Relation of blood pressure with body and plasma electrolytes in Conn's syndrome

Thirty-four patients with untreated Conn's syndrome were studied in a metabolic ward. The final diagnosis in each case was based on the finding and removal of an adrenal cortical adenoma with histological features typical of the disorder. Compared with 34 age and sex-matched normal controls the untreated patients had increased plasma aldosterone concentration, increased blood pressure (183/112 mmHg), increased exchangeable sodium (116.7% of normal), hypokalaemia and increased plasma sodium concentration. Exchangeable potassium was lower than normal and plasma concentrations of active renin, total renin and angiotensin II were lower than normal mean values. Arterial pressure correlated significantly and positively with plasma and exchangeable sodium and there was a significant negative correlation with plasma potassium concentration. Partial regression analysis showed that the relation of exchangeable sodium with blood pressure did not depend on age or renal function but that the relation of blood pressure and plasma potassium could be attributed to the correlation of exchangeable sodium and blood pressure. Multiple regression analysis suggested that exchangeable and plasma sodium were the most important determinants of blood pressure in untreated patients. Spironolactone, amiloride and surgical removal of the adenoma corrected the electrolyte abnormality and usually lowered blood pressure. The fall in exchangeable sodium was related to the fall in blood pressure. The pattern of correlation found by multiple regression analysis in postoperative patients was similar to that in normal subjects. The findings are relevant to some of the mechanisms proposed for the hypertension of mineralocorticoid excess.     

原发性高血压患者血压变化与血清电解质的关系

目的 :研究原发性高血压 (EH)患者的血压变化与血清电解质浓度之间的关系。方法 :对 85例 EH患者和 30例正常人进行动态血压、偶测血压和血清电解质检查 ,比较血压各参数与血清 K 、Na 、Na / K 比值之间的相关性。结果 :EH患者 2 4h平均收缩压 (SBP)、舒张压 (DBP) ,日间平均 SBP、DBP,夜间平均 SBP、DBP与血清 K 浓度呈明显负相关 ;与 Na / K 比值呈明显正相关 (均 P <0 .0 1) ;偶测血压与血清 Na 、K 浓度和 Na /K 比值之间无相关性 (P >0 .0 5 ) ;2 4h、日间、夜间平均 SBP与血清 Na 浓度均呈正相关 (P <0 .0 1)。结论 :在EH患者中 ,血清 K 、Na / K 比值是全日血压的决定因素之一。     

Arterial plasma norepinephrine correlates to blood pressure in middle-aged men with sustained essential hypertension

Increased plasma catecholamine levels assessed from the venous blood have been found in a number of studies of younger patients with essential hypertension, but hypertensive-normotensive differences could not easily be demonstrated in subjects above 40 years of age. For several reasons, measurement of arterial plasma catecholamines may be a more sensitive tool for the detection of hypertensive-normotensive differences. The present study therefore aimed at examining both venous and arterial plasma catecholamines in a group of white men, all 50 years of age, with never-treated, established essential hypertension (n = 61, blood pressure 165 +/- 2/112 +/- 1 mm Hg, means +/- SE) and comparing them with a similar group of normotensive men (n = 51, blood pressure 128 +/- 1/85 +/- 1 mm Hg). Arterial and venous plasma epinephrine, heart rate, and body weight were significantly elevated in the hypertensive group. Plasma norepinephrine was similar between the groups in the venous blood, whereas in the arterial blood the values in hypertensive subjects were moderately, but significantly increased (p less than 0.03). However, stepwise multiple regression analysis suggested arterial plasma norepinephrine was the only significant independent explanatory variable of raised blood pressure in the hypertensive group (r = 0.51, t = 4.05, p = 0.0002). Such a relationship was not found in the normotensive group. Thus based on measurements in arterial blood, we conclude that plasma norepinephrine, representing sympathetic tone, may be an important pathogenetic factor for high blood pressure in middle-aged men with established hypertension.     

