Essential Hypertensive Population Research Articles

Relationship between insulin resistance and nonmodulating hypertension: linkage of metabolic abnormalities and cardiovascular risk.

Insulin resistance is a feature common to patients with diabetes and to some with hypertension. It is assumed that this feature confers the increased metabolic risk in hypertension. However, the state of the renin-angiotensin system might contribute to cardiovascular risk, although there is no clear mechanistic explanation. Our recent observation that insulin levels are increased in a specific subset of patients with normal/high-renin hypertension, the nonmodulators, provided the background for the current hypothesis: to ascertain whether abnormalities in lipid and carbohydrate metabolism are observed in the same patients in whom alterations in sodium transport, sodium homeostasis, and the renin-aniotensin system response have been identified. Exploration of a family history of cardiovascular risk was a secondary goal. Insulin sensitivity (assessed by a 75-g oral glucose load), lipid levels, and two defects in the renin-angiotensin system were assessed in 62 hypertensive and 14 normotensive subjects placed on a high (210 mmol/l) and a low (10 mmol/l) sodium intake for 2 weeks, to classify them as low-renin, nonmodulator, or modulating hypertensive subjects. Only in nonmodulators were the following cardiovascular risk factors significantly increased: fasting insulin (P < 0.01); increment in post-glucose load insulin (P < 0.01); total, LDL, and VLDL cholesterol and triglyceride levels (P < 0.05); and erythrocyte Na+/Li+ countertransport activity (P < 0.001). Both nonmodulators and low-renin hypertensive subjects had a significantly (P < 0.01) increased frequency of a family history of hypertension by questionnaire compared with subjects with intact modulation. However, only nonmodulators had a significantly (P < 0.02) higher frequency of a family history of myocardial infarction. Thus, there is a clustering of metabolic abnormalities in a discrete subset of the essential hypertensive population with a specific dysregulation of the renin-angiotensin system--nonmodulation. The absence of this cluster in low-renin hypertensive subjects may explain their relatively diminished cardiovascular risk. Its presence in nonmodulators likely contributes to the increased cardiovascular risk observed in normal/high-renin hypertension.

Antihypertensive Effects of Mibefradil in the Treatment of Mild-to-Moderate Systemic Hypertension

This report summarizes the results of 4 double-blind, placebo-controlled studies designed to determine the efficacy, tolerability, and dose-response characteristics of the novel T-channel-selective calcium antagonist, mibefradil, in the treatment of mild-to-moderate essential hypertension. Two of these studies were conducted in the general population of essential hypertensives, 1 in elderly patients, and 1 in patients on chronic hydrochlorothiazide treatment. A total of 1,116 patients were randomized to receive 1 of 7 doses of mibefradil (6.25–200 mg; n = 927), or placebo (n = 189). Each study demonstrated a significant linear dose response in the reduction of sitting diastolic (SDBP) and sitting systolic (SSBP) blood pressure. In all 4 trials, SDBP was significantly reduced with the recommended doses of 50 and 100 mg mibefradil (placebo-corrected treatment effects of −4.1 to −6.8 mm Hg and −8.8 to −11.1 mm Hg, respectively, for the 50- and 100-mg doses). A similar reduction in SSBP occurred in 3 of 4 studies at the 50-mg dose (−7.5 to −10.7 mm Hg) and in 4 of 4 studies at the 100-mg dose (−6.8 to −16.7 mm Hg). Lower doses did not reduce blood pressure significantly; doses >100 mg had little additional effect and an increased incidence of adverse events. Overall, response and normalization rates were dose related and averaged 61% and 51%, respectively, for the 50-mg dose and 78% and 65%, respectively, for the 100-mg dose. The onset of the antihypertensive effect was gradual, with no first-dose effect; near maximal response was reached within 1–2 weeks. Trough/peak ratios ranged from 77–86% with the 50-mg dose and from 77–108% with the 100-mg dose, indicating a sustained effect over a 24-hour period. A slight decrease in heart rate was observed, ranging from −2.2 to −5.5 beats/min at the 50-mg dose and from −4.0 to −8.8 beats/min at the 100-mg dose. The efficacy and safety results were similar across all populations studied, including the elderly and hydrochlorothiazide-treated patients, indicating that no dose adjustment is needed for these populations. Thus, the results of these 4 placebo-controlled trials confirm that when taken at the recommended doses of 50 and 100 mg once daily, mibefradil is an effective, safe, and well-tolerated therapy for the treatment of mild-to-moderate hypertension.

