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Significance: Salt sensitivity of blood pressure (SSBP) is an independent risk factor for mortality and morbidity due to cardiovascular disease, and disproportionately affects blacks and women. Several mechanisms have been proposed, including exaggerated activation of sodium transporters in the kidney leading to salt retention and water. Recent Advances: Recent studies have found that in addition to the renal epithelium, myeloid immune cells can sense sodium via the epithelial Na(+) channel (ENaC), which leads to activation of the nicotinamide adenine dinucleotide phosphate oxidase enzyme complex, increased fatty acid oxidation, and production of isolevuglandins (IsoLGs). IsoLGs are immunogenic and contribute to salt-induced hypertension. In addition, aldosterone-mediated activation of ENaC has been attributed to the increased SSBP in women. The goal of this review is to highlight mechanisms contributing to SSBP in blacks and women, including, but not limited to increased activation of ENaC, fatty acid oxidation, and inflammation. Critical Issues: A critical barrier to progress in management of SSBP is that its diagnosis is not feasible in the clinic and is limited to expensive and laborious research protocols, which makes it difficult to investigate. Yet without understanding the underlying mechanisms, this important risk factor remains without treatment. Future Directions: Further studies are needed to understand the mechanisms that contribute to differential blood pressure responses to dietary salt and find feasible diagnostic tools. This is extremely important and may go a long way in mitigating the racial and sex disparities in cardiovascular outcomes. Antioxid. Redox Signal. 35, 1477–1493.

Introduction: Salt Sensitivity (SS) of blood pressure (BP) is an independent predictor of death due to cardiovascular disease, but its pathogenesis is poorly understood. Sodium (Na + ) is stored in the skin and muscle interstitium. This hyperosmolar Na + activates monocytes in vitro via oxidative stress with generation of isolevuglandin (isoLG) protein adducts that are immunogenic and activate the adaptive immune system. Methods: Five subjects with essential hypertension discontinued all anti-hypertensive therapy for two weeks before the study. SS was assessed by an inpatient protocol of salt loading (460 mmoL/24h) and salt depletion (10 mmoL/24h, plus furosemide 40 mg x 3). Muscle and skin Na + contents were measured at baseline (BA) by 23 Sodium magnetic resonance imaging ( 23 NaMRI). Urine and serum electrolytes, glomerular filtration rate and the % CD14 + monocytes containing isoLG adducts using flow cytometry were obtained at BA, after salt-loading (HI) and after salt-depletion (LO). All continuous data are displayed as median (interquartile range). Spearman’s correlation was used to test associations. Results: Median age was 54 years (44-55), 60% of subjects were female, screening systolic BP (SBP) was 140 mmHg (134-148), diastolic BP was 88 mmHg (84-99) and BMI was 35 kg/m 2 (30-39). SBP response to salt-depletion (salt-sensitivity index, SSI) varied from -13.8 to +1.8 mmHg. %isoLG + CD14 + cells were 48 (27-65) at BA, 55 (31-56) at HI, and 70 (33-72) at LO (p=0.594, by the Kruskal-Wallis test). The correlation between SSI and delta (Δ) %isoLG LO minus HI, was 0.86, [95% confidence interval (CI), -0.07-0.99] which may suggest conclusively as we gather more data that the greater the SSI, the larger the decrease in isoLGs by salt depletion. Muscle Na + content correlated with 24h urine Na + (BA) (r=0.90, 95% CI, 0.11-0.99), however, the correlation with BP, SSI or isoLGs was inconclusive, potentially due to the small sample size. Skin Na + content correlated with baseline %CD14IsoLG + (r=0.91; 95% CI, 0.12-0.99). Conclusions: Na + intake is a component of the determinants of muscle Na + . Skin Na + is associated with increased isoLGs in monocytes, a marker of immune cell activation. Variability in ΔCD14isoLG may serve as a biomarker for SS of BP in humans.

T and B cells have been implicated in hypertension, but the mechanisms by which they produce a coordinated response is unknown. T follicular helper (Tfh) cells that produce interleukin 21 (IL21) promote germinal center (GC) B cell responses leading to immunoglobulin (Ig) production. Here we investigate the role of IL21 and Tfh cells in hypertension. In response to angiotensin (Ang) II-induced hypertension, T cell IL21 production is increased, and Il21-/- mice develop blunted hypertension, attenuated vascular end-organ damage, and decreased interleukin 17A (IL17A) and interferon gamma production. Tfh-like cells and GC B cells accumulate in the aorta and plasma IgG1 is increased in hypertensive WT but not Il21-/-mice. Furthermore, Tfh cell deficient mice develop blunted hypertension and vascular hypertrophy in response to Ang II infusion. Importantly, IL21 neutralization reduces blood pressure (BP) and reverses endothelial dysfunction and vascular inflammation. Moreover, recombinant IL21 impairs endothelium-dependent relaxation ex vivo and decreases nitric oxide production from cultured endothelial cells. Finally, we show in humans that peripheral blood T cell production of IL21 correlates with systolic BP and IL17A production. These data suggest that IL21 may be a novel therapeutic target for the treatment of hypertension and its micro- and macrovascular complications.

