Subgroup Of Hypertensives Research Articles

Molecular basis of human hypertension: The role of angiotensin

On the basis of recent advances in molecular biology and statistical genetics, it has become possible to search for chromosome regions that contain genes predisposing to hypertension and to directly link specific mutations on candidate genes to hypertension. As the human genome has been extensively mapped, highly informative, polymorphic markers are available, which can be used to detect genes in their proximity with 'hypertensinogenic' alleles. Some of these markers have been shown to be tightly linked to the genes of the renin-angiotensin system. Furthermore, the coding and regulatory regions of the genes encoding for renin, ACE, angiotensinogen and the AT1 receptor have been partially characterized. This provides a basis for further definition of specific polymorphisms within these genes that are of functional importance and that can be used to examine their contribution to the inheritance of primary hypertension. The first studies of these links have already emerged and have been reviewed in this article. Several problems arise in performing such linkage studies in human primary hypertension, however. It is difficult to define the genetic background of heterogeneous, multigenetic and multifactorial diseases such as human hypertension. Extensive studies of population genetics, including the analysis of large numbers of generations and controlled breeding experiments, cannot be performed, for obvious reasons. Blood pressure is not a convenient study trait, because it exhibits great intraindividual variance and also because of the relatively low reliability of just a few indirect measurements obtained under loosely controlled environmental conditions. Twenty-four-hour ambulatory blood pressure measurements may improve such investigations in the near future. Ravogli et al (1990) reported that the 24-hour ambulatory systolic blood pressure is higher in normotensive subjects of hypertensive parents than in normotensive subjects of normotensive parents--a finding that had not been previously reported using the conventional method of measurement. Hypertension as a trait per se is also problematic: its classification (above 140/90 mmHg) is purely artefactual, and its aetiology is highly heterogeneous. Thus, we have to keep in mind that even strong gene effects, if present in only a small subgroup of hypertensives, may not be detected in these studies. Attempts are being made to strengthen the analysis by characterizing physiologically distinct subgroups. In addition, the investigation of intermediate phenotypes, such as plasma parameters, which are more reliable and less subject to variations, may be helpful.(ABSTRACT TRUNCATED AT 400 WORDS)

Ouabain-inhibiting activity of aldosterone antagonists

It has been suggested that endogenous substances (known as ouabain-like factors, OLF), secreted from the central nervous system in response to salt and water retention, inhibit the cell membrane Na +/K + pump in the renal tubules and reduce sodium reabsorption. However, by also acting upon vascular smooth muscle cells, they may induce cell Na + and Ca + + accumulation, vasoconstriction and systemic hypertension. Recently, an endogenous Na +/K + pump inhibitor was isolated from human plasma; this inhibitor is indistinguishable from the cardiac glycoside ouabain based on biochemical and immunological criteria. Its plasma concentration is close to the therapeutic range for ouabain (around 0.4 nmol/L). Since plant ouabain promotes natriuresis, vasoconstriction, and hypertension; endogenous ouabain may therefore control extracellular fluid volume and blood pressure. The highest plasma concentrations of endogenous ouabain and OLF were found in congestive heart failure, aldosterone producing adenoma, human and animal models of volume expanded hypertension (reduced renal mass and DOCA-salt hypertension), and in Milan hypertensive rats (MHS). Aldosterone antagonists (canrenone and canrenoate) exert both agonist and antagonist effects on the digitalis receptor site of the Na +/K + pump. They are effective antihypertensive agents in animal models of hypertension sustained by OLF (reduced renal mass-Na + and DOCA-salt hypertension in rats). Moreover, in a subgroup of essential hypertensives, 4 weeks of canrenoate administration reduced blood pressure, heightened red blood cell Na +/K + pump activity, and antagonized ouabain-induced vasoconstriction. None of these effects was seen in the other hypertensives. These data suggest that aldosterone antagonists stimulate the Na +/K + pump inhibited by endogenous ouabain and exert their antihypertensive action at least in part through this mechanism.

