Assessing resting heart rate in adolescents: determinants and correlates.

The aim of this study was to evaluate the distribution of resting heart rate and its biological and environmental determinants in adolescents. The study was cross- sectional and the population consisted of 2230 children and adolescents, age range 12-18 years, enrolled randomly from state schools in Turin, Italy. In all participants the following parameters were evaluated: heart rate, blood pressure (BP), weight, height, degree of sexual development, physical activity, parental socio-cultural level. Heart rate and BP were measured after 5, 10 and 15 min in a sitting position. Furthermore, to obtain regression equations to define heart rate as a function of the other variables available, a multiple regression analysis was performed. In both sexes BP, but not heart rate, declined significantly from the first to the last determination. Heart rate was positively and significantly correlated to BP level in both sexes; heart rate was higher in girls (3 bpm) and followed a progressive decreasing trend with age in both sexes, that was opposite to BP values. Age, sexual maturation, height, physical activity and parental socio-cultural level were independent determinants of resting heart rate. In conclusion, resting heart rate in adolescents is related to several methodological, constitutional and environmental factors that have to be taken into account when assessing heart rate values and constructing tables of normal values.

Ambulatory blood pressure monitoring and clinical characteristics of the true and white-coat resistant hypertension.

The resistant hypertension has been differentiated in true resistant hypertension and white-coat resistant hypertension by using ambulatory blood pressure monitoring. White-coat resistant hypertension was defined as high clinic blood pressure, despite triple treatment for at least 3 months, but day-time blood pressure values < 135/85 mmHg. The aim of this study was to evaluate the presence of different clinical characteristics between two types of resistant hypertension. The study group consisted of 49 patients with essential hypertension, resistant to an adequate and appropriate triple-drug therapy, that included a diuretic, with all 3 drugs prescribed in near maximal doses and that had persistently elevated clinic blood pressure (> 140/90 mm Hg), for at least 3 months. They represented the 2% of 2500 hypertensive outpatients that referred at our Hypertension Unit. Patients with white-coat resistant hypertension (n=19) were older (p<0.05) than those with true resistant hypertension (n=30). The sodium intake (p<0.05) and alcohol intake (p<0.05) were significantly higher in patients with true resistant hypertension than in those with white-coat resistant hypertension. The renin plasma activity and plasma aldosterone were higher (p<0.05) in patients with true resistant hypertension than in those with white-coat resistant hypertension with normal plasma electrolyte balance. There were no significant differences in mean values of office systolic and diastolic blood pressures between white coat resistant hypertensives and true resistant hypertensives (165+17 vs 172+28 and 98+12 vs 102+14 mmHg). Day-time and night-time ambulatory 24-h-systolic and diastolic blood pressures were significantly higher in the true resistant hypertensive patients when compared with white-coat resistant hypertensives (153+15 vs 124+10 mmHg and 97+9 vs 76+6 mmHg all p<0.001). Day-time and night-time ambulatory 24-h-heart rate were significantly higher in the true resistant hypertensive patients when compared with white-coat resistant hypertensives (79+11 vs 71+9 beats/min; p<0.01; 68+9 vs 60+6 beats/min, p<0.001). The ABP readings were analysed by a Fourier series with 4 harmonics. According to the runs test both two groups of patients showed a circadian rhythm for both systolic and diastolic blood pressure. The nocturnal fall in SBP, DBP and HR was not different in both groups of patients. In conclusion, our findings showed that true resistant hypertensive patients were characterized both by higher heart rate and higher plasma renin activity values as an expression of a possible increased sympathetic activity. Thus, the combination of ABPM with the assessment of the clinical characteristics allow to differentiate better the true drug-resistant hypertension from the white coat resistant hypertension.

Antihypertensive drugs and sympathetic nervous system.