Aims: \ud Monocytes play an important role in hypertension. Circulating monocytes in humans exist as classical, intermediate and non-classical forms. Monocyte differentiation can be influenced by the endothelium, which in turn is activated in hypertension by mechanical stretch. We sought to examine the role of increased endothelial stretch and hypertension on monocyte phenotype and function.\ud \ud Methods and Results: \ud Human monocytes were cultured with confluent human aortic endothelial cells undergoing either 5% or 10% cyclical stretch. We also characterized circulating monocytes in normotensive and hypertensive humans. In addition, we quantified accumulation of activated monocytes and monocyte-derived cells in aortas and kidneys of mice with Angiotensin II-induced hypertension. Increased endothelial stretch enhanced monocyte conversion to CD14++CD16+ intermediate monocytes and monocytes bearing the CD209 marker and markedly stimulated monocyte mRNA expression of interleukin (IL)-6, IL-1β, IL-23, chemokine (C-C motif) ligand 4 and tumor necrosis factor α. STAT3 in monocytes was activated by increased endothelial stretch. Inhibition of STAT3, neutralization of IL-6 and scavenging of hydrogen peroxide prevented formation of intermediate monocytes in response to increased endothelial stretch. We also found evidence that nitric oxide inhibits formation of intermediate monocytes and STAT3 activation. In vivo studies demonstrated that humans with hypertension have increased intermediate and non-classical monocytes and that intermediate monocytes demonstrate evidence of STAT3 activation. Mice with experimental hypertension exhibit increased aortic and renal infiltration of monocytes, dendritic cells and macrophages with activated STAT3.\ud \ud Conclusions: \ud These findings provide insight into how monocytes are activated by the vascular endothelium during hypertension. This is likely in part due to a loss of nitric oxide signaling and increased release of IL-6 and hydrogen peroxide by the dysfunctional endothelium and a parallel increase in STAT activation in adjacent monocytes. Interventions to enhance bioavailable nitric oxide, reduce IL-6 or hydrogen peroxide production or to inhibit STAT3 may have anti-inflammatory roles in hypertension and related conditions.

Primary autonomic failure is characterized by disabling orthostatic hypotension, but at least half of these patients have paradoxical supine hypertension. Renin–angiotensin mechanisms were not initially thought to contribute to this hypertension because plasma renin activity is often undetectable in autonomic failure. Plasma aldosterone levels are normal, however, and we recently showed that plasma angiotensin II is elevated and acts at AT 1 (angiotensin type 1) receptors to contribute to hypertension in these patients. Because aldosterone and angiotensin II can also bind mineralocorticoid receptors to elevate blood pressure, we hypothesized that mineralocorticoid receptor activation plays a role in the hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine hypertension completed this study (7 pure autonomic failure, 2 multiple system atrophy, 1 parkinson’s disease; 7 male; 70±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P =0.016), with no effect on nocturia (12-hour urine volume: 985±134 mL placebo versus 931±94 mL eplerenone, P =0.492; nocturnal weight loss: −1.19±0.15 kg placebo versus −1.18±0.15 kg eplerenone, P =0.766). These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure, likely independent of canonical mineralocorticoid effects, and provides rationale for use of eplerenone in these patients.

We measured epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) in 21 normotensive subjects classified as salt resistant (13) or salt sensitive (8) with an inpatient protocol of salt loading (460 mEq Na + /24 hours, HiNa) and depletion (10 mEq Na + /24 hours+furosemide 40 mg×3, LoNa). No urine EETs were detected; hence, enzyme linked innumosorbent assay 14,15-DHETs (dihydroxyeicosatrienoic acids) were considered the total converted 14,15-urine pool. We report ultra-performance liquid chromatography/tandem mass spectrometry plasma EETs, DHETs, and their sum (plasma total pool) for the 3 regioisomers (8,9-, 11,12-, 14,15-) and their sum (08,15-). In salt-resistant subjects, urine total pool was unchanged by HiNa, decreased by LoNa, and correlated with urine sodium excretion, fractional excretion of Na + , and Na + /K + ratio for the 3 days of the experiment combined ( P + /K + ratio but showed correlations between EETs, blood pressures, and catecholamines and between DHETs and aldosterone ( P + /K + ratio during LoNa only. Plasma total pool of salt-sensitive was lower than in salt-resistant subjects and did not correlate with blood pressures or aldosterone but did with catecholamines. We conclude that the urine total pool reflects a renal pool involved in regulation of natriuresis, whereas the plasma total pools are of systemic origin, uninvolved in Na + excretion, perhaps contributing to regulation of vascular tone. Data suggest that abnormalities in EETs in salt-sensitive subjects participate in their renal or vascular dysfunction, which has potential therapeutic implications.

We measured eicosatrienoic acids in 21 normotensive subjects classified as salt-resistant (SR=13) or salt-sensitive (SS=8) with the rapid protocol of Indiana University (high salt, HS=460 mEq Na/24 hrs, low-salt, LS=10 mEq Na/24 hrs + furosemide 40 mg x 3). No EETs were detected in urine; hence, ELISA 14-15 DHETs were taken to represent the total pool of this urine isoform (U-TP). Plasma total pools (8-9,11-12,14-15 and 14-15 P-TP) are the sum of EETs+DHETs (HPLC-MS), and their results were similar, so the former are reported. Analyses required log-transformation of not normally distributed data. U-TP was not changed by HS but decreased with LS (Δlog -0.47±0.19, p