Arterial distensibility and ambulatory blood pressure monitoring in essential hypertension

Arterial distensibility estimated by carotid femoral pulse wave velocity was evaluated in 22 patients with sustained essential hypertension, together with 3 different methods of blood pressure (BP) measurement: mercury sphygmomanometer, semiautomatic BP recording using the Dinamap apparatus and 24-hour ambulatory BP monitoring using a Spacelabs monitor. Although pulse wave velocity did not correlate with BP measured by mercury sphygmomanometer, it strongly and positively correlated with BP measurements using the other 2 procedures. The best correlation was observed with ambulatory BP with respect to systolic BP only (r = 0.685, p less than 0.001). Since cardiovascular morbidity and mortality in hypertensive patients is mainly related to lesions of the large arteries, the determination of pulse wave velocity together with ambulatory BP measurements is proposed for the evaluation of cardiovascular risk.     

Metabolic syndrome score and ambulatory blood pressure in untreated essential hypertension

BACKGROUND: The relationship between metabolic syndrome components, as defined by the Adult Treatment Panel III report, and ambulatory blood pressure in hypertensive patients has not been investigated to date. OBJECTIVE: To explore the relation between metabolic syndrome components ambulatory blood pressure levels and blood pressure day/night variations in a large population of never-treated essential hypertensive patients. METHODS: This investigation included 519 patients with uncomplicated grade 1 and 2 hypertension (mean age 45+11 years) who were attending a hypertension hospital outpatient clinic. They underwent the following procedures: (1) repeated clinic blood pressure measurements; (2) blood sampling for routine chemistry examinations; and (3) ambulatory blood pressure monitoring over two 24-h periods within 4 weeks. Because, by selection, all participants fulfilled one of the Adult Treatment Panel III criteria, the additional four criteria, abdominal obesity, hypertriglyceridemia, low HDL cholesterol and high blood fasting glucose, were specifically searched for. Patients were stratified according to the absence (group I) or the presence of one (group II), two (group III), three or four (group IV) components of the metabolic syndrome. Nocturnal dipping was defined as a night-time reduction in average systolic and diastolic blood pressure >10% compared to average daytime values. Each participant was classified according to the consistency of the dipping or nondipping status in the first and second ambulatory blood pressure measurement periods as follows: reproducible dipper (DD: decrease in blood pressure >10% in both ambulatory blood pressure measurement periods), reproducible nondipper (ND-ND: decrease in blood pressure <10% in both ambulatory blood pressure measurement periods) and variable dipper (VD: i.e dipper in one and nondipper in the other ambulatory blood pressure measurement period). RESULTS: In the whole population mean clinic and 48-h ambulatory blood pressures were 146/96 and 136/87 mmHg, respectively. In all, 197 patients (38%) had no metabolic syndrome components other than high blood pressure, 171 (33%) had one, 109 (21%) had two and 42 (8%) had three or four components. The four groups did not differ in age, clinic blood pressure, average 48-h, daytime, night-time systolic and diastolic blood pressure, and percentages of nocturnal fall in systolic and diastolic blood pressure. Furthermore, the distribution of three different ambulatory blood pressure patterns (DD, ND-ND and VD) was similar in the four groups: I=54.6%, 23.0%, 22.4%; II=51.1%, 21.7%, 27.2%; III=51.9%, 23.6%, 24.5%; and IV=52.7%, 27.2%, 25.1%, respectively. CONCLUSIONS: Our findings indicate that no significant relationship exists between the extent of metabolic alterations and ambulatory blood pressure levels or circadian variations in blood pressure in uncomplicated essential hypertensive patients.     

