋白尿排出率差异有统计学意义（27.1% 比 30.2%,P < 0.05）。（4）同等血压水平时,肥胖高血压患者的白蛋白尿检出率高于体质量正常者,但差异无统计学意义。（5）有蛋白尿的高血压患者发生更多的心脑肾血管事件。 结论 我国5021例高血压患者中,其白蛋白尿的发生率为28.8%,其中微量白蛋白尿的发生率为18.6%,临床白蛋白尿的发生率为10.2%。血压控制不良是蛋白尿发生的重要因素。     

Renin angiotensin involvement in transient hypertension after renal injury

Transient hypertension occurred in 3 patients shortly after blunt injury to the abdomen. Renal trauma was suspected in all 3 patients and radiological evidence for renal injury was present in 2. Plasma renin activity definitely was elevated in 1 patient and probably was elevated in another. There was a decrease in blood pressure in all 3 patients during infusion of the angiotensin II analogue--saralasin--showing that the hypertension in these patients was angiotensin-mediated. Renal function as reflected by the blood urea nitrogen, creatinine and electrolytes was not impaired significantly. Thus, acute hypertension after blunt abdominal trauma may be angiotensinogenic and is not necessarily sustained.     

Adiponectin in essential hypertension

Adiponectin (ADPN), the gene product of apM1, is the most abundant secretory protein of adipose tissue in human plasma. Synthesis of this substance may be reduced in endothelial dysfunction and cardiovascular diseases in humans. We investigated the relationship between plasma ADPN, body mass index (BMI), fat mass (BIA) and renal function in 36 patients with uncomplicated essential hypertension. Plasma ADPN was higher in hypertensive patients than in normotensive subjects, but the difference just failed to reach statistical significance (P=0.06). Hypertensive men had significantly higher plasma ADPN than normotensive men (6.7+/-2.6 vs 4.8+/-2.0 microg/mL, 40%, P=0.01). By contrast, the difference between hypertensive (8.5+/-3.9 microg/mL) and normotensive women (7.1+/-2.6 microg/mL) was not significant (20%). In hypertensive patients, plasma ADPN was inversely related to creatinine clearance and tended to be inversely related to serum insulin (r= -0.27) and HOMA-R index (r= -0.24). The relationship between plasma ADPN and renal function was confirmed in a multiple regression analysis which showed that creatinine clearance was the only independent predictor of plasma ADPN. Plasma ADPN in essential hypertension is dependent on sex and renal function. High levels in essential hypertensives may be the expression of a counter-regulatory response aimed at mitigating endothelial damage and cardiovascular risk associated with high arterial pressure.     

Vasopeptidase inhibition normalizes blood pressure and restores endothelial function in renovascular hypertension

BACKGROUND/AIMS: Vasopeptidase inhibitors by definition inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), therefore they may exceed the effect of ACE inhibitors in the treatment of hypertension. The present study investigated the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on systolic blood pressure (SBP) and endothelial function in renovascular hypertension. METHODS: Wistar-Kyoto rats with renovascular hypertension (two-kidney one-clamp-model) were randomized 2 weeks after unilateral clamping of the right renal artery for 3 weeks' oral treatment with either AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or placebo. SBP was measured by the tail-cuff method and endothelium-dependent and -independent vascular function was assessed in isolated preconstricted (norepinephrine 10(-7) mol/l) aortic rings as relaxation to acetylcholine (10(-10)-10(-4) mol/l) and sodium nitroprusside (10(-10)-10(-4) mol/l), respectively. RESULTS: Two weeks after clamping, SBP was significantly elevated (196 +/- 16 vs. 145 +/- 8 mm Hg for sham-operated rats; p < 0.01) and further increased in placebo-treated animals to 208 +/- 19 mm Hg. Treatment with AVE7688 and ramipril had a similar blood pressure-lowering effect (119 +/- 8 and 124 +/- 10 mm Hg, respectively; p < 0.01 vs. placebo). Maximum endothelium-dependent relaxation was reduced in hypertensive rats (72 +/- 6 vs. 99 +/- 7% in control rats; p < 0.05). Endothelium-dependent relaxation was restored by AVE7688 (101 +/- 6%) and ramipril (94 +/- 8%), respectively, whereas endothelium-independent relaxation was comparable in all groups. CONCLUSION: In renovascular hypertension the vasopeptidase inhibitor AVE7688 exhibited similar blood pressure-lowering and endothelial protective properties as compared to the ACE inhibitor ramipril. Therefore, in high renin models of hypertension, vasopeptidase inhibition may be considered an alternative treatment option to ACE inhibition.     