The simplest definition of salt sensitivity of blood pressure (SSBP) states that it is a physiological trait present in rodents and other mammals, including humans, by which the blood pressure (BP) of some members of the population exhibits changes parallel to changes in salt intake. In animals, the trait has been inbred such that the salt-sensitive (SS) ones will sustain increases in BP with salt loading and decreases with salt depletion, whereas the salt resistant (SR) ones will not. In humans, the trait is normally distributed; therefore, the distinction between SS and SR members of the population has been made by choosing an arbitrary magnitude of the salt-induced change in BP to define the groups. Regardless of possible causation by abnormalities of sodium handling, the SS phenotype is not usually characterized by alterations in salt balance (eg, impaired natriuresis or expanded plasma volume) but rather by a hypertensive response to maintain it. In an unselected population, SSBP is a continuous, normally distributed quantitative trait.1 As with any other trait with these characteristics, there is the issue of whether population members with the largest and smallest quantities of the trait represent the randomness of its distribution or are qualitatively different from the population at large. An example of this controversy is the old analyses of the unimodality versus bimodality of BP incidence or prevalence in humans that tried to determine whether hypertension is a distinct entity or simply an extreme of the gaussian distribution of BP.2 The development of the spontaneously hypertensive rat by Japanese investigators3 showing that the trait could be selected by inbreeding made it clear that hypertension had a genetic component. The gaussian distribution of population BP is probably the result of a random mixture of prohypertensive and antihypertensive genes and genetic variants in a …

Salt sensitivity of blood pressure has been studied in humans with a 48-hour inpatient protocol of salt loading and depletion or with longer outpatient protocols using high- and low-salt diets. Results have been reproducible, but both methods are laborious and costly. A 6-hour protocol of intravenous salt loading and furosemide has been reported but never validated. We studied 14 normal volunteers (39±2 years old; 86% women and 21% black) with the inpatient and 6-hour protocols, separated by 30 days. Four subjects (29%) were salt sensitive in the inpatient protocol. They had higher systolic blood pressure, higher body mass index, and somewhat lower plasma renin activity than salt-resistant subjects. Baseline systolic blood pressure before both protocols was highly reproducible ( r =0.90; P r =0.09). Three salt-sensitive and 4 salt-resistant subjects were misclassified by the short protocol. Three-hour natriuresis by furosemide in the short protocol (344±15 mmol) was not different from the 12-hour natriuresis in the inpatient protocol (357±19). However, stimulation of plasma renin activity and aldosterone was significantly less in the short (+0.10±0.07 ngA I /L/sec and −61±44 pmol/L) than in the inpatient protocol (+1.80±0.60 ngA I /L/sec and +256±88 pmol/L; P

We investigated 24-hour hemodynamic changes produced by salt loading and depletion in 8 salt-sensitive (SS) and 13 salt-resistant (SR) normotensive volunteers. After salt loading, mean arterial pressure was higher in SS (96.5±2.8) than in SR (84.2±2.7 mm Hg), P -5 *s), P =0.05, whereas cardiac output was not different between groups (SS 4.5±0.3 versus SR 4.4±0.2 L/min, not significant). Following salt depletion, cardiac output was equally reduced in both groups. Total peripheral resistance increased 24±6% ( P + balance was similar in SR and SS during salt loading or depletion. However, SR did not gain weight during salt retention (−158±250 g), whereas SS did (819±204), commensurate to iso-osmolar water retention. During salt depletion, SR lost the expected amount of weight for iso-osmolar Na + excretion, whereas SS lost a greater amount that failed to fully correct the fluid retention from the previous day. We conclude that SS are unable to modulate total peripheral resistance in response to salt depletion, mirroring their inability to vasodilate in response to salt loading. We suggest that differences in water balance between SS and SR indicate differences in salt-and-water storage in the interstitial compartment that may relate to vascular dysfunction in SS.

OBJECTIVE To investigate whether endothelin and aldosterone participate in the increased prevalence and severity of nephrosclerosis in human low-renin hypertension, analogous to observations in experimental hypertension. DESIGN Comparison of endothelin, aldosterone and their relationships with proteinuria, in hypertensive patients with high aldosterone : renin ratios (HARR group, n = 14) or normal aldosterone : renin ratios (NARR group, n = 15). METHODS Urine protein and radioimmunoassay measurements of plasma renin activity, endothelin and aldosterone were carried out in individuals taking their usual diet, and after salt loading and salt depletion. RESULTS Compared with the NARR group, patients in the HARR group had higher blood pressure, greater salt sensitivity of their blood pressure, significantly greater urine protein and lower serum potassium concentrations, lower renin activities [0.14 +/- 0.03 ng AngiotensinI (AI)/l per s compared with 0.76 +/- 0.16 ng AI/l per s; P < 0.005], blunted renin-aldosterone responses to salt loading and salt depletion, enhanced catecholamine responses to salt depletion, and increased plasma endothelin (5.1 +/- 0.5 fmol/ml compared with 3.7 +/- 0.3 fmol/ml; P < 0.03). In the HARR group, endothelin and aldosterone concentrations were highly correlated, and both correlated with blood pressure and urine protein. In contrast, in the NARR group, endothelin and aldosterone did not correlate between them or with blood pressure, and only endothelin, not aldosterone, correlated with urine protein. Multivariate regression confirmed that the interaction between aldosterone and endothelin was the major predictor of urine protein in the HARR group (r = 0.442), whereas endothelin, renin and their interaction were predictors in the NARR group (r = 0.467). CONCLUSIONS Our results concur with experimental evidence for participation of endothelin in renal damage of angiotensin-dependent hypertension and for that of an endothelin-aldosterone interaction in low-renin hypertension. We propose that combined pharmacological antagonism of endothelin and aldosterone may confer renal protection beyond blood pressure reduction in patients with low-renin hypertension, a population at high risk for hypertensive nephrosclerosis.

