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The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which omapatrilat induces an antihypertensive response in salt sensitive hypertension.

Previously, we have shown that an acute injury to the kidney produced by an intrarenal injection of phenol causes an immediate increase in blood pressure and in norepinephrine (NE) secretion from the posterior hypothalamus. The studies suggest that in this model afferent impulses from the kidney to central integrative structures in the brain may be responsible for the increase in blood pressure. To further evaluate whether a renal injury caused by the intrarenal injection of phenol leads to a permanent elevation of blood pressure and whether this is mediated by increased sympathetic nervous system activity, we examined the chronic effects (4 weeks) of an intrarenal injection of 50 microL of 10% phenol on blood pressure and NE secretion from the posterior hypothalamus. Systolic blood pressure increased from 128 +/- 2.1 to 176 +/- 1.5 mm Hg (P.01) 4 weeks after receiving the intrarenal injection of phenol, but it did not change in rats that received the vehicle (128 +/- 2.4 and 135 +/- 1.7 mm Hg) and in rats that were subjected to renal denervation (127 +/- 3.4 and 124 +/- 1.0 mm Hg). The secretion of NE from the posterior hypothalamic nuclei was greater (P.01) in rats that received phenol (253 +/- 9.6 pg/mL) than in controls (158 +/- 8.6 pg/mL) and denervated rats (170 +/- 2.1 pg/mL). These studies have shown that a limited injury to one kidney may cause a permanent elevation of blood pressure and this is associated with increased sympathetic nervous system activity.

Hyperinsulinemia, insulin resistance, or both have been described in a proportion of patients with essential hypertension, and also are considered a risk for atherosclerotic cardiovascular disease. In this study, we have examined whether salt sensitivity and hyperinsulinemia are associated in patients with essential hypertension. We have measured blood insulin and glucose response to an acute oral glucose load in a group of hypertensive patients, classified according to their salt sensitivity. To determine salt sensitivity, patients received a diet containing a low (20 mEq/day) Na+ intake for 1 week followed by a high (250 mEq/day) Na+ intake for 1 week more. Twenty-nine patients were classified as salt sensitive, and 23 as salt resistant. Baseline plasma glucose and insulin were not different between salt-sensitive and salt-resistant patients. Following an oral glucose load, the area-under-the curve of glucose was greater (P < .05) in salt-sensitive than in salt-resistant hypertensive patients (900 +/- 26.4 and 810 +/- 29.1 mmol/L x 2 h, respectively). The area-under-the curve of insulin was greater (P < .01) in salt-sensitive (52,664 +/- 3,666 pmol/L x 2 h) than in salt-resistant patients (37,977 +/- 3,300 pmol/L x 2 h). A direct correlation was present between insulin area-under-the curve and salt sensitivity (r = 0.26), but did not reach statistical significance (P < .06). Salt-sensitive patients manifested increased serum levels of total cholesterol, LDL-cholesterol and increased urinary albumin excretion when compared with salt-resistant patients. In conclusion, these studies have demonstrated that in response to an oral glucose load, salt-sensitive patients with essential hypertension manifest increased insulin secretion. The studies have confirmed the presence of increased urinary albumin excretion and serum levels of atherogenic lipoproteins in salt-sensitive compared with salt-resistant patients. In salt-sensitive hypertensive patients, hyperinsulinemia, hyperlipidemia and microalbuminuria form a cluster with possible atherogenic potential. Salt sensitivity can be a marker for increased cardiovascular risk in patients with essential hypertension.

Overweight individuals (body mass index (BMI) 25–29.9 kg/m2) are at higher risk for developing hypertension and cardiovascular disease when compared with lean individuals of normal weight (BMI 18.5–24.9 kg/m2).1,2 The mechanisms underlying the increased risk have not been fully elucidated, but may include abnormalities of the sympathetic nervous system (SNS). Chronic baseline sympathetic overactivity, as well as greater sympathetic responses to stressful stimuli, are potential abnormalities that might predispose overweight individuals to developing hypertension and cardiovascular disease. Heightened cardiovascular and sympathetic reactivity to stressful stimuli has been associated with the development of hypertension and cardiovascular disease.3–7 Increased cardiovascular reactivity to the cold pressor test (CPT), a known sympathoexcitatory stimulus,8 predicts the future development of hypertension,9 and may represent a preclinical manifestation of hypertension before elevations in peripheral arterial blood pressure (BP) are detected. Augmented sympathetic reactivity may be one possible mechanism underlying the increased risk of developing hypertension and cardiovascular disease in overweight individuals, especially because sympathetic activity is known to be chronically elevated in obesity (BMI ≥30 kg/m2),10–12 and likely contributes to the pathogenesis of obesity-related hypertension. It is less established if overweight individuals, with a lesser degree of excess weight than obese patients, also have heightened baseline SNS activity, and sympathetic responses to sympathoexcitatory stimuli have never before been studied in normotensive overweight individuals. The purpose of this study was to test the hypothesis that normotensive overweight individuals have chronic baseline sympathetic overactivity, and exaggerated pressor and SNS responses to stressful stimuli. To test this hypothesis, we made hemodynamic measurements and direct measurements of muscle sympathetic nerve activity (MSNA) using microneurography at baseline and during two sympathoexcitatory maneuvers (CPT and static handgrip exercise (SHG)) in healthy overweight individuals, and lean age-matched controls.