Several studies have demonstrated that essential hypertension is accompanied by sympathetic activation, which contributes to blood pressure elevation. Sympathetic activation also has adverse consequences in hypertensive patients beyond initiating blood pressure elevation. There is evidence that neural vasoconstriction has metabolic effects in skeletal muscle, impairing glucose delivery to muscles. In the liver, retarding of post prandial clearance of lipids contributes to hyperlipidemia. Cardiac sympathetic activation is a probable cause of sudden death in hearth failure. A trophic effect of sympathetic activation on cardiovascular growth is also likely, contributing to the development of left ventricular hypertrophy. Consequently, one of the major aims of antihypertensive therapy should be to attenuate sympathetic tone. It is possible that, among the antihypertensive drugs available, those inhibiting the sympathetic nervous system might best reduce cardiovascular risk.

Peripheral adrenergic system and hypertension.

Hypertension is a condition where adrenergic responsiveness, sympathetic activity and adrenoceptors are somewhat altered. Many techniques are available to assess human sympathetic nervous system activity. They each present limitations and disadvantages. Characterization and subdivision of the alpha and beta-adrenoceptors, according to their localization and answer to different agonists, was facilitated in recent years by the extensive use of pharmacological and molecular biology techniques. Some adrenoceptor studies were conducted on animal models, human tissues and peripheral blood cells to assess their changes in various forms and stages of hypertension. Our group has pointed out that alpha1-adrenergic receptors expressed by human peripheral blood lymphocytes underwent changes of density in essential hypertensives, compared to normotensive control subjects. The importance of these findings could provide an assessment of alpha1-peripheral receptors with possible future clinical implications in the pathophysiology and treatment of hypertension.

Obesity and autonomic function in adolescence.

Hypertension and obesity are risk factors for coronary heart diseases in adults. In turn, childhood overweight and high blood pressure increase the risk of subsequent obesity and hypertension in adulthood. Human obesity is characterized by profound alterations of hemodynamic and metabolic states. Whether these alterations involve sympathetic nervous system control on cardiac function is controversial. We report the results of our study, conducted in a sample of obese adolescents by using power spectral analysis of heart rate variability. An increase in sympathetic tone coupled with a reduction in vagal tone was found. This allowed us to hypothesize that autonomic nervous system changes depend on the time course of obesity development. It is still unclear if treatment of obesity in adolescence prevents subsequent autonomic imbalance and hypertension.

Heart rate variability and left ventricular diastolic function in patients with borderline hypertension with and without left ventricular hypertrophy.

The relationships between heart rate variability (HRV), left ventricular mass and diastolic function in borderline hypertensive patients (BHT) were evaluated. 24 h Holter electrocardiogram (ECG) and blood pressure (BP) monitoring, M and 2 D echocardiogram and Doppler analysis in 42 BHT with and without left ventricular hypertrophy (LVH) and in 20 normotensive controls were assessed. From 24-h ECG, time domain indexes of HRV were calculated. Standard Deviation of all Cycles (SDNN) and Standard Deviation of the means of heart periods over five-minute intervals (SDANN) were significantly reduced in BHT with LVH but not in BHT without LVH. No significant differences of short-term variability measures were detectable, although a progressive decrease among control subjects and BHT with and without LVH was observed. Diastolic left ventricular compliance evaluated by early to late transmitral flow velocity ratio (E/A ratio) significantly declined from normotensive subjects to BHT with LVH. There was a significant positive correlation between E/A and SDNN and SDANN throughout all studied groups. This indicates that BHT with LVH has a reduced HRV compared to other groups. This impairment is probably related to left ventricular mass and left ventricular filling abnormalities.

Baroreflex sensitivity in secondary hypertension.

A deranged baroreceptor control of the cardiovascular functions has been reported in essential hypertension. Studies performed in experimental animals and in humans using different approaches have documented an impairment of both baroreflex heart rate modulation (resetting and loss of sensitivity) and baroreceptor control of peripheral vasomotor tone (only resetting). Baroreflex alterations have been reported also in secondary forms of hypertension, but data are controversial. This paper reviews recent works concerning baroreflex function in secondary hypertension. Either structural changes of arterial wall (decrease of vascular distensibility) or functional processes (involving angiotensin II, aldosterone, catecholamines, nitric oxide) have been proposed as potential mechanisms responsible for baroreflex readjustments in secondary hypertension. It remains unclear, and it is difficult to define exactly, if baroreflex changes associated with secondary form of hypertension are primarily due to factors specific for different hypertensive conditions, or merely follow blood pressure elevation.