各種β遮断薬の血圧日内変動プロフィールに及ぼす影響

The purpose of this study was to investigate the effects of various beta-blockers on blood pressure (BP) and pulse rate (PR) profiles of 77 patients with essential hypertension (49 men and 28 women aged 56±16 years) and 86 normotensive individuals (controls).The drugs tested were atenolol (50 mg), nipradilol (6 mg), metoprolol (80 mg), and pindolol (10 mg). Each drug was randomly administered to a subgroup of essential hypertensives twice a day. BP and PR were noninvasively measured at 30-min intervals for 24 hours using an ABPM-630 (Nippon Colin Ltd.) before and 4 weeks after the start of treatment. The effects of each drug on the level (MESOR) and the pattern (amplitude and acrophase) of diurnal variations in the periodic regression curve, which fitted data to a periodicity of 24 and 12 hours, were investigated using periodic analysis of covariance.There was no significant difference in BP or PR levels between all groups before treatment. The mean 24-hour systolic blood pressure (SBP), diastolic blood pressure (DBP), and PR were significantly (p<0.01) reduced after treatment in each group; there was no significant difference in the degree of SBP reduction between the hypertensive groups. DBP reduction was significantly (p<0.01) greater in the nipradilol group (-13 mmHg) than in the pindolol group (-5 mmHg), but no significant difference was found between the atenolol or metoprolol groups and the other 3 groups. There was a significant (p<0.01) change in PR levels after treatment between the atenolol group (-8 bpm) and the metoprolol (-3bpm) or pindolol groups (-4 bpm).The diurnal BP or PR patterns of all groups before treatment were basically the same as those of the normal controls. The diurnal post-treatment pattern of the atenolol and nipradilol groups remained the same as that of the normal controls, but that of the meto-prolol and pindolol groups was significantly (p<0.05) different compared with the controls. The reason for this was that atenolol and nipradilol caused proportional daytime and nighttime reductions, while metoprolol had little effect on the morning BP and pindolol had a lesser effect during sleep.Metoprolol is relatively short acting and pindolol has intrinsic sympathetic activity.Thus, different beta-blockers have specific hypotensive or depressive effects on the BP and PR profiles; these characteristics seem important to consider in the treatment protocol of individual hypertensive patients.

Blood pressure reactivity predicts myocardial infarction among treated hypertensive patients

High blood pressure (BP) defines a prognostically heterogeneous group. Because BP varies according to time, setting and means of observation, it has been postulated that BP reactivity might better predict cardiovascular disease (CVD) than does unidimensional measurements. To assess BP reactivity, the difference between pretreatment nurse (RN) and physician (MD) diastolic BP (DBP systematically recorded in that order-or MD - RN DBP, was obtained in 1737 previously untreated patients with sustained, RN BP ⩾ 160 and/or 95 mmHg. Patients stratified by tertiles of MD-RN DBP [(I) 5 ⩽ −3, (II) −2 to 3 and (III) ⩾ 4 mmHg] were similar by sex, race, age, body mass index, cholesterol, electrocardiography, prior CVD, smoking and pretreatment or attained in-treatment BPs. During 14 years of followup, myocardial infarction (MI) incidence per 1000/year were, tertile I (3.2), II (3.7), III (7.6) (relative risk = 2.4, III vs I + II, p < 0.05), whereas stroke incidence and non-CVD mortality were evenly distributed. By Cox survival analysis, controlling for other entry characteristics only age, sex and DBP reactivity remained predictive ( p ⩽ 0.03) of MI or total CVD. Thus, BP reactivity, probably a centrally-mediated phenomenon, identifies a subgroup of hypertensives with an increased propensity for MI despite successful BP control.

Effects of dilevalol on renal function

Renal function was measured in a total of 35 volunteers and patients who were given dilevalol, the R,R optical isomer of labetalol. Young normotensive volunteers (n = 6) and elderly normotensive volunteers (n = 12) received single 400- and 200-mg doses of dilevalol, respectively. Renal function was determined in these subjects on the same day before and after dosing. In addition, patients with mild to moderate essential hypertension (n = 11) and hypertensive patients with renal insufficiency (n = 6) were treated with placebo to establish baseline blood pressure and then were given dilevalol, 400 to 1,600 mg/day, for 2 to 6 weeks until blood pressure was controlled. Renal function was determined at the end of the baseline period and again at the end of dilevalol treatment. A subgroup of elderly hypertensives from the 2 protocols used to study hypertensive patients was treated as a separate study group. The only effect on parameters of renal function seen in any of the study groups was a statistically significant 15% decrease in glomerular filtration rate after single-dose treatment in the elderly normotensive group. Effective renal plasma flow, filtration fraction, renal blood flow and renal vascular resistance were unchanged before and after treatment in all groups. Mean arterial pressure was reduced significantly in all groups except in the elderly normotensive volunteers. Dilevalol appears to be a well-tolerated, effective therapeutic agent that is neutral regarding its effect on renal function and potentially useful in a variety of patient populations.