Microalbuminuria has been shown in approximately 40% of patients with essential hypertension. Previous studies have failed to demonstrate any consistent relationship between microalbuminuria and levels of office blood pressure. Because average ambulatory blood pressure correlates with incidence of cardiovascular morbidity and mortality better than office blood pressure, we have studied whether levels of urinary albumin excretion correlate with average diurnal, nocturnal, or 24-h blood pressure better than with office blood pressure. Sixty-three patients with essential hypertension and 21 healthy volunteers were included in the study. Twenty-four hypertensive patients failed to show the normal nighttime fall in blood pressure of at least 10/5 mm Hg and were defined as "nondippers"; the remaining were defined as "dippers." Office blood pressure was not different between dippers and nondippers. However, nighttime systolic and diastolic blood pressures were significantly greater in nondippers than in dippers. The median urinary albumin excretion in nondippers (42 mg/24 h) was significantly greater (P < .001) than in dippers (17.5 mg/24 h), and in normal subjects (8.6 mg/24 h). A significant correlation was present between nighttime systolic and diastolic blood pressure and urinary albumin excretion (UAE) and between 24-h systolic blood pressure and UAE in all hypertensive patients; in addition, a significant correlation was present between 24-h diastolic and nighttime diastolic blood pressure and UAE in nondippers. The increased amount of UAE in nondipper hypertensive patients suggests the presence of greater renal damage than in dippers.

High dietary Na+ raises mean arterial pressure (MAP) by more than 10% in salt-sensitive (SS) patients with essential hypertension. To test whether the rise in MAP in these patients is caused by a Na(+)-linked increase in [Ca2+]i in vascular smooth muscle cells, we measured [Ca2+]i in the lymphocytes of 14 patients with essential hypertension kept on a Na+ intake of 20 mEq/day for 9 days, and 200-mEq/day for 14 days. Nifedipine gastrointestinal transport system (GITS) (30 mg/day) was given during the last 4 days of each diet. We isolated lymphocytes on Ficoll-Hypaque gradient and measured [Ca2+]i levels using Fura-2 fluorescent dye. During low Na+ intake, there was no difference in MAP (102 +/- 3.5 v 93 +/- 3.8 mm Hg) and in lymphocytes [Ca2+]i (80 +/- 3.0 v 87 +/- 5.4 nmol/L) between the seven salt-sensitive and the seven salt-resistant patients. During high Na+ intake, MAP (92 +/- 2.8 mm Hg) and [Ca2+]i (85 +/- 6.8 nmol/L) did not change in salt-resistant patients. On the contrary, MAP (115 +/- 3.4 mm Hg) and [Ca2+]i (130 +/- 11.1 nmol/L) increased significantly (P less than .01) in the salt-sensitive patients. Nifedipine did not significantly alter MAP and [Ca2+]i in both groups of patients during low Na+ and in salt-resistant patients during high Na+ intake. On the contrary, during high Na+ intake, nifedipine decreased significantly (P less than .01) both MAP (104 +/- 2.4 mm Hg) and [Ca2+]i (89 +/- 5.7 nmol/L) in salt-sensitive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Several patients with essential hypertension manifest an abnormal (greater than 30 mg/24 h) urinary albumin excretion (UAE). Since microalbuminuria is considered an independent predictor of cardiovascular morbidity and mortality, studies are currently being undertaken to determine the effect of various antihypertensive agents on UAE, on the assumption that a reduction of UAE might result in improved prognosis in patients with essential hypertension. Twenty-four patients with essential hypertension were randomly divided into two groups of 12. The first group received 20 mg/day enalapril for 8 weeks, followed by 20 to 40 mg/day nitrendipine for 8 more weeks. The second group received nitrendipine for 8 weeks, followed by enalapril. Mean arterial pressure decreased similarly during both therapeutic regimens in the two groups of patients. In patients of group 1, UAE decreased significantly (P less than .01) from 74 +/- 7.0 to 33 +/- 5.8 mg/24 h after 8 weeks of treatment with enalapril; during the following 8 weeks of treatment with nitrendipine, UAE increased to 58 +/- 5.3 mg/24 h (P less than .02). In patients of group 2, UAE did not change during the first 8 weeks of therapy with nitrendipine despite a significant reduction in blood pressure; subsequently, after 8 weeks of therapy with enalapril, UAE decreased from 62 +/- 9.2 to 31 +/- 4.8 mg/24 h (P less than .01). This study demonstrates that enalapril but not nitrendipine may reduce UAE in patients with essential hypertension despite similar antihypertensive efficacy. The significance of microalbuminuria and the impact of the normalization of UAE on cardiovascular morbidity and mortality in patients with essential hypertension remains to be determined.