Autonomic nervous function in de novo parkinsonian patients in basal condition and after acute levodopa administration.

The aims of this study were to assess autonomic nervous function in subjects with recently diagnosed Parkinson's disease (de novo patients) and to evaluate its changes following acute levodopa administration. In 13 patients (8 males, 5 females) and 13 age-matched control subjects, three cardiovascular autonomic function tests (Deep Breathing, Valsalva, Lying to Standing) were performed, the QT interval was calculated on a 12-lead electrocardiogram, and the response of plasma norepinephrine to standing was assessed in basal conditions. The cardiovascular tests and the measurement of the QT interval were repeated in de novo Parkinsonian patients 90 minutes after the administration of levodopa 200 mg per os. The results of the Deep Breathing and Valsalva tests were worse and the QT interval longer in patients than in control subjects (although the differences were not statistically significant). The heart rate increase at 30 seconds after standing up was significantly higher in Parkinsonian patients than in the control group. The response of plasma norepinephrine to standing was similar in both groups. Levodopa administration produced a slight improvement in the Deep Breathing test, a shortening of the QT interval and increased tachycardia on standing. Our data suggest that a mild subclinical impairment of parasympathetic function can be a feature of de novo Parkinsonian patients and that levodopa therapy could have a beneficial effect on this autonomic dysfunction.

CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism.

Primary aldosteronism is characterized by autonomous production of aldosterone and arterial hypertension, and it occurs in 2 principal forms: aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). APA can be cured through removal of the adenoma, whereas IHA leads to hypertension that must be treated with medication. The origin of the autonomous aldosterone production in IHA is poorly understood, but genetic factors may contribute to its cause. To test the hypothesis that variants of the aldosterone synthase gene may contribute to susceptibility to IHA, we compared genotypes at 3 polymorphic sites in the CYP11B2 gene in patients with IHA (n=90) with those found in patients with APA (n=38), in patients with essential hypertension (n=72), and in normotensive individuals (n=102). We observed significant linkage disequilibrium among the 3 polymorphisms with 2 frequent haplotypes in all groups studied. One haplotype (C2R) was found to be increased in frequency in the IHA group (47%) compared with the other groups, which had a similar haplotype frequency (36%). The 3 polymorphisms studied have been implicated in either essential hypertension or excess aldosterone production in previous studies. Because of the strong linkage disequilibrium, the observed results could be due to the action of any 1 of the 3 alleles or to another allele in linkage disequilibrium with them. Our results suggest that variations in the CYP11B2 gene may contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.

Relationship between birth weight and blood pressure in adolescence.

BACKGROUND: Several studies have found a relation ship between small size at birth and high blood pressure (HBP). However, this association has not been fully evaluated in adolescence. The aim of the present study was to evaluate the relation of birth weight (BW) to BP in adolescence, controlling for factors related to BP, to extrauterine environment, and to maternal risk of fetal distress. METHODS: In 1310 adolescents (ages 12-14 years), randomly selected from Turin school children, we evaluated BP, heart rate (HR), weight, height, familial risk of hypertension, parental cultural level, BW, and maternal history of diseases during pregnancy. The BW-BP association was tested by using multiple regression analysis and adjusting for the other variables mentioned above. The same analysis was done for the subgroup at high risk of fetal distress. RESULTS: The association between BW and BP was negative but weak when we adjusted for all confounders (= -0.07 in males; = -0.27 in females). The association was negative and became stronger after the inclusion of all confounders, particularly HR (= -3.92), in the group of children at high risk of fetal distress. CONCLUSIONS: Intrauterine environment, as reflected by BW, has little effect on BP in early adolescence without concomitant maternal diseases or environmental conditions leading to severe placental hypoperfusion.

