Clarence E. Grim

Association of Adrenal Steroids With Hypertension and the Metabolic Syndrome in Blacks

Blacks have a high prevalence of hypertension and adrenal cortical adenomas/hyperplasia. We evaluated the hypothesis that adrenal steroids are associated with hypertension and the metabolic syndrome in blacks. Ambulatory blood pressures, anthropometric measurements, and measurements of plasma renin activity (PRA), aldosterone, fasting lipids, glucose, and insulin were obtained in 397 subjects (46% hypertensive and 50% female) after discontinuing antihypertensive and lipid-lowering medications. Hypertension was defined as average ambulatory blood pressure >130/85 mm Hg. Late-night and early morning salivary cortisol, 24-hour urine-free cortisol, and cortisone excretion were measured in a consecutive subsample of 97 subjects (40% hypertensive and 52% female). Compared with normotensive subjects, hypertensive subjects had greater waist circumference and unfavorable lipid profiles, were more insulin resistant, and had lower PRA and higher plasma aldosterone and both late-night and early morning salivary cortisol concentrations. Twenty-four-hour urine-free cortisol and cortisone did not differ. Overall, ambulatory blood pressure was positively correlated with plasma aldosterone (r=0.22; P<0.0001) and late-night salivary cortisol (r=0.23; P=0.03) and inversely correlated with PRA (r=−0.21; P<0.001). Plasma aldosterone correlated significantly with waist circumference, total cholesterol, triglycerides, insulin, and the insulin-resistance index. Based on Adult Treatment Panel III criteria, 17% of all of the subjects were classified as having the metabolic syndrome. Plasma aldosterone levels, but not PRA, were elevated in subjects with the metabolic syndrome (P=0.0002). The association of aldosterone with blood pressure, waist circumference, and insulin resistance suggests that aldosterone may contribute to obesity-related hypertension in blacks. In addition, we speculate that relatively high aldosterone and low PRA in these hypertensive individuals may reflect a mild variant of primary aldosteronism.

Arterial Pressure, Left Ventricular Mass, and Aldosterone in Essential Hypertension

The purpose of the present study was to evaluate the relationship of aldosterone to blood pressure and left ventricular size in black American (n=109) and white French Canadian (n=73) patients with essential hypertension. Measurements were obtained with patients off antihypertensive medications and included 24-hour blood pressure monitoring, plasma renin activity and aldosterone, and an echocardiogram. Compared with the French Canadians, the black Americans had higher body mass indexes, higher systolic blood pressures, attenuated nighttime reduction of blood pressure, and lower serum potassium concentrations (P <0.01 for each). Left ventricular mass index, posterior wall thickness, interventricular septal thickness, and relative wall thickness were also greater (P <0.01 for each) in the black American patients. Supine and standing plasma renin activity was lower (P <0.01 and P <0.05, respectively) in the black Americans, whereas supine plasma aldosterone concentrations did not differ, and standing plasma aldosterone was greater (P <0.05) in the black Americans (9.2±0.7 ng/dL) than in the French Canadians (7.3±0.6 ng/dL). In the black Americans, supine plasma aldosterone was positively correlated with nighttime systolic (r =0.30;P <0.01) and diastolic (r =0.39;P <0.001) blood pressures and inversely correlated with the nocturnal decline of systolic (r =−0.29;P <0.01) and diastolic (r =−0.37;P <0.001) blood pressures. In the black Americans, standing plasma aldosterone was positively correlated with left ventricular mass index (r =0.36;P <0.001), posterior wall thickness (r =0.33;P <0.01), and interventricular septal thickness (r =0.26;P <0.05). When the black American patients were divided into obese and nonobese groups, significant correlations between plasma aldosterone and both blood pressure and cardiac mass were observed only in the obese. In the French Canadians, overall, plasma aldosterone did not correlate with either blood pressure or any measures of heart size. However, among obese French Canadians, supine plasma aldosterone correlated with nighttime diastolic (r =0.53, P <0.02) and systolic (r =0.44, P <0.01) blood pressures but not with cardiac mass. These results are consistent with the hypothesis that aldosterone contributes to elevated arterial pressure in obese black American and obese white French Canadian patients with essential hypertension and to the attenuated nocturnal decline of blood pressure and left ventricular hypertrophy in obese, hypertensive black Americans.