Changes in blood pressure and plasma norepinephrine during sleep in essential hypertension

A fall in blood pressure (BP) and the presence of a period of unstable BP during sleep has been reported in humans. However the mechanisms responsible for these phenomena are unclear. In order to examine the role of the sympathetic nervous system in these phenomena, plasma norepinephrine (PNE) was measured in patients with essential hypertension. Blood pressure was monitored under unrestricted conditions by a canula inserted into the brachial artery. During sleep, systolic (SBP) and diastolic blood pressure (DBP) fell by 18.8/13.7 mmHg, respectively. The magnitude of the fall in SBP correlated significantly (p less than 0.05) with the level of PNE in the daytime and with the magnitude of the fall in PNE during sleep. The period of unstable BP and pulse rate was observed during sleep. During this unstable period, BP changed periodically with 20 to 120-second cycles associated with parallel changes in pulse rate. PNE during this period was higher (p less than 0.05) than that during the period of stable BP during sleep. These data suggest that the sympathetic nervous system may play an important role in the fall in BP and unstability of BP during sleep.     

Polymorphic differences from normal in the aldosterone synthase gene (CYP11B2) in patients with primary hyperaldosteronism and adrenal tumour (Conn's syndrome).

OBJECTIVE: The hypertension of Conn's syndrome is due to autonomous aldosterone production by a unilateral adrenocortical adenoma. The source of tumour initiation and the reasons for excess aldosterone production as opposed to cortisol are not known, although variations in the promoter region of the gene coding for aldosterone synthase (CYP11B2) might account for the altered rate of aldosterone secretion. DESIGN: In a series (n = 27) of well-characterized Conn's syndrome cases, the aldosterone synthase gene (CYP11B2) was screened by single-strand conformational polymorphism (SSCP) for differences from the consensus sequence. RESULTS: No new mutations were found. The frequencies of two previously described linked polymorphisms, one a change of -344C to T in a putative steroidogenic factor-1 (SF-1) binding site and the other an exchange of intron 2 for that of CYP11B1 (conversion) were measured in tumour and genomic DNA. The frequency of the SF-1 T allele (P < 0.0001) and the conversion allele (P < 0.001) were markedly different between the Conn's syndrome group and the normal controls. However, the frequency did not differ between tumour and genomic DNA in the patient group. CONCLUSION: While it is unlikely that this difference from normal is related to tumour growth, these genotypes may predispose the tumour to aldosterone production.     

Effect of doxazosin monotherapy on blood pressure and plasma lipids in patients with essential hypertension

The efficacy and safety of doxazosin (DOX) for the treatment of hypertension was investigated. A multicenter, double-blind, placebo-controlled, parallel design was employed. A 4-week placebo runin period was followed by a 9-week double-blind period during which patients were randomly assigned to placebo or 2, 4, or 8 mg doxazosin. Blood pressures (BP) and heart rates (HR) were measured 24 hours postdose. The mean changes in standing BP (mmHg) were -6.2/-6.9 (2-mg regimen), -5.7/-5.8 (4-mg regimen), -8.5/-7.7 (8-mg regimen) for DOX patients and 0.7/-2.9 for placebo patients. The mean changes in supine BP (mmHg) were -3.2/-4.7 (2-mg regimen), -4.0/-5.1 (4-mg regimen), -4.6/-5.6 (8-mg regimen) for DOX patients and -0.5/-3.3 for placebo patients. There was no evidence of a dose-response relationship for DOX; however, DOX serum levels were linearly related to the dose. Responder rate for the combined DOX patients was 38% (32/84) and for the placebo patients 27% (8/30). HR (24 hours postdose) was not modified by DOX. Patients in the 8-mg regimen had a significantly higher gain in mean body weight (+ 1.3 +/- 0.3 kg; P less than 0.05) compared to the 2-mg regimen, 4-mg regimen, and placebo groups. Plasma norepinephrine was not significantly modified by DOX. DOX had a favorable effect on plasma lipids. DOX lowered LDL cholesterol (P less than 0.05), total cholesterol, and apoprotein B and increased HDL/(LDL + VLDL) ratio (0.05 less than or equal to P less than 0.1) compared to placebo. Dropout rate and treatment-related side effects were equally distributed among the DOX and placebo groups. No patients had the dose of medication reduced because of side effects. Three DOX patients were withdrawn because of postural dizziness.     