Vasoactive hormones induce nitric oxide synthase mRNA expression and nitric oxide production in human endothelial cells and monocytes.

Isoform-2 nitric oxide synthase (NOS-2) mRNA expression and nitric oxide (NO) production are induced in endothelial cells and monocytes by cytokines such as gammaIFN and LPS. We evaluated NOS-2 and isoform-3 NOS (NOS-3) mRNA expression and NO production in human monocytes and human umbilical vein endothelial cells (HUVEC), under basal conditions and after incubation with physiologic concentrations of vasoactive hormones. NOS mRNA expression was detected by reverse transcription polymerase chain reaction (RT-PCR) and NO production by electronic paramagnetic resonance spectroscopy (EPR). We showed that NOS-2 mRNA expression and NO production were induced by stimulation with epinephrine, dopamine, endothelin-1, and angiotensin II, both in monocytes and HUVEC. NOS-3 mRNA expression and NO production were detected under basal conditions in monocytes and HUVEC and were not modified by the presence of vasoactive hormones. Human endothelial cells and monocytes express the NOS-2 and NOS-3 mRNA and the inducible NOS-2 mRNA expression increases after vasoactive hormone stimulation.

Baroreflex control of heart rate is impaired in pre-eclampsia.

Autonomic nervous dysfunction, such as parasympathetic and sympathetic impairment, has been suggested as possible cause of pre-eclampsia, but the studies are not conclusive. Our purpose was to assess non-invasively if pre-eclampsia is associated with a decreased baroreflex function. Nine women with pre-eclampsia (PE), eight normotensive pregnant women, and seven healthy normotensive non-pregnant women were studied. Continuous finger blood pressure was recorded by a Portapres device in the left lateral recumbent position and active standing. Baroreflex gain was evaluated by cross-spectral analysis of systolic blood pressure and pulse interval. The result was that baroreflex gain at rest was lower in pre-eclamptic women both compared to non-pregnant and healthy pregnant subjects (P<0.05). Moreover, a decrease of the baroreflex sensitivity was present in all pregnant women in the orthostatic position (P<0.05). In conclusion pregnancy per se is associated with a decrease in the baroreflex control of the heart, whereas in pre-eclampsia, the baroreflex sensitivity is impaired further.

Impaired baroreflex function and arterial compliance in primary aldosteronism.

The purpose of this study was to evaluate if changes in vascular properties were related to baroreflex function in patients with primary aldosteronism. Twenty-three patients with primary aldosteronism, 22 essential hypertensive patients and 16 normal controls were studied. Continuous finger blood pressure (BP) was recorded by Portapres device during supine rest and active stand up. Compliance was estimated from the time constant of pressure decay during diastole. Baroreflex sensitivity was calculated by autoregressive cross-spectral analysis of systolic BP and interbeat interval. The result was that baroreflex gain and compliance were lower in primary aldosteronism patients in the supine position (P = 0.002 and P < 0.05 respectively). Aldosterone plasma levels (R2 = 0.31, P = 0.01), age, systolic and diastolic BP, high and low frequency components of diastolic BP variability were independently related to compliance in primary aldosteronism. In conclusion primary aldosteronism is associated with an impaired baroreflex function related in part to a reduced arterial compliance. Despite a reduction of BP values and aldosterone levels, surgical or pharmacological treatment did not significantly change compliance values.

Noninvasive assessment of spontaneous baroreflex sensitivity in patients with liver cirrhosis.

