Myron H. Weinberger

Salt Sensitivity of Blood Pressure in Humans

A variety of different techniques have been used for the assessment of the blood pressure response to changes in salt and water balance in humans. These have generally been found to be reproducible and to yield congruent results. This review surveys the characteristics of subjects identified as salt sensitive and salt resistant by different investigators from demographic and physiological perspectives.

Salt Sensitivity, Pulse Pressure, and Death in Normal and Hypertensive Humans

Although factors such as age, blood pressure, and its responsiveness to changes in sodium balance and extracellular fluid volume status (salt sensitivity) are associated with an increased risk of end-organ disease and cardiovascular events in hypertensive subjects, no such relationship with mortality has been demonstrated for salt sensitivity in normotensive subjects. We conducted long-term follow-up of 430 normal and 278 hypertensive subjects in whom assessment of salt sensitivity of blood pressure was performed as long as 27 years ago. We ascertained the status of 596 subjects (85% of the total population), 123 (21%) of whom had died. The following initial measurements were significantly (P <0.002) associated with subjects who had died compared with subjects known to be alive: age at study, pulse pressure, systolic, diastolic, and mean arterial pressures, hypertension, salt sensitivity, baseline renin levels, and body mass index (but not body weight). A stepwise logistic regression found the following independent predictors of death (odds ratio, 95% CI): age at initial study (1.08, 1.06 to 1.10), baseline blood pressure (1.03, 1.01 to 1.04), sodium sensitivity (1.73, 1.02 to 2.94), and male gender (1.91, 1.15 to 3.17). When survival curves were examined, normotensive salt-sensitive subjects aged >25 years when initially studied were found to have a cumulative mortality similar to that of hypertensive subjects, whereas salt-resistant normotensive subjects had increased survival (P <0.001). These observations provide unique evidence of a relationship between salt sensitivity and mortality that is independent of elevated blood pressure.

Sodium and volume sensitivity of blood pressure. Age and pressure change over time.

Salt sensitivity has been implicated in the age-related increase in blood pressure. We studied the reproducibility of a rapid method for assessing sodium sensitivity and resistance of blood pressure as well as the effect of age on this phenomenon. Blood pressure after volume expansion with 2 1 intravenous saline (0.9%) over 4 hours was compared with that after 1 day of 10 mmol sodium chloride intake and 3 and 40 mg oral doses of furosemide. Normal and hypertensive subjects (n=28) were studied twice within a year. Cross-sectional observations of the effect of age were made from studies in 230 hypertensive and 430 normotensive subjects. Longitudinal observations of blood pressure change over time were made 10 or more years after categorization of sodium responsivity in 31 subjects. The blood pressure response was reproducible in 28 subjects studied twice (r=0.56,p<0.002). Four subjects changed salt-responsiveness status and six were indeterminate on restudy. Sodium sensitivity of blood pressure increased significantly with increasing age in the entire population (n=660, r= ‐038,p<0.001). The relation was more striking in hypertensive subjects (n=230, r= -0.31,p<0.001) in whom a progressive increase in salt sensitivity with decades was seen than in the normotensive group (n=430, r=‐0.19, p<0.01) in whom salt sensitivity was not observed until the sixth decade. Salt-sensitive subjects had a significantly greater increase in systolic (p<0.001) and diastoiic (/?<0.01) pressure over time than those who were salt-resistant Salt sensitivity is a reproducible phenomenon that is related to the age-associated increase in blood pressure characteristic of industrialized societies. In addition, salt sensitivity can be shown to be a predictor of subsequent, age-related blood pressure increase.

Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension

BACKGROUND Eplerenone, a selective aldosterone blocker (SAB) that is highly specific for the aldosterone receptor, has the potential to be efficacious in the treatment of hypertension. METHODS This 8-week, multicenter, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of eplerenone in eligible patients randomized to eplerenone 50, 100, or 400 mg once daily; eplerenone 25, 50, or 200 mg twice daily; spironolactone 50 mg twice daily; or placebo. The primary efficacy variable was the adjusted mean change in baseline to final visit for seated diastolic blood pressure (DBP). RESULTS Of 417 randomized patients, 409 were evaluated for efficacy. The adjusted mean change from baseline to final visit in seated and standing systolic blood pressure (SBP) and DBP was significantly greater (P < .05) in all eplerenone groups than in the placebo group. The adjusted mean change in 24-h ambulatory blood pressure monitoring (ABPM) measurements of SBP and DBP also documented a 24-h duration significantly greater (P < .05) than placebo in eplerenone-treated patients. For all measurements, the antihypertensive effect of eplerenone increased in a dose-response fashion. Eplerenone (100 mg) reduced BP by 75% compared with spironolactone (100 mg) and had an adverse events incidence rate similar to placebo. No antiandrogenic or progestational effects or clinically relevant safety issues were observed in eplerenone-treated patients. However, one spironolactone-treated patient reported menstrual irregularities. CONCLUSIONS Eplerenone doses of 50 to 400 mg once daily are well tolerated and effective in reducing BP in patients with mild-to-moderate hypertension during a 24-h period.