Analogous to observations in Dahl salt-sensitive (SS) rats, we have shown that 20-hydroxyeicosatetraenoic acid (20-HETE) is involved in the pathogenesis of SS essential hypertension. A strong negative correlation between urine 20-HETE and body mass index (BMI) remains unexplained. We measured BP, urine sodium (UNaV), and 20-HETE in obese hypertensive subjects during a 24-hour salt load (160 mmol NaCl diet+2 L intravenous saline). We classified them into insulin-resistant (IR) (n=14) and insulin-sensitive (IS) (n=12), with the average insulin sensitivity index (SI=22.5×[fasting glucose×insulin] −1 ) of 3 days (cutoff for IR, SI P 2 , P P P r =−0.39, P r =−0.53, P −1 /μU · mL −1 , P r =−0.40, P

Background— Twenty-hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450 metabolite of arachidonic acid that produces vasoconstriction and inhibition of renal tubular sodium transport. In Dahl rats, a 20-HETE deficiency plays a role in salt-sensitive (SS) hypertension. In humans, there are no data on regulation of 20-HETE by salt intake or on a role for this compound in SS hypertension. Methods and Results— Thirteen salt-resistant (SR) and 13 SS hypertensive subjects had urine 20-HETE excretion measured during salt-loading and depletion. In all patients, 20-HETE was 66.6% higher in the salt-replete (1.75±0.25 μg/h) than in the salt-depleted state (1.05±0.16, P r =0.61, P r =0.66, P r =−0.79, P Conclusions— We demonstrate for the first time that 20-HETE excretion is regulated by salt intake in hypertension. We find a disrupted relationship between sodium excretion and 20-HETE in SS patients, which results in dependence of their salt excretion on blood pressure and may be related to the magnitude of their obesity. We conclude that salt-sensitivity of blood pressure in essential hypertension may result from impairment of a natriuretic mechanism dependent on 20-HETE.

An rs3890011 variant of CYP4A11, which is in linkage disequilibrium with the loss-of-function variant rs1126742, is associated with hypertension in humans. In mice, Cyp4a deficiency results in salt-sensitive hypertension through activation of ENaC. We tested the hypothesis that the rs3890011 variant is associated with blood pressure response to drugs acting via the ENaC pathway. African Americans with volume-dependent, resistant hypertension were randomized to treatment with placebo, spironolactone, amiloride, or combination. Blood pressure responses were analyzed by CYP4A11 genotypes. Rs3890011 (GG:GC:CC = 20:35:28) and rs1126742 (TT:TC:CC = 45:31:7) were in linkage disequilibrium (D' = 1, r = 0.561). Expected small number of rs1126742 CC homozygotes precluded analysis of the effect of this genotype on treatment responses. Spironolactone reduced blood pressure in rs3890011 GG and GC individuals, but not in CC homozygotes (P = .002), whereas amiloride reduced blood pressure similarly in all rs3890011 genotypes. The antihypertensive effects of spironolactone and amiloride were comparable in GG and GC participants, but only amiloride reduced pressure in CC homozygotes (-6.3 ± 7.3/-3.2 ± 4.0 vs. +6.8 ± 7.9/+4.8 ± 8.6 mm Hg, P .01/.05). The aldosterone response to spironolactone was also blunted in the CC genotype. In individuals homozygous for the CYP4A11 rs3890011 C allele, blood pressure is resistant to mineralocorticoid receptor antagonism, but sensitive to ENaC inhibition, consistent with ENaC activation. Studies in a larger population are needed to replicate these findings.

Background —Salt dependency of blood pressure (BP) characterizes most models of experimental hypertension in which endothelins play a significant vasoconstrictor role. Despite this, there are no data on the regulation of plasma endothelin by salt balance in human hypertension. Methods and Results —Plasma endothelin was measured in 47 patients with essential hypertension. Endothelin, catecholamine, and plasma renin activity (PRA) responses to 24-hour sodium deprivation (↓Na) were assessed in 29 of these patients. Endothelin was higher in hypertensive patients (4.6±0.2 fmol/mL) than in 20 control subjects (3.3±0.3 fmol/mL, P P t statistic for the difference in BP before and after ↓Na. Systolic BP falls were −15±1, −2±2, and −9±1 mm Hg, respectively. PRA, its response to ↓Na, and its level after ↓Na were lowest (albeit nonsignificant) in salt-sensitive patients. Baseline catecholamine and endothelin levels did not differ among the groups. In response to ↓Na, catecholamines increased more significantly in salt-sensitive patients (+2.4±0.9 nmol/L) than in the other groups (0.4±0.2 and 0.7±0.2 nmol/L for indeterminate and salt-resistant groups, respectively; P P P P Conclusions —Our data suggest that salt-depleted salt-sensitive hypertensives with blunted renin responses exhibit enhanced catecholamine-stimulated endothelin levels and may therefore respond better than unselected patients with essential hypertension to endothelin receptor blockers.