AIMS/BACKGROUND: An impairment of baroreceptor sensitivity has been found in liver cirrhosis. Noninvasive and spontaneous estimates of baroreflex sensitivity are obtained from beat-to-beat blood pressure and heart rate recordings by means of cross-spectrum analysis and calculation of alpha-index (as a measure of baroreflex gain). The aim of the present study was to investigate the function of the spontaneous baroreflex sensitivity related to clinical Child score in liver cirrhosis. METHODS: The alpha-index was evaluated in 40 cirrhotic patients (18 with and 22 without ascites) and 17 healthy subjects by analysing finger arterial pressure recorded noninvasively with the Portapres device. RESULTS: Baroreflex sensitivity was significantly lower in cirrhotic patients with and without ascites compared with healthy subjects (p<0.01). Furthermore, in patients with ascites the baroreflex gain was significantly related to plasma sodium (p<0.01). A significant inverse relationship was present between baroreflex gain and grade of Child score and the severity of ascites (p<0.01). There were no significant relationships between hormonal parameters (catecholamines, renin, aldosterone, arginine-vasopressin, atrial natriuretic peptide and nitric oxide) and baroreflex gain. No significant differences were found between healthy subjects and cirrhotic patients with respect to systolic and diastolic blood pressure total variability in a supine position, whilst it was lower in cirrhotic patients with ascites in a tilted position (p<0.05). CONCLUSION: Our findings showed that baroreflex sensitivity was significantly impaired in cirrhotic patients when compared with healthy subjects. In addition, there was a significant trend toward lower baroreflex sensitivity values with the grade score of Child class (p<0.01). Spectral analysis of the alpha-index provides viable alternatives to the pharmacological approach for estimation of baroreflex sensitivity and may represent a prognostic tool to identify cirrhotic patients at increased risk of adverse events.

Autonomic function and autoantibodies to autonomic nervous structures, glutamic acid decarboxylase and islet tyrosine phosphatase in adolescent patients with IDDM.

Recent studies have linked autoimmunity to nervous tissue structures and diabetic autonomic neuropathy, but data on the early stage of IDDM and on the natural history of this association are not available. For this reason, we investigated autonomic nervous function, and the presence of autoantibodies to sympathetic and parasympathetic nervous structures, to glutamic acid decarboxylase (GAD) and tyrosine phosphatase (IA-2/ICA512) in 85 adolescents with insulin-dependent diabetes mellitus (IDDM) (mean age 14.7+/-1.6 yr, mean duration of diabetes 6.8+/-3.5 yr), and 45 age and sex-matched healthy subjects. Nervous tissues autoantibodies were detected using an indirect immunofluorescent complement-fixation technique, with monkey adrenal gland, rabbit cervical ganglia and vagus nerve as substrates. GAD and IA-2/ICA512 autoantibodies were detected by radioimmunoprecipitation assay. Seven patients (8%) had anti-vagus nerve autoantibodies, 7 other patients (8%) had anti-cervical ganglia autoantibodies, while all controls were negative (P < 0.05). Anti-adrenal medulla antibodies were detected in 16 patients (19%) and in 2 control subjects (P<0.02). None of the patients had autonomic symptoms. When patients were divided according to the presence or absence of autoantibodies, values of the cardiovascular tests (deep breathing, 30:15 ratio, Valsalva ratio) were similar in the two groups and similar to those in healthy subjects. However, when considered together, patients positive for one or more autoantibody showed a trend for lower values of deep breathing test and 30:15 ratio test, compared with healthy control subjects, which failed to reach conventional significance values (P=0.17 and P=0.07, respectively). No correlation was found between cardiovascular parameters and metabolic control or diabetes duration. There was no association between autoimmunity to nervous tissue structures and presence of GAD and IA-2/ICA512 Ab, and no correlation between these two autoantibodies and values of cardiovascular tests. Our data indicate that autonomic dysfunction is not a characteristic of young diabetic patients, but that autoantibodies against autonomic nervous structures are present during the first 1 to 15 yr of diabetes. GAD and tyrosine phosphatase appear to be excluded as target autoantigens within autonomic structures. Follow-up studies are required to evaluate future autonomic dysfunction and symptoms in these patients, and to establish whether the subtle autonomic dysfunction detected and/or the nervous tissue autoantibodies, are predictive of the development of this complication.

Blood pressure and heart rate in young thalassemia major patients.