Cardiovascular and humoral responses to extremes of sodium intake in normal black and white men.

To examine possible racial differences in the relationship between urinary sodium excretion (UNaV) and blood pressure in whites and blacks, and to characterize cardiovascular, renal and humoral responses, we studied 14 normotensive men (seven white and seven black) at six levels of sodium intake from 10–1500 mEq/24 hrs. Systolic and diastolic pressure increased from 113 ± 2/69 ± 2 mm Hg (SEM) at the 10 mEq/24 hr level of sodium intake to 131 ± 4/85 ± 3 mm Hg at the 1500 mEq/24 hr level of sodium intake (p < 0.001). Cardiac index increased concomitantly from 2.6 ± 0.1 to 3.6 ± 0.3 I/min/M2 (p < 0.001). Linear and quadratic regression analysis of the relationship of UNaV and blood pressure revealed that blacks had higher blood pressures with sodium loading than whites. Sodium loading caused a significant kaliuresis that was greater in whites than blacks. Six subjects were restudied while receiving potassium replacement. Compared with initial responses, blood pressure was elevated to a lesser degree (p < 0.02) and a greater natriuresis appeared at a level of 1500 mEq/24 hr of sodium intake (p < 0.02). The data suggest that blacks have an intrinsic reduction in the ability to excrete sodium compared with whites. The increases in blood pressure with acute sodium loading can be attributed to an increase in cardiac index. Potassium balance appears to influence the responses in blood pressure that occur with sodium loading

Selective Aldosterone Blockade with Eplerenone Reduces Albuminuria in Patients with Type 2 Diabetes

Previous studies have shown that the selective aldosterone blocker eplerenone, in doses of up to 200 mg/d, reduces albuminuria in patients with type 2 diabetes. This study was conducted to ascertain whether lower doses of eplerenone (50 or 100 mg/d) co-administered with the angiotensin-converting enzyme (ACE) inhibitor enalapril would produce a similar antialbuminuric effect while obviating the hyperkalemia observed previously. After open-label run-in with enalapril 20 mg/d, patients with diabetes and a urinary albumin:creatinine ratio (UACR) > or = 50 mg/g were randomly assigned to receive enalapril plus one of three double-blind daily treatments for 12 wk: placebo, eplerenone 50 mg (EPL50), or eplerenone 100 mg (EPL100). After week 4, amlodipine 2.5 to 10 mg/d was allowed for BP control (systolic/diastolic BP < or = 130/80 mmHg). The primary study end points were the percentage change from baseline at week 12 in UACR and the incidence of hyperkalemia. Secondary end points included percentage changes from baseline in UACR at weeks 4 and 8 and changes from baseline in systolic and diastolic BP. Treatment with EPL50 or EPL100 but not placebo significantly reduced albuminuria from baseline. By week 12, UACR was reduced by 7.4% in the placebo group, by 41.0% in the EPL50 group, and by 48.4% in the EPL100 group (both eplerenone groups, P < 0.001 versus placebo). The incidences of sustained and severe hyperkalemia were not significantly different in any of the three treatment arms and did not differ on the basis of quartile of estimated GFR (all NS). For the secondary end points, both eplerenone treatment groups significantly reduced albuminuria from baseline as early as week 4 (P < 0.001), whereas placebo treatment (including enalapril) did not result in any significant decreases in UACR. Systolic BP decreased significantly in all treatment groups at all time points, but, generally, all treatment groups experienced similar decreases in BP. Co-administration of EPL50 or EPL100 with an ACE inhibitor as compared with an ACE inhibitor alone significantly reduces albuminuria in patients with diabetes without producing significant increases in hyperkalemia.

Primary Aldosteronism: Diagnosis, Localization, and Treatment

New diagnostic techniques have enhanced the detection of primary aldosteronism. However, the response of blood pressure after operation in unilateral and bilateral adrenal disease is different. We have compared four localizing techniques--adrenal venography, adrenal isotopic scanning, a modified adrenal venous sampling for steroid measurements, and the anomalous postural decrease in plasma aldosterone concentration--in 51 patients with primary aldosteronism, all of whom had undergone operative confirmation. Adrenalectomy resulted in normal blood pressure in 59%, improvement in 25%, and no change in 16%. Correct localization of the lesion was obtained in 47% by the adrenal isotopic scan, in 66% by adrenal venography, and in 91% by the modified adrenal venous hormone technique despite four false-positives. Of the 26 patients with an anomalous postural decrease in plasma aldosterone, 88% had a unilateral lesion.

Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial.