Exercise Activates Renal Dysfunction in Hypertension

A bilateral, exercise-mediated renal functional abnormality was first described more than a decade ago. The disturbance is specific for hypertension, is seen in different forms of hypertension, and has been studied most extensively in hypertensives with renovascular disease. The bilateral-abnormal exercise renogram identifies the disturbance. Hypertensives with unilateral renovascular disease were studied in the continuing evaluation of the bilateral function disturbance. We examined 31 hypertensives with documented unilateral renovascular disease, all of whom had renography at rest and during 60 to 80 W ergometric exercise. An additional seven normotensives and 17 essential hypertensives served as controls, and had the same sequence of studies. All patients reported upon continued on to an infusion clearance with 131I-hippurate and 111In-diethylenetriamine pentaacetic acid to determine glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) at rest, and during 25 W ergometric exercise. Eighteen of 31 hypertensives with unilateral renovascular disease were found to have a bilateral-abnormal exercise renogram. Clearance examinations in these identified a prominent reduction of the GFR and a lesser decrease in the ERPF during exercise. Hypertensives with normal exercise renograms did not have the exercise mediated abnormal clearance pattern. Similar results were observed in the control population of essential hypertensives, 65% of whom developed the functional disturbance. The seven normotensives controls did not exhibit the exercise mediated function changes. We conclude that an exercise-mediated bilaterally occuring functional disturbance exists in certain hypertensives, who then have a bilateral-abnormal exercise renogram. Associated with this is a distinctly abnormal clearance during exercise which is characterized by a low filtration fraction. Am J Hypertens 1996;9:653–661

Microalbuminuria, renal dysfunction and cardiovascular complication in essential hypertension.

To evaluate the prevalence of microalbuminuria (albumin excretion rate, AER) in a wide hypertensive population, and to evaluate any relationship with cardiovascular damage and renal dysfunction. A transversal study. In 383 hospitalized Caucasian essential hypertensives (198 men, 185 women) of mean age 44 +/- 0.5 years and mean clinic blood pressure 170.3 +/- 0.95/ 103.4 +/- 0.47 mmHg, metabolic parameters, serum creatinine level (Cs), creatinine clearance rate (Ccs), 24 AER and plasma renin activity (PRA) were measured. Furthermore, each patient underwent 24 h ambulatory blood pressure monitoring (ABPM) and echocardiography to measure left ventricular mass, which was indexed both by body surface area to obtain left ventricular mass index (LVMI) and by height to obtain the left ventricular mass indexed for height (LVMH). By Doppler echocardiography, the diastolic compliance by early:late peak filling velocity ratio was analysed. The fundus oculi was also observed. Three subsets of hypertensives were obtained by dividing the 383 essential hypertensives on the basis of their AER: < or = 11 (group A), 11 < or = 20 (group B) and > 20 micrograms/min (group C). Microalbuminuria, creatinine clearance, PRA, ABPM, LVMI, LVMH, early:late peak filling velocity ratio, hypertensive retinopathy. Among the 383 essential hypertensives, AER was < 11 micrograms/min in 55% of the patients (group A), 18% had AER in the range 11-20 micrograms/min (group B) and 27% had AER > 20 micrograms/min (group C). In the entire essential hypertensive population the prevalence of left ventricular hypertrophy was 44.39% and hypertensive retinopathy was observed in 54.83%. Moreover, AER significantly correlated with clinic systolic blood pressure (SBP) and diastolic blood pressure (DBP), with 24 SBP and DBP and with 24 h daytime and night-time mean blood pressure (MBP). AER was correlated also with LVMH and creatinine clearance. The analysis of the three subsets revealed no differences in age, body mass index, serum creatinine level and PRA. Group C in comparison with group A showed higher values of clinic SBP, 24 h SBP, DBP and MBP, and of daytime and night-time MBP. Furthermore, in group C, LVMI and LVMH were significantly greater than in group A, with a prevalence of left ventricular hypertrophy of 55% in the former group. Group C showed a prevalence of hypertensive retinopathy of 69% whereas in group A the prevalence was 48%. In group C, AER was significantly correlated with serum creatinine level. The transversal phase of our research, performed in a homogeneous population of Caucasian essential hypertensives with no metabolic disturbances, confirms the relationship between blood pressure pattern and early glomerular changes in essential hypertensives without overt proteinuria. Furthermore, these results emphasize the role of microalbuminuria as a marker of early cardiac, renal and retinal structural and functional changes in essential hypertension. The longitudinal study, which is in progress, will confirm the prognostic value of microalbuminuria in essential hypertension.