Intrarenal injection of phenol in rats causes a persistent elevation in blood pressure (BP) and in norepinephrine (NE) secretion from the posterior hypothalamus (PH), and downregulation of neuronal nitric oxide synthase (nNOS) and interleukin-1beta (IL-1beta) in the PH. These studies suggest that afferent impulses from the kidney to the brain may be responsible for hypertension associated with renal injury. Downregulation of nNOS and IL-1beta, two modulators of sympathetic nervous system (SNS) activity may mediate this activation. In this study we measured the effects of intrarenal phenol injection on peripheral SNS activity by direct renal nerve recording, plasma NE, nNOS, and IL-1beta abundance in the brain. We also determined whether renal denervation or administration of clonidine prevented these effects of phenol. Acutely, the phenol injection increased both afferent and efferent renal sympathetic nerve activity, decreased urinary sodium excretion, and increased plasma NE. Three weeks after the phenol injection, BP and plasma NE remained elevated. Renal denervation and pretreatment with clonidine prevented the increase in BP and plasma NE caused by phenol. Chronic renal injury caused by phenol was associated with decreased abundance of IL-1beta and nNOS in the PH. These studies have shown that a renal injury caused by phenol injection increases BP and central as well as peripheral SNS activity, which persist long after the injury. Renal denervation and antiadrenergic drugs abolish the effects of phenol on BP and plasma NE. Because NO and IL-1beta modulate SNS activity, the stimulatory action of phenol on the SNS could be mediated by downregulation of nNOS and IL-1beta in the brain.

Microalbuminuria in patients with essential hypertension is associated with increased incidence of cardiovascular morbidity and mortality. Reduction of urinary albumin excretion (UAE) with therapy could reduce cardiovascular events. The long-term effect of commonly used antihypertensive agents on UAE has not been properly investigated. In the present study, we have prospectively studied the effects of therapy for 24 months with a converting enzyme inhibitor, enalapril, or a calcium channel blocker, nicardipine, on UAE in 40 patients with essential hypertension and microalbuminuria. Enalapril and nicardipine were equally effective in reducing arterial pressure. However, enalapril decreased UAE from 77.1 +/- 10.4 to 30.4 +/- 7.9 mg/24 h after 1 year, and to 24.7 +/- 4.8 (P < .01) after 2 years of therapy. UAE however, did not change in patients treated with nicardipine (from 65.2 +/- 12 to 73 +/- 14 after 1 year, and to 52.7 +/- 21 mg/24 h after 2 years of therapy). The impact of reducing UAE on overall cardiovascular morbidity and mortality and on future progression of renal failure in patients with essential hypertension remains to be established.

Several abnormalities of calcium metabolism have been described in patients with essential hypertension, and they have been linked to the pathogenesis of hypertension. Intestinal calcium absorption has been shown to be decreased in rats with spontaneous hypertension, but it has not been studied in patients with essential hypertension. In these studies we have for the first time measured intestinal absorption of calcium (using oral and intravenous administration of 47Ca), along with other parameters of calcium metabolism, in 14 patients with essential hypertension and normal renal function and in 16 normal subjects. There was no difference in serum total or ionized calcium, serum phosphorus, parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and 24,25-dihydroxy-vitamin D(24,25(OH)2D) among hypertensives and normotensives. The urinary excretion of calcium, on the other hand, was greater in hypertensive than in normotensive subjects (195 +/- 33 v 107 +/- 13 mg/24 h, P less than .05). There was also no difference in intestinal absorption of calcium after 2 and 24 h among hypertensives and normotensives. When hypertensive patients were stratified according to plasma renin activity (PRA) we found that patients with low PRA had higher intestinal absorption of calcium at 2 h (23 +/- 2.9 v 18 +/- 0.6%, P less than .05) but not at 24 h. Serum total and ionized calcium, PTH, and 1,25(OH)2D were not different between patients with low and those with normal-high PRA. The major derangement of calcium metabolism in patients with essential hypertension is hypercalciuria. This abnormality is more pronounced in patients with low PRA, and it may lead to increased vitamin D-dependent intestinal absorption of calcium.

This review critically analyzes the available information on the relationship among calcium, parathyroid hormone, and blood pressure regulation. Both acute and chronic hypercalcemia increase blood pressure primarily via direct effects on vascular smooth muscle contractility. The evidence for indirect effects through activation of hormonal pressor systems is inconclusive. In apparent contrast with the notion that hypercalcemia can cause hypertension, more recently it has been proposed that calcium deficiency may be important in the genesis of hypertension both in humans and in spontaneously hypertensive animals. However, the evidence supporting this notion is still conflicting. Parathyroid hormone exerts complex actions on the cardiovascular system. On one hand, if injected in pharmacological doses, it is a vasodilator and antagonizes the pressor action of norepinephrine and angiotensin II; on the other hand, parathyroid hormone can potentiate the pressor effect of hypercalcemia.