Objectives This double-blind study compared long-term efficacy, safety and tolerability of the oral direct renin inhibitor aliskiren and the angiotensin-converting enzyme inhibitor ramipril alone and combined with hydrochlorothiazide in patients with hypertension. Methods After a 2–4-week placebo run-in, 842 patients [mean sitting diastolic blood pressure (msDBP) 95–109 mmHg] were randomized to aliskiren 150 mg (n = 420) or ramipril 5 mg (n = 422). Dose titration (to aliskiren 300 mg/ramipril 10 mg) and subsequent hydrochlorothiazide addition (12.5 mg, titrated to 25 mg if required) were permitted at weeks 6, 12, 18 and 21 for inadequate blood pressure control. Patients completing the 26-week active-controlled treatment period were re-randomized to their existing regimen or placebo for a 4-week double-blind withdrawal phase. Results Six hundred and eighty-seven patients (81.6%) completed the active treatment period. At week 26, aliskiren-based therapy produced greater mean reductions in mean sitting systolic blood pressure (17.9 versus 15.2 mmHg, P = 0.0036) and msDBP (13.2 versus 12.0 mmHg, P = 0.025), and higher rates of systolic blood pressure control (< 140 mmHg; 72.5 versus 64.1%, P = 0.0075) compared with ramipril-based therapy. During withdrawal, blood pressure increased more rapidly after stopping ramipril than aliskiren-based therapy; median blood pressure reached 140/90 mmHg after 1 and 4 weeks, respectively. Blood pressure reductions were maintained with continued active treatment. Aliskiren therapy was well tolerated. Overall adverse event rates were similar with aliskiren (61.3%) and ramipril (60.4%); cough was more frequent with ramipril (9.5%) than aliskiren (4.1%). Conclusions Aliskiren-based therapy was well tolerated and produced sustained blood pressure reductions in patients with hypertension over 6 months, greater than those with ramipril-based therapy.

Plasma and urinary norepinephrine values at extremes of sodium intake in normal man.

SUMMARY To examine the effects of a wide range of sodium intake on plasma and urinary norepinephrine values in normal man, we studied 14 men at six levels of sodium intake from 10 to 1500 mEq/24 hrs. Mean blood pressure increased from 83.8 ± 1 (SEM) to 1003 ± 3 mm Hg, while cardiac index increased from 2.6 ± 0.1 to 3.6 ± 0 3 llters/min/m1 (p < 0.001). Upright venous plasma norepinephrine concentration decreased from 467 ± 6 3 to 67 ± 24 pg/ml, while urinary norepinephrine excretion decreased from 543 ± 3.4 to 23.4 ± 2.9 Mg/24 hrs. There was no effect of sodium intake on blood pressure responses to isometric hand-grip contraction. The urinary sodium excretion was inversely correlated with urinary norepinephrine excretion (r = − 0.46, p < 0.001). There was a significant inverse multiple correlation of mean blood pressure and plasma and urinary norepinephrine values (correlation coefficient = 0.72, p < 0.001). These results indicate that sodium homeostasis has a signiflcant effect on plasma and urinary norepinephrine values. Sympathetic nervous system activity appears to decrease with sodium loading in normal subjects. These responses may have facilitated the excretion of massive salt loads in normal subjects and may nave modulated the increases in blood pressure.

Influence of Race and Dietary Salt on the Antihypertensive Efficacy of an Angiotensin-Converting Enzyme Inhibitor or a Calcium Channel Antagonist in Salt-Sensitive Hypertensives

Dietary salt restriction is a recommended adjunct with antihypertensive therapy. There may be racial differences in blood pressure response to salt restriction while on antihypertensive therapy. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (black, n=96; Hispanic, n=63; white, n=232). Participants were initially preselected for stage I to III hypertension and then further selected for salt sensitivity (> or = 5 mm Hg increase in diastolic blood pressure after 3 weeks of low salt [< or = 88 mmol/d Na+] and high salt [>190 mmol/d Na+] diet). We compared the antihypertensive effect of an angiotensin-converting enzyme inhibitor (enalapril 5 or 20 mg BID) or a calcium channel antagonist (isradipine 5 or 10 mg BID) during alternating periods of high and low salt intake. The main outcome measure was blood pressure change and absolute blood pressure level achieved with therapy. During the high salt diet (314.7+/-107.5 mmol/d urinary Na+) there was greater downward change in blood pressure with both enalapril and isradipine compared with the low salt diet (90.1+/-50.8 mmol/d Na+); however, the absolute blood pressure achieved in all races was consistently lower on a low salt diet for both agents. Black, white, and Hispanic isradipine-treated salt-sensitive hypertensives demonstrated a smaller difference between high and low salt diets (black, -3.6/-1.6 mmHg; white, -6.2/-3.9 mmHg; Hispanic, -8.1/-5.3 mm Hg) than did enalapril-treated patients (black, -9.0/-5.3 mm Hg; white, -11.8/-7.0 mm Hg; Hispanic, -11.1/-5.6 mm Hg). On the low salt diet, blacks, whites, and Hispanics had similar blood pressure control with enalapril and isradipine. On the high salt diet, blacks had better blood pressure control with isradipine than with enalapril, whereas there was no difference in the blood pressure control in whites and Hispanics treated with either drug. Dietary salt reduction helps reduce blood pressure in salt-sensitive hypertensive blacks, whites, and Hispanics treated with enalapril or isradipine. These data demonstrate that controlling for salt sensitivity diminishes race-related differences in antihypertensive activity.