To investigate the role of the renin-angiotensin system in the regulation of adrenal growth in deoxycorticosterone (DOC)-salt hypertensive rats, and the adrenal gene expression of angiotensin AT 1 and AT 2 receptors, three groups of uninephrectomized rats+DOC pellet+0.9% NaCl were given water (DOC), losartan (DOC-L), or ramipril (DOC-R) by gavage. Controls had sham surgery and water gavage. Tail-cuff systolic and mean intra-arterial blood pressures were significantly higher in the three DOC groups than in controls and not different among the groups. Adrenal weight of DOC was slightly but not significantly greater than that of controls, while those of DOC-L and DOC-R were greater than that of controls ( P 1 and AT 2 gene expression was significantly reduced in DOC (by 33% and 60%), while that of AT 1 (but not AT 2 ) was significantly reduced further (versus control and DOC) in DOC-L and DOC-R. There were negative correlations between adrenal weight and AT 1 ( r =−.80, P 2 ( r =−.60, P 1 and AT 2 gene expression by different mechanisms. Removal of the effects of angiotensin by losartan or ramipril downregulates AT 1 further and promotes adrenal growth, indicating the presence of an AT 1 -mediated growth-inhibitory action of angiotensin II on the adrenal gland. These observations constitute an additional example of a growth-inhibitory role for the AT 1 receptor, opposite to its more common growth-promoting actions in other organs and tissues.

We studied the characteristics of insulin resistance in 19 normotensive and 25 hypertensive subjects who underwent an acute protocol for determination of salt-sensitivity of blood pressure. Hypertensive subjects were older and more obese, with higher creatinine, lipids, and aldosterone than normotensive volunteers. They also had higher glucose and insulin levels with a marked decrease in insulin sensitivity (HOMA2-S index). Once all participants were classified into salt-sensitive (SS) and salt-resistant (SR) groups, most of these differences were no longer present. In contrast, SS had classical characteristics of this phenotype (higher percentage of blacks, suppressed plasma renin, increased aldosterone-to-renin ratio, and blunted renin and aldosterone responses to changes in salt balance). Despite similar insulin levels, HOMA2-S was significantly lower in SS than SR. Salt-loading did not change HOMA2-S in SS or SR. In contrast, salt-depletion, by significantly increasing glucose and insulin of SR, decreased their HOMA2-S to the levels observed in SS. Correlates of insulin resistance in SR included age, triglycerides, body mass index, mean arterial pressure, aldosterone, and epinephrine. However, only body mass index and aldosterone remained as significant predictors in multivariate analyses. Correlates of insulin resistance in SS were mean arterial pressure, epinephrine, and norepinephrine, all remaining as significant predictors in multivariate modeling. Our data confirm that salt-sensitivity of blood pressure is associated with insulin resistance, suggest that salt restriction may be beneficial in SS but perhaps detrimental in SR subjects, and uncover possible differences in mechanisms of insulin resistance between SS and SR, with implications for pharmacological therapy.

To compare the relative effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in reducing cardiovascular mortality in chronic hemodialysis patients, we conducted an observational analysis of all patients initiated on ACEI or ARB therapy undergoing chronic hemodialysis at a large dialysis provider. Survival curves with mortality hazard ratios (HR) were generated using the Kaplan-Meier method and Cox regression. Outcomes were compared using inverse probability of treatment weighting and propensity score matching. Over 6-years, 22,800 patients were newly initiated on an ACEI and 5,828 were initiated on an ARB after at least 60 days of chronic hemodialysis. After adjustment for baseline cardiovascular risk factors, there was no significant difference in the risk of cardiovascular, all cause, or cerebrovascular mortality in patients initiated on an ARB versus ACEI (HR of 0.96). A third of 28,628 patients, newly started on an ACEI or ARB went on to initiate another antihypertensive medication in succession. After adjustment for risk factors, 701 patients initiated on combined ACEI and ARB therapy (HR of 1.45) or 6866 patients on ACEI and non-ARB antihypertensive agent (HR=1.27) were at increased risk of cardiovascular death compared with 1758 patients initiated on an ARB and non-ACEI antihypertensive therapy. Thus, an ARB, in combination with another antihypertensive medication (but not an ACEI), may have a beneficial effect on cardiovascular mortality. As observational studies may be confounded by indication even when adjusted, randomized clinical trials are needed to confirm these findings.

A role for a deficit in transport actions of 20-hydroxyeicosatetraenoic acid (20-HETE) in hypertension is supported by the following: (1) diminished renal 20-HETE in Dahl-S rats; (2) altered salt- and furosemide-induced 20-HETE responses in salt-sensitive hypertensive subjects; and (3) increased population risk for hypertension in C allele carriers of the T8590C polymorphism of CYP4A11, which encodes an enzyme with reduced catalytic activity. We determined T8590C genotypes in 32 hypertensive subjects, 25 of whom were phenotyped for salt sensitivity of blood pressure and insulin sensitivity. Urine 20-HETE was lowest in insulin-resistant, salt-sensitive subjects (F=5.56; P r 2 =0.53; F=11.1; P