原发性高血压患者血浆肾素活性水平与血压和尿钠的关系

目的分析原发性高血压患者血浆肾素活性水平与血压、尿钠排泄的关系。方法原发性高血压患者479例,根据血浆肾素活性水平的5分位排序,分为3组,低肾素组93例,中间肾素组291例,高肾素组95例。各组血浆肾素活性与24 h动态血压及24 h尿钠排泄情况进行相关性分析。结果与低肾素组比较,中间肾素组和高肾素组年龄明显偏低,血浆肾素活性明显增高,差异有统计学意义(P<0.05,P<0.01)。低肾素组老年人、女性、非杓型血压比例明显高于高肾素组,差异有统计学意义(P<0.01)。血浆肾素活性水平与24 h尿钠排泄、24 h血压呈负相关(P<0.05,P<0.01)。结论老年和女性原发性高血压患者血浆肾素活性水平较低。低肾素患者血压昼夜节律改变更明显,以非杓型血压多见。     

Circadian variation of blood pressure and endothelial function in patients with essential hypertension:a comparison of dippers and non-dippers

OBJECTIVES: The purpose of this study was to evaluate the relationship between the circadian blood pressure (BP) rhythm and endothelial function in patients with essential hypertension. BACKGROUND: Hypertension is associated with alterations in resistance artery endothelial function. Patients with a non-dipper circadian pattern of BP have a greater risk of cerebrovascular and cardiovascular complications than do patients with a dipper circadian pattern. METHODS: We evaluated the forearm blood flow (FBF) response to intra-arterial acetylcholine (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, infusion in 20 patients with non-dipper hypertension and 20 age- and gender-matched patients with dipper hypertension. The FBF was measured using a mercury-filled Silastic strain-gauge plethysmograph. RESULTS: The 24-h systolic BP, as well as nocturnal systolic and diastolic BPs were higher in non-dipper patients than in dipper patients. The 24-h urinary excretion of nitrite/nitrate and cyclic guanosine monophosphate was lower in non-dippers than in dippers. The response of FBF to ACh was smaller in non-dippers than in dippers (25.1 +/- 3.1 vs. 20.2 +/- 3.0 ml/min/100 ml tissue, p < 0.05). The FBF response to ISDN was similar in dippers and non-dippers. The FBF response to ACh was similar in the two groups following intra-arterial infusion of the nitric oxide (NO) synthase inhibitor N(G)-monomethyl-L-arginine. CONCLUSIONS: These findings suggest that endothelium-dependent vasodilation is blunted through a decrease in NO release in non-dippers compared with patients who have dipper hypertension.     

Relation between body fat-corrected ECG voltage and ambulatory blood pressure in patients with essential hypertension.

Because adipose tissue has high electric resistance, the amount of body fat influences ECG voltage. In this study, body fat weight of patients with essential hypertension was measured by means of the impedance method and was used to correct mean ECG voltage. Then the relation between body fat-corrected mean ECG voltage (Vfm) and ambulatory blood pressure (BP) was investigated. The subjects were 172 patients with essential hypertension (88 men, 84 women, none receiving medication) between the ages of 30 and 75 years. Ambulatory BP was measured by a multi-biomedical recorder. Minimum sleep-time BP (base BP) was calculated to correspond with minimum sleep-time heart rate. The tetrapolar bioelectric impedance method was used to measure body fat (kg). Left ventricular mass (LVM) was obtained by echocardiography. Then comparisons were made with standard 12-lead ECG, and the statistical mean ECG voltage (Vm) and Vfm were derived by multivariate statistical analysis. The following formula was devised to obtain Vfm resulting from the multivariate analysis that demonstrated a high correlation with LVM (r=0.85): Vfm=0.175(Body Fat)1/3xVm+0.5 (mV). The coefficient of correlation (r) between Vfm and ambulatory BP was not smaller than that between LVM and ambulatory BP. Base systolic BP demonstrated a significantly higher r value (r=0.83) with Vfm/BSA1/2 (where BSA is body surface area) than mean daytime SBP (r=0.65). In many subjects with white-coat hypertension, Vfm/BSA1/2 was <1.33 mV/m (34 of 38 cases; sensitivity, 89%; specificity, 89%). These results indicate that Vfm is a better indicator of hypertensive left ventricular hypertrophy and that it may be useful in estimating minimum sleep-time systolic BP and in diagnosing white-coat hypertension in the outpatient clinic.     