Glucocorticoid-remediable aldosteronism.

GRA is an inherited disorder of aldosterone biosynthesis. To date, all cases have been the result of chimeric gene duplications in which the regulatory region of the 11-beta hydroxylase gene is fused to more distal coding sequences of the aldosterone synthase gene. This results in ectopic expression of aldosterone synthase in fasciculata cells. Genetic testing has been remarkably precise in identifying these individuals with 100% concordance of the presence of the chimeric gene with increases in 18-oxygenated cortisol products. Several implications follow from these findings. First, GRA may be more common in the hypertensive population than had been previously estimated, and second, genetic testing of subsets of the essential hypertensive population (e.g., those who have low plasma renin activity) may allow the identification of GRA patients who could then be treated specifically. We recommend that hypertensive patients with signs of aldosteronism and no radiologic evidence of an aldosteronoma, especially young hypertensive subjects with low renin activity, be genetically screened for GRA. To track the success of this approach and to identify responses to various therapeutic programs, a central international registry for GRA has been established. This registry not only provides access to screening for GRA, but also informational resources for patients and physicians.

Obesity, the sympathetic nervous system, and essential hypertension.

There is ample evidence that the sympathetic nervous system is important in the etiology of essential hypertension. Plasma catecholamines such as norepinephrine and epinephrine are the most common indexes of sympathetic function used in studies of essential hypertension. Plasma norepinephrine is higher in young essential hypertensive patients than in normotensive subjects. Other methods to examine sympathetic activity, such as blood pressure response to sympatholytic agents, measurement of regional sympathetic activity, vascular reactivity to sympathetic agonists, power spectral analysis, and microneurography, have all provided further evidence for enhanced sympathetic activity in essential hypertension, especially in younger subjects. Certain groups that make up a substantial part of the essential hypertensive population, such as obese subjects, have heightened sympathetic activity that could contribute to hypertension. Plasma norepinephrine levels are significantly higher in obese compared with nonobese subjects, and the remarkable fall in blood pressure with weight loss in obese subjects is correlated with reductions in plasma norepinephrine. Antihypertensive agents have variable effects on sympathetic activity; some agents (diuretics and direct vasodilators) have elevating effects, some agents (centrally acting agents and alpha-antagonists) have lowering effects, and others (converting enzyme inhibitors, calcium blockers, and beta-blockers) have mixed effects. Tailoring therapy toward agents that reduce sympathetic activity for specific groups perceived as having neurogenic hypertension, such as obese subjects, is a goal yet to be attained.