The analysis of blood pressure (BP) and heart rate (HR) variability is currently used to investigate the mechanisms responsible for cardiovascular control; therefore, we assessed whether an impairment of 24-h BP and HR profiles and sympathovagal interaction modulating cardiovascular function was present in patients with thalassemia major (TM) in preclinical phase of heart disease. Nine beta-thalassemic patients 18 years old without clinical signs of cardiac failure and 9 age- and sex-matched controls were studied. Twenty-four-hour-ambulatory BP and HR were measured using the SpaceLabs 90207 device. A truncated Fourier series with four harmonics was used to describe the diurnal blood pressure profile. Mean 24-h ambulatory systolic BP, diastolic BP, and mean arterial pressure were significantly lower in TM patients than in normal subjects (P < .05). A significantly higher nighttime HR value was found in TM patients (P < .05). More than 40% of the TM patients did not show a significant diurnal BP and HR rhythm. In TM patients, the overall amplitude of systolic BP, diastolic BP, and HR was significantly lower than in controls (P < .01). The night/day differences of systolic BP, diastolic BP, and HR were significantly lower in TM patients than in normals (P < .01). Furthermore, we performed power spectral analysis on short-term continuous finger BP and HR data in supine position and during passive head-up tilt. Total spectral power of systolic BP was significantly lower in patients than controls (P < .05). Low-frequency (LF) power of systolic BP and diastolic BP and LF/high-frequency (HF) ratio of HR were significantly lower during tilt in TM patients compared to controls (P < .05). High-frequency power of HR was significantly higher in patients than controls (P < .05). The baroreflex gain assessed by alpha-index was the same in supine position but was higher in TM patients during passive tilt (P < .05). An inverse relationship between LF/HF ratio of HR and hemoglobin levels in TM patients was found. Finally, plasma norepinephrine levels were significantly lower in thalassemics (P < .005). In young TM patients in a preclinical stage of heart disease, these findings demonstrated abnormal 24-h BP and HR rhythms and a decreased short-term variability of BP and HR, in particular in the LF range, showing a diminished sympathetic activity.

Evaluation of serotonin levels in human aqueous humor.

PURPOSE: Serotonin is biochemically present in the iris and ciliary body of animals and humans. Controversial findings are reported about the concentrations of serotonin in aqueous humor with respect to plasma in humans. The aim of this study was to evaluate the levels of serotonin both in aqueous humor and plasma in human subjects. METHODS: In 50 patients with glaucoma or cataract, plasma and aqueous humor serotonin levels were measured by HPLC with electrochemical detection. Serotonin plasma levels were also measured in 25 healthy subjects as controls. RESULTS: In all patients with cataract or glaucoma, the aqueous humor serotonin concentration is significantly lower than that in plasma [1.14+/-0.29 (SEM) vs. 5.33+/-1.03 ng/ml, p<0.01]. Furthermore, in the same patients and in 25 healthy controls, serotonin plasma levels were similar. CONCLUSION: Our study shows that serotonin is present in human aqueous humor and its concentration is 4 times lower than in plasma.

Differential Response in Left Ventricular Mass and Arterial Resistive Index following Fosinopril Therapy.

The aim of this study was to assess the differential response in left ventricular mass and resistive index (RI) of renal and carotid arteries in mild to moderate essential hypertensive patients after 1 year of ACE inhibitor therapy. Twenty-six patients (mean age 42.9 +/- 10.9 years) underwent 24-hour ambulatory blood pressure monitoring, echocardiography and renal and carotid echo-Doppler (by measuring RI, as an expression of arterial impedance) after a placebo period and 12 months of fosinopril treatment (20 mg/day). Our study showed a significant decrease in 24-hour BP (p < 0.05), left cardiac mass (p < 0.05) and RI of common carotid and hilum renal arteries (p < 0.05). In contrast, there were no significant reductions in the interlobar renal RI (as an expression of unchanged intrarenal resistance) and in the internal carotid artery RI. While the 24-hour BP decrease was strongly correlated with the left cardiac mass modifications (r = 0.73, p < 0.005), no significant relationship was observed with the renal and carotid artery parameters. In conclusion, the present study demonstrated that long-term treatment with fosinopril produced a differential response in left ventricular mass and arterial RI in patients with mild to moderate essential hypertension. In addition, the arterial impedance modifications of common carotid and hilum renal artery were largely unrelated to the 24-hour BP reduction.