Plasma immunoreactive proopiolipomelanocortin-derived peptides in patients with primary hyperaldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperaldosteronism

Immunoreactive plasma levels of the proopiolipomelanocortin-derived peptides, ACTH, beta-endorphin-lipotropin, and gamma 3MSH, were measured in patients with primary hyperaldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperaldosteronism. Plasma peptide concentrations in patient groups were not different from those in normal controls. Removal of aldosterone-producing adenomas in three patients and of an aldosterone-producing adrenocortical carcinoma in one patient did not affect plasma peptide concentrations. Furthermore, infusion of the opiate antagonist naloxone (0.2 mg/min) in one patient with bilateral adrenal hyperplasia had no effect on either plasma aldosterone or cortisol. These results suggest that the proopiolipomelanocortin-derived peptides are not overproduced in states of hyperaldosteronism.     

Increased ratio between changes in blood pressure and plasma norepinephrine in essential hypertension.

The pathogenic role of the sympathetic system in essential hypertension was evaluated by combined analysis of plasma catecholamine levels and the pressor sensitivity to endogenous norepinephrine. The latter was estimated indirectly by the ratio between changes in blood pressure and those in plasma norepinephrine after adrenergic neuronal blockage with debrisoquine (given orally for 6 weeks). Normal subjects and patients with borderline or established essential hypertension had comparable pretreatment levels of plasma norepinephrine and epinephrine. Debrisoquine lowered plasma norepinephrine by a similar degree (almost 50%) in these three groups; in contrast, blood pressure decreased only slightly in normal or borderline hypertensive subjects [-3.4 +/- 3.2% and -5.4 +/- 1.6% (SE), respectively] but fell significantly more (P less than 0.005) in patients with established essential hypertension (-20.7 +/- 3.9%). The ratio between percentile changes in blood pressure and those in endogenous norepinephrine levels was comparable in normal and borderline hypertensive subjects (0.03 +/- 0.08 and 0.17 +/- 0.04, respectively), but increased (P less than 0.001) in established essential hypertension (0.62 +/- 0.11). This suggests that essential hypertension may be maintained, at least partly, by the inappropriate association of normal plasma norepinephrine levels with increased norepinephrine pressor sensitivity.     

Long-term effects of pindolol and a thiazide diuretic on plasma lipids and blood pressure in patients with essential hypertension

A retrospective analysis was made from the charts of 53 patients with mild to moderate essential hypertension to determine the effects of pindolol (PIN) monotherapy, hydrochlorothiazide (HCTZ) added to PIN monotherapy, and PIN added to HCTZ monotherapy on serum lipids and blood pressure. PIN monotherapy (Group I, n = 24) resulted in a significant decrease in systolic and diastolic pressure of 12.0 and 9.0 mmHg at three months and 14.0 and 11.0 mmHg at 12 months, respectively. Serum triglycerides, total cholesterol, low density lipoprotein and high density lipoprotein cholesterol fractions remained unchanged. The addition of 25 mg of HCTZ to PIN (Group II, n = 7) resulted in a significant decrease in both systolic and diastolic pressure of 21.0 and 11.0 mmHg at three months and 24.0 and 11.0 mmHg at 12 months, respectively. No change in serum lipids was noted. Adding PIN to 25 mg HCTZ (Group III, n = 22) resulted in a significant decrease in systolic and diastolic pressure of 18.0 and 9.0 mmHg at three months and 20.0 and 10.0 mmHg at 12 months, respectively, with no change in serum lipids noted. These data indicate that long-term administration of PIN, a drug possessing intrinsic sympathomimetic activity, alone or added to a low dose of a thiazide diuretic does not adversely affect serum lipids. The addition of a small dose of a thiazide diuretic to PIN has no long-term effect on plasma lipids.     