Genetic Determinants of Hypertension Identification of Candidate Phenotypes

Our long-term objective is to identify genes whose expression results in hypertension and in phenotypic changes that may contribute to hypertension. The purpose of the present study was to describe evidence for the heritability of hypertension-related phenotypes in hypertensive, hyperlipidemic black sib pairs. Outpatient anthropomorphic measurements were obtained in >200 affected sib pairs. In addition, 68 of these sib pairs were studied under controlled, standardized conditions at an inpatient clinical research center while off both antihypertensive and lipid-lowering medications. Heritability was estimated on the basis of sib-sib correlations and with an association model. Higher heritability estimates for blood pressure were observed with multiple measurements averaged over 24 hours than with measurements at a single time point, and heritability estimates for nighttime blood pressures were higher than those for daytime blood pressures. Heritability estimates for several of the phenotypes were augmented by obtaining measurements in response to a standardized stimulus, including (1) blood pressure responses to the assumption of upright posture, standardized psychological stress, and norepinephrine infusion; (2) plasma renin, aldosterone, epinephrine, and cAMP and cGMP responses to the assumption of upright posture; (3) para-aminohippurate and inulin clearances in response to norepinephrine infusion; and (4) plasma arginine vasopressin in response to NaCl infusion. High heritability estimates were also observed for various measures of body size and body fat, left ventricular size, cardiac index, stroke volume, total peripheral resistance, and serum concentrations of LDL and HDL cholesterol and leptin. These heritability estimates identify the hypertension-related phenotypes that may facilitate the identification of specific genetic determinants of hypertension in blacks with hyperlipidemia.

Hyperaldosteronism and Hypertension. Ethnic Differences

The purpose of this study is to evaluate the relationship between aldosterone and blood pressure in a total of 220 normotensive and 293 essential hypertensive subjects in 2 genetically distinct populations—blacks and white French Canadians. The 24-hour blood pressure monitoring was performed under standardized conditions after discontinuing antihypertensive medications. Plasma renin activity and plasma aldosterone were measured in the supine position and after standing for 10 minutes. Plasma atrial natriuretic factor was also measured. Supine and standing plasma renin activities were lower (P≤0.01), plasma aldosterone was higher (P<0.0001), and the aldosterone/renin ratios were higher (P<0.0001) in the hypertensive subjects. Atrial natriuretic factor was also higher in the hypertensive subjects (P<0.0001). Among blacks, blood pressures did not correlate with plasma renin activity. However, both average daytime and nighttime systolic and diastolic blood pressures were correlated with supine and standing plasma aldosterone and with the aldosterone/renin ratio (P<0.005 or less). In French Canadians, blood pressures tended to be positively correlated with standing plasma renin activity and aldosterone, but not with the aldosterone/renin ratio. Correlations of blood pressure with aldosterone were more consistent and more striking in blacks than in French Canadians. In both ethnic groups, there were inconsistent correlations of blood pressure with atrial natriuretic factor. These observations are consistent with the hypothesis that aldosterone-induced volume expansion is an important contributor to hypertension, especially in blacks.

Effects of omapatrilat on the renin-angiotensin system in salt-sensitive hypertension*

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.

Genetic influences on renin, aldosterone, and the renal excretion of sodium and potassium following volume expansion and contraction in normal man.

SUMMARY To investigate the influence of heredity on plasma renin activity (PRA), plasma aldosterone concentrations (PAC), blood pressure, and the renal excretion of sodium and potassium following volume expansion and contraction in normal man, we studied 37 pairs of monozygotic (MZ) and 18 pairs of dizygotic (DZ) twins. Volume expansion was achieved by the intravenous infusion of 2L normal saline; volume contraction was accomplished by a low-sodium diet and 120 mg oral furosemide. The presence of genetic variance was tested by calculating the within pair and among component estimates of genetic variance.Outpatient 24-hour-urine collections suggested that MZ and DZ twins ingested diets similar in sodium and potassium content, and failed to reveal genetic influences on the dietary preferences for these electrolytes. The PRA values suggested heritable influences during both the volume expanded and contracted state with the added stimulus of upright posture. Heritable influences were observed on PAC and were most apparent in the basal state on the day of volume expansion. An influence of heredity on blood pressure was most apparent during volume contraction. Urinary sodium excretion (UNaV), urinary potassium excretion (UKV), fractional excretion of sodium (FENa), and fractional excretion of potassium (FEK) revealed evidence of significant genetic variance under the condition of volume expansion. In that state, systolic blood pressure was directly correlated with PRA, PAC, and inversely with FENa. The data suggest that the renal regulation of sodium and potassium excretion is in part influenced by heritable factors that may in turn contribute to the development of hypertension in some individuals.

Glomerular Hyperfiltration in Hypertensive African Americans

The incidence of end-stage renal disease attributable to hypertension is 5-fold greater in African Americans than in whites. To determine whether glomerular hyperfiltration is an antecedent to renal failure, we compared responses of renal blood flow and glomerular filtration rate to graded infusions of norepinephrine (0. 01, 0.025, and 0.05 microg. kg(-1). min(-1) for 30 minutes each) in 29 African Americans and 33 age-matched French Canadian whites with essential hypertension. Renal blood flow and glomerular filtration rate were measured by using a constant-infusion technique of PAH and inulin, respectively. Studies were conducted on an inpatient clinical research center, and antihypertensive medications had been discontinued for at least 1 week. Based on 24-hour blood pressure monitoring, nighttime blood pressures decreased (P<0.01) in the French Canadians but not in the African Americans. Baseline renal blood flow was higher (P<0.05) in the African Americans (1310+/-127 mL. min(-1) per 1.73 m(2)) than in the French Canadians (1024+/-42 mL. min(-1) per 1.73 m(2)); baseline glomerular filtration rate was also higher (P<0.01) in the African Americans (140+/-4 versus 121+/-4 mL. min(-1) per 1.73 m(2)). In response to norepinephrine-induced blood pressure increases, renal blood flow was autoregulated and did not change in either patient group. In the African Americans, glomerular filtration rate increased (P<0.01) to 167 mL. min(-1) per 1.73 m(2) during the first norepinephrine infusion, without subsequent change. In contrast, glomerular filtration rate did not change with norepinephrine-induced increases of blood pressure in the French Canadians. In the African Americans, the elevation of baseline glomerular filtration rate, with a further increase in response to norepinephrine, may be indicative of glomerular hyperfiltration. Glomerular hyperfiltration and lack of nocturnal blood pressure decline may contribute to the higher incidence of end-stage renal disease in hypertensive African Americans.