Dominance of blood pressure in natriuresis associated with supraventricular tachycardia.

Supraventricular tachycardia was induced in 10 patients by programmed cardiac stimulation through esophageal lead. Blood pressure, heart rate, renal function, and hormonal factors were measured before, during, and after tachycardia. The patients were divided into two groups, depending on whether antinatriuresis occurred during tachycardia; one group (n = 5) with antinatriuresis during tachycardia associated with a decrease in blood pressure and the other group (n = 5) with neither antinatriuresis nor changes in blood pressure. The urinary sodium excretion tended to increase after tachycardia only in the latter group. On the other hand, urine volume and free water clearance increased during or after tachycardia in both groups. Plasma levels of atrial natriuretic peptide significantly increased and the urinary vasopressin excretion significantly decreased during tachycardia in both groups. During tachycardia, natriuresis due to atrial natriuretic peptide secretion seems to be hampered by hypotension, but polyuria is preserved despite the fall in blood pressure probably related to suppression of vasopressin release.     

Pressure natriuresis in AT(2) receptor-deficient mice with L-NAME hypertension

AT(2) receptor-disrupted (AT(2) -/-) mice provide a unique opportunity to investigate the cardiovascular and BP-related effects of NO depletion. This study compared the pressure-diuresis-natriuresis relationship in (AT(2) -/-) and wild-type (AT(2) +/+) mice after treating the animals with L-NAME (130 mg/kg body wt per day) for 1 wk. L-NAME increased mean arterial pressure (MAP) more in AT(2) -/- than in AT(2) +/+ mice (118 +/- 2 versus 108 +/- 4 mmHg). This difference occurred even though L-NAME-treated AT(2) +/+ mice had a greater sodium excretion than AT(2) -/- mice (10.9 +/- 0.5 versus 8.0 +/- 1.0 micro mol/h). The pressure-natriuresis relationship in conscious AT(2) -/- mice was shifted rightward compared with controls. RBF was decreased in AT(2) -/- compared with AT(2) +/+ mice. L-NAME decreased RBF in these mice further from 4.08 +/- 0.43 to 2.79 +/- 0.15 ml/min per g of kidney wt. GFR was not significantly different between AT(2) +/+ and AT(2) -/- mice (1.09 +/- 0.08 versus 1.21 +/- 0.09 ml/min per g of kidney wt). L-NAME reduced GFR in AT(2) -/- to 0.87 +/- 0.07 ml/min per g of kidney wt. Fractional sodium (FE(Na)) and water (FE(H2O)) curves were shifted more strongly to the right by L-NAME in AT(2) -/- mice than in AT(2) +/+ mice. AT(1) receptor blocker treatment lowered BP in both L-NAME-treated strains to basal values. It is concluded that the AT(1) receptor plays a key role in the impaired renal sodium and water excretion induced by NO synthesis blockade. Changes in RBF, GFR, and tubular sodium and water reabsorption are involved and may be also responsible for the greater BP increase in L-NAME-treated AT(2) -/- mice.     

Effect of aging on salt sensitivity of blood pressure in patients with essential hypertension

Background. Aging is considered to modulate the salt sensitivity of blood pressure (BP), but its mechanisms have not been precisely elucidated. We investigated aging-related changes in salt sensitivity and their mechanisms in patients with essential hypertension. Methods. A high-sodium (Na, 250 mEq/day, for 6 days) diet was given to 32 essential hypertensive patients of different ages (younger, aged <30 years, n = 8; middle-aged, 30–50 years, n = 10; older, ≥50 years, n = 14) after they had had a low-Na diet (25 mEq Na/day) for 3 days. Cardiac output was measured by dye-dilution, and forearm blood flow (FBF) and venous volume (VV40) by strain-gauge plethysmography. Results. The Na-induced rise in mean BP increased with age (3.2 ± 2.0%; 6.9 ± 2.1%; and 11.7 ± 1.4% respectively, in the younger, middle-aged, and older groups, and this was accompanied by a salt-induced rise in cardiac index and FBF. VV40 decreased with the high-Na diet in older hypertensives (−15.7 ± 6.1%) and the change was significantly less (P < 0.05) than in the younger group (9.3 ± 9.0%). Conclusion. The enhanced salt sensitivity of BP that occurs with aging in patients with essential hypertension is due to increased cardiac output, probably through a venous constriction-related elevation of venous return. Received: May 6, 1998 / Accepted: July 17, 1998