Dysregulation of Aldosterone Secretion and Its Relationship to the Pathogenesis of Essential Hypertension

The level of sodium intake has a reciprocal influence on the vascular and adrenal responses to angiotensin II, with sodium restriction enhancing the adrenal responses and reducing vascular, and particularly renal vascular, responses. In two subgroups of the essential hypertensive population, this relationship is abnormal. Both subgroups have sodium-sensitive hypertension. One is a subset of the low renin essential hypertensive subgroup and its abnormality is an enhanced aldosterone response to angiotensin II with sodium loading, ie, a failure to down-regulate the aldosterone response. The other subgroup, termed nonmodulators, is a subset of the normal-high renin essential hypertensive subgroup. In these patients, sodium intake modifies either adrenal or vascular responses, including renal vascular responses, to angiotensin II--resulting in a reduced aldosterone response to angiotensin II with sodium restriction. Of clinical importance, the nonmodulator's abnormality is corrected by the administration of converting enzyme inhibitors--this class of drugs therefore being a specific form of therapy in these patients.

Sleep apnea syndrome (SAS): Prevalence and risk factors in an essential hypertensive population

Sleep apnea syndrome (SAS): Prevalence and risk factors in an essential hypertensive population

Are non-modulating patients with essential hypertension a distinct subgroup? Implications for therapy

In 40 to 50 percent of the essential hypertensive population, a high intake of sodium does not increase renal blood flow. These patients have been called “non-modulators” since their adrenal and renal vascular responses to angiotensin II are not modified by changes in sodium intake. To determine if these patients form a distinct subgroup, the frequency distribution of four characteristics that have been reported to be abnormal in non-modulators were analyzed: aldosterone secretory response to acute volume depletion, plasma aldosterone response to angiotensin II infusion, plasma renin activity response to saline infusion, and renal blood flow response to salt loading. All four characteristics had a bimodal distribution in patients with hypertension. The effect of angiotensin converting enzyme inhibition on two of these abnormalities was also reviewed. In both cases—aldosterone secretory response to angiotensin II and renal blood flow response to salt loading—converting enzyme inhibition restored the abnormal responses towards normal values in non-modulators without altering the responses in normotensives or modulators. Indeed, the correction of the abnormal renal blood flow response to salt loading through converting enzyme inhibition may explain how converting enzyme inhibitors normalize blood pressure in 50 percent of the patients in whom the renin-angiotensin system is suppressed by an unrestricted, typically high, intake of salt. In summary, non-modulators are a distinct subset of the hypertensive population. Converting enzyme inhibition corrects the abnormalities that may be responsible for their hypertensive condition and, therefore, may be a specific form of therapy for these patients.

Renin activity, sodium and potassium in hypertensive patients

A retrospective study of 200 hypertensive patients was performed in order to investigate various clinical and biochemical relationships. The physical parameters which were studied included serum cholesterol, fasting blood glucose, serum sodium, potassium, uric acid, carbon dioxide, chloride and plasma renin activity. Renal function was evaluated by blood urea nitrogen, serum creatinine and creatinine clearance tests. Special diagnostic data such as intravenous pyelography, radioactive renography, aortography and renal arteriography were also considered. Electrocardiographic data were also recorded. Various drug regimens were taken into account along with specific diagnosis. The above information for each patient was transferred to punch cards and various statistical computations were done with a computer. The population was composed of two distinct populations; patients with essential hypertension and those with renovascular hypertension. With the exception of increased levels of uric acid and fasting glucose, all of the chemistry values, including plasma renin activity, were within the normal range. Nearly 30 per cent of the essential hypertensive population had evidence of left ventricular hypertrophy. The blood pressures of the renovascular hypertensive (RVH) population were generally much higher than those of the essential hypertensive (EH) population. Exactly 70 per cent of the RVH population had either a non-specific cardiac abnormality or left ventricular hypertrophy. Plasma renin activity was significantly elevated in the RVH population only. RVH patients who were taking diuretics had an increased blood urea nitrogen level and a decreased creatinine clearance rate. These patients also had a significantly higher plasma renin activity level. Correlation studies revealed a significant negative correlation between serum potassium levels and renin activity, and between serum potassium levels and systolic and diastolic blood pressures in the RVH population. This population also showed a strong positive correlation between serum potassium levels and creatinine clearance rates as well as between BUN and renin activity. No other statistically significant correlations, including serum sodium levels, were demonstrated in either the RVH or EH population.