Dietary Calcium Lowers the Age-Related Rise in Blood Pressure in the United States: The NHANES III Survey

This analysis of the third National Health and Nutrition Examination Survey (NHANES III) was designed to investigate the impact of dietary calcium intake on age‐related changes in blood pressure and pulse pressure. Data on 17,030 participants 20 years or older (mean age, 48.8±0.2 years; 47% male, 42% Caucasian, and 28% African American) were used. Data included demographics, body mass index, blood pressure, and daily dietary calcium. Overall, average calcium intake was 761 mg/day. After adjusting for demographic and anthropomorphic variables, as well as total energy consumption, higher calcium intake was associated with lower rates of age‐related increases of systolic blood pressure and pulse pressure (p<0.001). If the calcium intake of the general population were to increase to above 1200 mg, the incidence of isolated systolic hypertension in the elderly might be decreased.

Altered relationship of blood pressure to adiposity in hypertension.

BACKGROUNDnBlood pressure levels and the prevalence of hypertension are related to adiposity. We evaluated the relationship of adiposity to blood pressure in normotensive and untreated hypertensive African Americans-an ethnic group with a high prevalence of hypertension and obesity.nnnMETHODSnOutpatient measurements were obtained in 1,858 normotensive and 1,998 hypertensive subjects (44% untreated) residing in Milwaukee. The blood pressure-adiposity relationship was also analyzed in non-Hispanic black (n = 908) and non-Hispanic white (n = 2182) National Health and Nutrition Examination Survey (NHANES) participants.nnnRESULTSnIn Milwaukee subjects, body mass index (BMI), waist/hip ratio, waist/height ratio, and percent body fat were higher in hypertensives (P < 0.0001). Combining normotensive and untreated hypertensive subjects, each of the anthropometric indices was correlated with systolic and diastolic blood pressure (P <0.0001). In separate analyses, correlations of the indices with blood pressure were observed in normotensive subjects (P < 0.0001), but generally not in hypertensive subjects. Further, separating all subjects into quartiles based on systolic blood pressure, indices of adiposity correlated with blood pressure only in subjects in the lowest blood pressure quartile (blood pressure <120/78 mm Hg). Similarly, among NHANES participants, blood pressure correlated with anthropometric indices in normotensive (P < 0.0005), but not in untreated hypertensive blacks or whites.nnnCONCLUSIONSnAlthough indices of adiposity were greater in hypertensive than in normotensive subjects, blood pressures were significantly correlated with measures of adiposity in normotensive, but not in untreated hypertensive subjects. We hypothesize that the blood pressure-adiposity relationship in hypertensives is modulated by a combination of environmental and genetic factors.

Aldosterone Contributes to Blood Pressure Variance and to Likelihood of Hypertension in Normal-Weight and Overweight African Americans

BACKGROUNDnHypertension and obesity are highly prevalent among African Americans (AAs). We have previously reported that both plasma aldosterone (PA) and body mass index (BMI) are higher in hypertensive than in normotensive AAs. This study evaluates the relative contributions of adiposity and PA to hypertension in AAs.nnnMETHODSnA total of 466 AAs (50% hypertensive, 51% women) were evaluated in a Clinical Research Center by stratifying them into three subgroups based on BMI (normal weight, overweight, and obese). Anthropometric measurements, ambulatory blood pressure (BP), fasting glucose, insulin, 24-h urine sodium and potassium, creatinine clearance, standing PA and plasma renin activity (PRA) were measured. Insulin resistance was estimated by the homeostasis model assessment.nnnRESULTSnCompared to normotensives, hypertensives had higher BMI, waist circumference (WC), and were more insulin resistant (P < or = 0.01). When stratified by BMI, hypertensives in each BMI strata had higher PA (P < or = 0.05) and lower PRA (P < or = 0.01) compared to normotensives. Compared to normotensives, WC was greater in overweight and obese hypertensives, but not in normal-weight hypertensives. In the overall sample, age, WC, PA, and PRA were the major contributors to BP variance and to hypertension. Among normal-weight subjects, PA and PRA significantly predicted BP and the odds ratio for hypertension, whereas WC had no predictive value.nnnCONCLUSIONSnPA, but not WC, is associated with BP and likelihood of hypertension in normal-weight AAs, whereas both WC and PA are predictive of hypertension in overweight and obese individuals. This suggests that aldosterone antagonists may be useful for the treatment of hypertension among AAs, regardless of BMI.