Autonomic nervous dysfunction in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA): possible pathogenic role of autoantibodies to autonomic nervous structures.

Autonomic nervous dysfunction has been previously reported in SLE, RA and systemic sclerosis, but the pathogenesis of such a complication is poorly understood. In the present study, four standard cardiovascular autonomic function tests were performed in 34 female patients with connective tissue diseases and in 25 healthy control subjects, and results expressed as cardiovascular (CV) test scores. Moreover, in each subject the presence of circulating complement-fixing autoantibodies directed against sympathetic and parasympathetic nervous structures, represented by superior cervical ganglia and vagus nerve, respectively, was simultaneously assessed by an indirect immunofluorescent complement-fixation technique, using rabbit tissue as substrate. None of the patients reported autonomic symptoms. However, an abnormal CV test score (> or = 5) was detected in 15% of the patients and in none of the healthy control subjects, approaching statistical significance (P = 0.07). No correlation was found between CV test results and disease duration, type of therapy or presence of conventional autoantibodies. One or two autoantibodies to autonomic nervous structures were detected in six patients (18%) and not in the control subjects (P < 0.05). Values of deep breathing test were significantly lower in autoantibody-positive patients compared with those amongst the control subjects (P < 0.05), and an abnormal CV test score was significantly associated with the presence of autoantibodies to autonomic nervous structures (P < 0.05). In conclusion, we confirm that autonomic nervous function can be impaired in patients with connective tissue diseases, and suggest that autoantibodies directed against autonomic nervous system structures may play a role in the pathogenesis of the autonomic dysfunction.

Impaired cortisol binding to glucocorticoid receptors in hypertensive patients.

We compared glucocorticoid receptor binding characteristics and glucocorticoid responsiveness of human mononuclear leukocytes (HML) from hypertensive patients and matched normotensive volunteers. We also considered associations of these variables with plasma renin activity, aldosterone, cortisol, corticotropin, and electrolyte concentrations. We calculated binding affinity (Kd; nmol/L) and capacity (Bmax; sites/cell) for dexamethasone and cortisol from homologous and heterologous competition curves for specific [3H]dexamethasone binding sites on HML isolated from the blood of normotensive volunteers and subjects with essential hypertension. Glucocorticoid responsiveness of HML was evaluated as IC50 values (nmol/L) for dexamethasone and cortisol for the inhibition of lysozyme release. We measured plasma hormones by radioimmunoassay. Kd values (mean+/-SE) for cortisol in HML of hypertensive patients were higher than in control subjects (24.6+/-2.4 versus 17.5+/-1.7 nmol/L, P<.04). Binding capacity (4978+/-391 versus 4131+/-321 sites/cell), Kd values for dexamethasone (6.7+/-0.5 versus 5.7+/-0.3 nmol/L), and IC50 values for dexamethasone (3.4+/-0.3 versus 3.1+/-0.2 nmol/L) and cortisol (12.2+/-1.6 versus 9.5+/-0.3 nmol/L) were not significantly different. Patients with renin values less than 0.13 ng angiotensin I/L per second were markedly less sensitive to cortisol than those with higher values. Both Kd (30.3+/-2.5 versus 19.2+/-2.4 nmol/L) and IC50 values (15.5+/-1.8 versus 8.9+/-1.2 nmol/L) for cortisol were significantly higher in patients with lower renin values (P<.03). Other variables, including plasma hormone and electrolyte values and binding characteristics for dexamethasone, were not different. These data suggest that cortisol binding to glucocorticoid receptor is slightly impaired in patients with essential hypertension. In vivo, this could lead to inappropriate binding of cortisol to mineralocorticoid receptors. Hence, decreased sensitivity to cortisol is associated with renin suppression. This hypothesis is supported by evidence of hypertension and low renin activity, which others have described in patients with primary glucocorticoid resistance due to mutations of the glucocorticoid receptor.