Relationships between plasma catecholamines, renin, age and blood pressure in essential hypertension

The aim of this study was to examine the interrelationships between age, plasma catecholamines, plasma renin activity (PRA) and blood pressure in essential hypertensive (EH) patients. PRA, plasma noradrenaline (NA) and adrenaline (A) were measured in 76 consecutive EH patients (WHO stages 1-2, aged 24-66 years) and in 28 normotensive subjects (aged 25-64 years) studied at rest in supine position after 5 days of normal fixed sodium and potassium intake. Both plasma NA and A were slightly but significantly higher in EH patients (p less than 0.05). While no relationship was found between the various parameters in normotensive subjects, in EH patients, particularly those at WHO stage 2, plasma NA was directly related to mean blood pressure (MBP) (p less than 0.001) and PRA (p less than 0.01). Plasma A was weakly related to MBP (p less than 0.05); PRA was inversely related to age (p less than 0.01) but no relationship was found between NA or A and age. Partial correlation analysis confirmed all these relationships. In fact, NA was related to MBP also considering constant PRA (p less than 0.001) or age (p less than 0.001), and NA was related to PRA also considering constant MBP (p less than 0.01) or age (p less than 0.001). Acute pharmacological alpha- and beta-blockade, with labetalol 100 mg i.v., induced a reduction of MBP which was directly related to basal plasma NA (p less than 0.001). These results support the view that in EH the sympathetic nervous system might be in part responsible for PRA levels and for the severity of hypertension.     

Concurrent adrenocortical carcinoma and Conn's adenoma in a man with primary hyperaldosteronism. In vivo and in vitro studies.

This is a report of a rare and unusual case of adrenal pathology. A patient presented with clinical and biological signs of primary aldosteronism and computed body tomography scan led to our suspecting the presence of a left adrenocortical carcinoma. The in vitro studies performed on the resected tumour showed very low synthesis of mineralocorticoids and glucocorticoids. The patient could not be reexamined until 15 months later, when he still suffered hypertension; another tomography scan revealed a mass on the right adrenal gland. The studies performed on this second tumour confirmed the diagnosis of Conn's adenoma: active in vitro biosynthesis of 18-hydroxy-corticosterone and aldosterone from exogenous tritiated precursors.     

KCNJ5 mutations in the National Institutes of Health cohort of patients with primary hyperaldosteronism: an infrequent genetic cause of Conn's syndrome

KCNJ5 mutations were recently described in primary hyperaldosteronism (PH or Conn's syndrome). The frequency of these mutations in PH and the way KCNJ5 defects cause disease remain unknown. A total of 53 patients with PH have been seen at the National Institutes of Health over the last 12 years. Their peripheral and tumor DNAs (the latter from 16 that were operated) were screened for KCNJ5 mutations; functional studies on the identified defects were performed after transient transfection. Only two mutations were identified, and both in the tumor DNA only. There were no germline sequencing defects in any of the patients except for known synonymous variants of the KCNJ5 gene. One mutation was the previously described c.G451C alteration; the other was a novel one in the same codon: c.G451A; both lead to the same amino acid substitution (G151R) in the KCNJ5 protein. Functional studies confirmed previous findings that both mutations caused loss of channel selectivity and a positive shift in the reversal potential. In conclusion, the KCNJ5 protein was strongly expressed in the zona glomerulosa of normal adrenal glands but showed variable expression in the aldosterone-producing adenomas with and without mutation. The rate of KCNJ5 mutations among patients with PH and/or their tumors is substantially lower than what was previously reported. The G151R amino acid substitution appears to be the most frequent one so far detected in PH, despite additional nucleotide changes. The mutation causes loss of this potassium channel's selectivity and may assist in the design of new therapies for PH.