Behavioral Determinants of 24-Hour Blood Pressure Patterns in Borderline Hypertension

Borderline hypertension is a heterogeneous condition; only a minority of patients will progress to fixed essential hypertension or suffer cardiovascular damage. Ambulatory blood pressure monitoring can detect the subgroup of borderlines with sustained blood pressure elevation outside the office setting and can also provide a measure of blood pressure variability. Patients in the former group may be at greatest risk for cardiovascular complications while the latter have been theorized to be at risk for progression to fixed hypertension. Evidence we have gathered utilizing ambulatory monitoring does not support the contention that there is a subgroup of borderline hypertensives with excessive blood pressure variability in natural settings. Such recordings have been of benefit in identifying patients with excessive pressor responses to office visits. Future studies employing ambulatory monitoring may be useful in the detection of clinically important subgroups of borderline hypertension.

Cardiovascular and adrenal sensitivity to angiotensin II in essential hypertension.

Regulation of aldosterone secretion by sodium chloride is impaired in a group of essential hypertensives: high-salt diet fails to suppress aldosterone in these patients despite low renin values. The mechanism of this impaired regulation of aldosterone has not been clarified so far. We tested the sensitivity of aldosterone secretion and blood pressure to A II in 20 normotensive controls (aged 20-60, MAP 92 +/- 3 mm Hg), in ten normotensives with one or two parents with hypertension, and in 21 patients with essential hypertension (aged 17-65, MAP 119 +/- 4 mm Hg). After a period of 6 days on high-salt intake (300-320 mEq Na+/day), A II (0.1, 0.5, 1.0 and 2.0 ng/kg/min) was infused, each concentration for 30 min. According to aldosterone excretion during sodium loading, patients were divided into group A with complete suppression (n = 12, aldosterone excretion 3.6 +/- 0.4 microgram/day) and in group B with insufficient suppression (n = 9, aldosterone excretion 15.5 +/- 2.3 micrograms/day). Despite similarly low plasma renins, rise of serum aldosterone levels during A II infusion was significantly higher in group B patients than in group A patients and normotensive controls. Rise in mean arterial blood pressure, however, brought about by graded A II infusion was similar in both groups of hypertensives and in normotensive controls. The results demonstrate an increased adrenal sensitivity to A II in a subgroup of essential hypertensives only. A similar adrenal hypersensitivity to A II found by others in patients with hyperaldosteronism due to adrenal hyperplasia supports the hypothesis that the same mechanism underlies both disorders.

Defect in the sodium-modulated tissue responsiveness to angiotensin II in essential hypertension.

In normal subjects, dietary sodium intake modulates renovascular, adrenal, and pressor responses to infused angiotensin II (AII). To examine the hypothesis that this modulation is abnormal in some patients with essential hypertension, we studied 18 hypertensives and 9 normal subjects twice--during dietary sodium restriction and during loading. Paraaminohippurate (PAH) clearance was used to assess renal plasma flow. AII was infused in graded doses (0.3-3.0 ng/kg per min). Plasma aldosterone, cortisol, renin activity, AII, sodium, potassium, and PAH clearance were measured at the onset and end of each AII dose. During dietary sodium repletion, eight of the subjects with essential hypertension showed a normal renovascular response (greater than 125 ml/min per 1.73 m2) to AII infusion (3 ng/kg per min). The decrement in renal blood flow in these normal responders (NR) was 168 +/- 10, which was comparable to the range in normotensive subjects (206 +/- 25 ml/min per 1.73 m2). All of the remaining hypertensive patients, designated abnormal responders (AbR), had lower (less than 125) renal blood flow responses to the same dose of infused AII (mean decrement: 84 +/- 11 ml/min per 1.73 m2) compared with the NR and normotensive subjects. Renal blood flow responses to all AII doses were statistically greater on a high-vs.-low salt diet in the NR (P less than 0.001, chi-square) and normotensives (P = 0.004, chi-square) but sodium intake had no effect on this response in the AbR. Basal renal blood flow in NR increased significantly (P less than 0.001, paired t test) with dietary sodium repletion, from 491 +/- 36 (low salt) to 602 +/- 40 ml/min per 1.73 m2 (high salt), but was almost identical in the AbR on differing dietary sodium intakes (429 +/- 24 vs. 425 +/- 26 ml/min per 1.73 m2). The adrenal responses to sodium intake and infused AII also differed in the two subgroups. In the NR, the adrenal response to AII was significantly greater (P = 0.011, Wilcoxon signed rank test) after sodium restriction. In contrast, there was no significant difference in the aldosterone response to AII infusion between the low and high sodium diets in the AbR. Thus, a substantial subgroup of essential hypertensives has an abnormality in responsiveness to AII in two systems central to volume homeostasis: the kidney and adrenal. They fail to modulate their renal blood flow and aldosterone responses to AII with changes in dietary sodium intake. Moreover, basal renal blood flow does not increase appropriately with increased sodium intake. These abnormalities, which may be due to an increased local production of AII or a defect in the AII receptors in these three target tissues, could contribute to the elevated blood pressure.