The controversy over beneficial versus harmful effects of salt on cardiovascular outcomes may be caused by different effects of salt on intermediate phenotypes of hypertension not characterized in epidemiological studies. Hence, we investigated acute effects of salt on oxidative stress in hypertensive subjects classified as salt sensitive (SS, n=14) or salt resistant (SR, n=13) by an inpatient protocol of salt loading (460 mmol NaCl) and salt depletion (10 mmol NaCl and furosemide). Oxidative stress was assessed by measuring the plasma isoprostane 8-iso-PGF2α. SS had lower plasma renin activity, higher aldosterone/renin ratios, and exaggerated endothelin and catecholamine responses to salt depletion compared with SR. Baseline lipid-bound isoprostanes (749±70 pmol/L) were 83% of the total and were slightly but not significantly higher in SS than SR. Baseline free isoprostanes did not differ between groups. After salt loading, lipid-bound isoprostanes were higher in SS (945±106) than SR (579±57; P P value not significant). Free isoprostanes were decreased by salt depletion only if data in all of the patients were analyzed together. Total isoprostanes followed the pattern of the lipid-bound fraction. Correlations between salt depletion-induced changes in lipid-bound isoprostanes, plasma renin activity ( r =0.45; P r =−0.41; P

Cyclooxygenase metabolites of arachidonic acid modulate the natriuretic effect of furosemide. It is not known whether 20-HETE, a monooxygenase metabolite of arachidonic acid that also inhibits sodium transport, participates in the action of furosemide. We measured urine sodium (UNaV) and 20-HETE during furosemide diuresis (40 mg three times over 12 hours) in 12 salt-sensitive (SS) and 11 salt-resistant (SR), salt-replete hypertensive subjects (126±24 mmol/24 hours positive sodium balance produced by 160-mmol-sodium diet and 2 L saline infusion). Individual systolic blood pressure decreases from the salt-replete to the salt-depleted state were the index of salt-sensitivity. SS had low plasma renin with blunted responses to changes in salt balance, inappropriate plasma aldosterone, and an increased aldosterone/renin ratio. UNaV by furosemide was less in SS (263±25 mmol/12 hours) than in SR (351±25 mmol/12 hours, P P r =0.56, P r =−0.55, P r =0.60, P r =−0.73, P

Little is known about essential hypertension in Hispanic Americans, despite the fact that they are the fastest-growing minority in the United States and have a disproportionate degree of hypertensive target organ damage. The authors studied 89 Caribbean Hispanic hypertensive patients who participated in six double-blind, randomized trials of antihypertensive agents. Demographics, laboratory data, sodium excretion, plasma renin activity, and atrial natriuretic peptide were obtained after 3-4 weeks on placebo. Blood pressure responses to angiotensin-converting enzyme (ACE) inhibitors, beta blockers, calcium channel blockers, hydrochlorothiazide (HCTZ), and fixed combinations of ACE inhibitors and HCTZ, were compared to the placebo values after 8-12 weeks of treatment. Patients had a multiple risk factor profile (obesity and diabetes) and a wide spectrum of blood pressure elevation, left ventricular hypertrophy, and hypertensive renal damage. Urine sodium excretion rates indicated inability to comply with salt restriction in 65% of patients. Plasma renin activity was lower than that of Hispanic normotensive controls, and 62% of patients had low-renin essential hypertension by renin profiling to sodium excretion. On analysis of variance, blood pressure reductions by calcium channel blockers, HCTZ, and ACE inhibitor/HCTZ combinations were significantly greater than that with placebo, while those of ACE inhibitors and beta blockers as monotherapy were not. The authors conclude that essential hypertension of Caribbean Hispanics is associated with multiple risk factors and is largely of the low-renin type. Responses to therapy are consistent with those observed in other populations with the low-renin phenotype and suggest salt-sensitivity of blood pressure in this population. Confirmation of the latter has implications for prevention and treatment of essential hypertension in Hispanics.

Historically, physiological modulation of the activity of the renin-angiotension system (RAS) was thought to be mediated only by changes in renin secretion. Hence, altered dietary sodium (Na) intake, changes in renal perfusion pressure, and/or renal adrenoreceptor activity would lead to changes in renin release and plasma angiotensin II (Ang II) concentration, which in turn contribute to regulation of blood pressure and sodium balance. Later, it became apparent that angiotensinogen availability and Ang-converting enzyme activity are also rate-limiting factors that influence the activity of RAS. Finally, over the past few years, evidence has accumulated that indicates the number of Ang II receptors and their subtypes are of great importance in regulating the activity and function of RAS. Cloning of the Ang II receptor genes, development of specific receptor-antagonist ligands, and establishment of genetically mutated animal models have led to greater understanding of the role of Ang II receptors in the regulation of RAS function and activity. This review focuses on the functions and regulation of Ang II receptors in vascular tissues and in the adrenal gland. The authors suggest that identification of control elements for Ang II receptor expression, which are tissue-specific, may provide a basis for future therapeutic manipulation of Ang II receptors in cardiovascular disease states.

The effects of 10 weeks of treatment with atenolol (n = 9) or the converting enzyme inhibitor zofenopril (n = 25) on plasma atrial natriuretic peptide (ANP) were studied in 34 essential hypertensive patients. After 4 weeks on placebo, pretreatment ANP, 56 +/- 7 pg/ml, was slightly but not significantly higher than that of 29 controls (41 +/- 4) and correlated with age (r = 0.44), ECG score for left ventricular hypertrophy (LVH) (r = 0.51) and serum creatinine (r = 0.67), and negatively with creatinine clearance (r = -0.39). Atenolol reduced blood pressure (BP) by 0 +/- 6/8 +/- 2 mm Hg (ns/P0.01), and zofenopril by 14 +/- 4/6 +/- 2 (P0.01/P0.01), not significantly different between the two agents. Heart rate was decreased by atenolol (-16 +/- 4 bpm, P0.01) but not by zofenopril (+1 +/- 2 bpm, ns). Atenolol increased ANP in all patients but one (delta = +42 +/- 9 pg/ml, P0.01), while zofenopril did not change it significantly (-6 +/- 6 pg/ml), due to 15 patients exhibiting decreases and 10 increases in plasma ANP. The effect of atenolol on ANP positively correlated with duration of hypertension (r = 0.74), ECG score for LVH (r = 0.73) and serum creatinine (r = 0.68). Individual changes in ANP by zofenopril negatively correlated with pretreatment ANP (r = -0.69), ECG score for LVH (r = -0.44) and serum creatinine (r = -0.41). No correlations were found between BP, heart rate or their changes by treatment and the effect of either agent on plasma ANP. Multiple linear regression showed that the change in ANP was explained by the therapeutic agent used, the pretreatment plasma level of ANP, and the ECG score for LVH (F = 12.5, P0.001, r2 = 0.56). We conclude that the effect of antihypertensives on plasma ANP is independent of their action on BP, but dependent on an interaction between the type of drug employed and those clinical characteristics of the patient that reflect pre-existing hypertensive target organ damage.

Abstract We studied outcome of management of metabolic cardiovascular risk factors in 155 randomly chosen Hispanic hypertensive patients (mean age, 63±1 years; 79% female) screened for dyslipidemia. Hypertriglyceridemia (n=12) or high risk–adjusted low-density lipoprotein cholesterol (LDL-C) (n=89) was found in 65%. Triglycerides did not change (6.16±0.58 to 7.44±2.34 mmol/L; P =NS) over 2.2±0.5 years. Only 58 patients with high LDL-C were treated, and 8 had no follow-up lipid tests. In the other 50, LDL-C decreased by 10±3% ( P P =NS; n=40) over 2.7±0.3 years. Forty-four of 63 patients with type II diabetes had repeated measurement of glycosylated hemoglobin, with no change (10.5±0.5% to 11.2±0.5%; P =NS) over 2.2±0.3 years. Ten-year risk of coronary events (Framingham cohort parametric regression) calculated for 61 patients with known untreated blood pressures (169±3/98±1 mm Hg) was 21.0±1.7%, with a skewed distribution reaching high values (66%) and attributable in large part (72%) to modifiable risk factors. With the use of the model, hypothetical correction of metabolic risk factors was more powerful than reduction of systolic blood pressure to 140 mm Hg (Δrisk, −8.3±0.9% versus −4.2±0.5%; P P =NS). In summary, Hispanics with essential hypertension exhibit a multifactorial risk profile, with the potential (as yet unrealized) for large reduction in cardiovascular morbidity. Our studies make it apparent that in this population, adequate treatment of concomitant metabolic illnesses is equally as important as or even more important than management of blood pressure.

Predictive models for the pressor response to the outpatient clinic visit (PRC) in essential hypertensives with and without diabetes are proposed. The hypotheses are derived from previous studies about the univariate correlates of this response. PRC was measured with ambulatory monitors. Twenty-four hour blood pressures and average PRCs were similar in the two groups. Diabetics had faster 24-h heart rates, decreased heart rate variability, a broader range of PRCs and more depressor responders. PRC of nondiabetics correlated with duration of hypertension and was dependent on race; the predictive model had R2 of 0.19. In contrast, PRC of diabetics exhibited correlations with age, weight, BP and blood glucose and the model had R2 of 0.71. The data suggest that: diabetics had autonomic dysfunction, that their PRC can be modelled with predictors that are accepted correlates of autonomic neuropathy, and that these predictors attenuated PRC or its buffering. If these results were confirmed by prospective application of the model to a larger group of patients, 'true' blood pressures could be estimated by subtraction of predicted PRC from office blood pressures in diabetic, but not in nondiabetic, hypertensive patients.

Dose-response curves to angiotensin II were consecutively performed in rats after anesthesia (pentobarbital 60 mg/kg ip), converting enzyme inhibition (SQ14225 1 mg/kg iv), and ganglionic blockade (pentolinium 10 mg/kg sc) to explore the participation of the sympathetic nervous system in the immediate pressor action of the peptide. Experiments were conducted after the animals were maintained on a sodium-deficient diet for 2 weeks. Converting enzyme inhibition was maintained during ganglionic blockade to avoid changes in the circulating level of endogenous angiotensin II which might be caused by the latter maneuver. SQ14225 caused a 35 ± 4 mm Hg (P < 0.001) fall in systolic pressure and a significant shift to the left of the dose-response curve to angiotensin II compared to that obtained after anesthesia alone. In contrast, pentolinium did not further modify responses to angiotensin II despite significantly lowering systolic blood pressure 49 ± 5 mm Hg (P < 0.001). Our data confirm that a major det...