Blood pressure, heart rate, and plasma catecholamines in normal and hypertensive children and their siblings at rest and after standing.

Heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma norepinephrine (NE), and epinephrine (E) levels at rest and in response to orthostatic stress of quiet standing were compared in 19 subjects with borderline hypertension (BH) (SBP-135 mm Hg, DBP-80 mm Hg), nine with significant hypertension (SH) (SBP-150 mm Hg, DBP-95 mm Hg), 14 normotensive siblings (NS) of hypertensives (SBP-113 mm Hg, DBP-64 mm Hg), and 21 age-matched normotensive controls (NC) (SBP-116 mm Hg, DBP-61 mm Hg). Group resting plasma NE levels were significantly higher in BH (454 pg/ml, p less than 0.001 pg/ml) and SH (384 pg/ml, p less than 0.01 pg/ml) than in NC (281 pg/ml) or NS (309 pg/ml), and more than 2 SD above the NC mean value in 50% of BH, 28% of SH, and 7% of NS. Plasma E levels were similar. On standing, mean arterial pressure (MAP) rose 13.7 mm Hg in NC, 3.9 mm Hg in BH, and 2.8 mm Hg in NS, and fell 7.3 mm Hg in SH. These differences reflect the frequent occurrence of hypotensive responses in study group subjects, which were not observed in NC. The mean rise in plasma NE with standing was blunted in hypertensives, increasing 40% to 50% compared with 95% in NC. In BH and NS, SBP was positively correlated with plasma NE levels at rest and with standing. These observations offer support for the hypothesis that altered adrenergic sympathetic nervous system (SNS) activity is present in a subgroup of young hypertensives and can be a contributing factor to their hypertension. Findings of similar SNS activity in some normotensive siblings suggest that genetic factors might be involved.

Evidence for a subgroup of essential hypertensives with non-suppressible excretion of aldosterone during sodium loading.

In patients with grade I and II essential hypertension studied during sodium loading (Na+ excretion above 175 meq·d−1) we found a bimodal behaviour of aldosterone excretion and could distinguish two groups of patients: In the major part of essential hypertensives sodium loading led to a suppression of aldosterone excretion below 6 µg·d−1, which is the highest control value during sodium loading, with an average of 2.7±1.4 (SD) µg·d−1. Aldosterone excretion in a second group of patients was not suppressible below 6 µg·d−1 despite forced sodium loading; it resulted in an average value of 10.0±3.0 (SD) µg·d−1. During sodium deprivation or free sodium intake, aldosterone excretion in the first group of patients followed exactly the behaviour of normotensive controls, while in the second group of essential hypertensives the correlation of aldosterone excretion and log. Na excretion or log. Na+/K+ ratio in 24 h urine (r=−0.59) was far below the control value ofr=−0.87. Serum potassium concentration during sodium loading was significantly (p<0.001) lower (3.81±0.44 meq·l−1) in the essential hypertensives with non-suppressible aldosterone excretion compared to those with suppressible aldosterone excretion (4.26±0.37 meq·l−1). The blood pressure response to treatment with 200 mg spironolactone·d−1 was better (p<0.05) in patients with non-suppressible aldosterone excretion compared to the essential hypertensives with normal aldosterone regulation. The plasma renin activity of both groups of patients was not significantly different, however, a tendency prevailed towards lower PRA-values in the patient group with non-suppressible aldosterone excretion during sodium loading.