The renin-angiotensin system was evaluated by inhibition of converting enzyme (CEI) and by testing sensitivity to angiotensin II (AII) in sodium-depleted rats made hypertensive by methylprednisolone (MP), 20 mg/kg im. During a 2-wk period blood pressure rose 38 +/- 4 mmHg (P less than 0.001) in MP and 3 +/- 4 mmHg in controls. After pentobarbital anesthesia, intra-arterial pressure and dose-response curves to AII were determined, before and after SQ14225 (d-3-mercapto-2-methylpropranoyl-l-proline) (1 mg/kg iv). CEI reduced pressure significantly in both MP and controls, although the decrease was smaller in the former (P less than 0.05). Pressor responses to AII were nearly identical in MP and controls and were enhanced to a similar extent by CEI. Ganglionic blockade with pentolinium tartrate, given after CEI, did reduce the pressure in both groups to equal levels. Responses to AII after pentolinium were similar to those obtained after CEI alone. These results indicate that the renin component of glucocorticoid hypertension during sodium deficiency is smaller than that of the normotensive controls. No evidence of glucocorticoid-induced vascular hypersensitivity to AII was detected in this model of experimental hypertension.

The vasoconstrictor and vasopressor actions of vasopressin have been revealed in recent research through the use of highly specific and sensitive radioimmunoassays, employment of peptide antagonists, and comparison with an animal model which has hereditary absence of this hormone, the Brattleboro rat. Factors now known to modify the pressor effect of vasopressin are the baroreflexes, local vascular prostaglandin production, and a specific interaction with angiotensin II. In experimental models the volume retaining, but not the vasoconstrictor effect of vasopressin is necessary for mineralocorticoid-salt hypertension. Vasopressin contributes directly to the increase in arterial pressure of glycerol induced acute renal failure. In nephrectomized rats, plasma vasopressin is elevated and contributes directly to maintenance of pressure. Vasopressin antagonism may reduce arterial pressure in Goldblatt 1 and 2 kidney hypertension and in one genetic model, spontaneously hypertensive rat (SHR), but the peptide is not necessary for hypertension in these models. Plasma vasopressin is reduced in primary aldosteronism, but may be elevated in malignant hypertension. In essential hypertension, there is considerable disagreement among various studies in which plasma vasopressin, urine vasopressin excretion, platelet associated vasopressin, or vasopressin-neurophysin were measured as to whether there is evidence for increased secretion of vasopressin. Only preliminary studies of vasopressin antagonism in clinical hypertension have been reported. At present, there is no conclusive evidence that elevated vasopressin secretion occurs or is necessary for any form of clinical hypertension.

Participation of vasopressin and the renin-angiotensin system in the maintenance of systemic arterial pressure was evaluated in unanesthetized adrenalectomized rats. Adrenalectomized and sham-operated rats with implanted arterial and venous catheters were given 1% sodium chloride and 2.5% glucose as drinking fluid for 72 hours following adrenalectomy. Serum and urine samples were obtained for measurement of electrolyte and solute concentration. The pattern of serum electrolytes, serum osmolality, and renal excretion of electrolytes, solute, and water observed in the adrenalectomized rats was entirely consistent with previous observations in this model. Mean arterial pressure of unanesthetized unrestrained adrenalectomized rats was significantly lower than controls. In adrenalectomized rats, dPMeTyrAVP reduced mean arterial pressure 9 +/- 1 mm Hg, p less than 0.001; captopril then caused an additional reduction of 17 +/- 2 mm Hg, p less than 0.01. Neither antagonist altered arterial pressure in the control group. Our results indicate that vasopressin and the renin-angiotensin system play a compensatory pressor role in adrenal insufficiency, preventing a larger decrease of arterial pressure in this model of chronic hypotension.

The effect of vasopressin infusion on the pressor dose responses to angiotensin II and norepinephrine was studied in pentobarbital-anesthetized and unanesthetized nephrectomized rats. Pressor vasopressin (2–15 ng X kg-1 X min-1) given to anesthetized rats decreased sensitivity to angiotensin II in a dose-dependent manner (r = 0.88), an effect completely reversible by dPMeTyrAVP, a vasopressin vascular antagonist. Subpressor vasopressin (0.5-1 ng X kg-1 X min-1) given to unanesthetized rats diminished sensitivity to angiotensin II in the presence or absence of pentolinium (10 mg/kg). Shifts in dose-response curves to angiotensin II were always parallel. In contrast, dose responses to norepinephrine were not modified by vasopressin in pentolinium-treated rats and showed a small nonparallel rightward shift in animals without pentolinium. In animals without pentolinium, the baroreflex-mediated reduction in heart rate elicited by angiotensin II was not altered by vasopressin infusion. Our data suggest that vasopressin reduces angiotensin II pressor action by diminishing pressor sensitivity to the peptide. They indicate that the effect may be specific, mediated through the vascular receptor for vasopressin and independent of actions of this hormone on the autonomic nervous system.

The effect of captopril was explored in salt-depleted methylprednisolone (MP)-hypertensive rats. MP treatment raised BP by 41+/-2 mmHg over 2 weeks. Controls (C) had no change in BP. Sodium balance and weight data indicated a greater salt depletion in MP than in C. On day 15, captopril reduced BP in both MP (20+/-4 mmHg) and C (31+/-4 mmHg). The effect was significantly smaller in MP than in C (p less than 0.05). Plasma renin activity (PRA) was similarly elevated in both groups, consistent with salt depletion. Serum (SCE) and lung-converting enzyme (LCE) activity were similar in MP and C. The diminished antihypertensive effect of captopril in MP is therefore not attributable to differences in PRA, SCE, or LCE. Our data suggest that depressor actions of captopril unrelated to the renin-angiotensin system are impaired in MP. Glucocorticoid-induced changes in vasodilator systems may explain these findings.