Lymphocyte Beta-adrenoceptor Research Articles

Defective Adrenergic Responses in Patients With Arsenic-induced Peripheral Vascular Disease

Blackfoot disease is an endemic arsenic-induced peripheral vascular disease in southern Taiwan. The main pathologic feature is atherosclerosis, which may relate to imbalances of the adrenergic system. The purpose of this study is to investigate the peripheral adrenergic responses of patients with blackfoot disease. Eight patients with blackfoot disease and four age-matched healthy controls were enrolled in this study. Baseline cutaneous perfusion was measured with a laser Doppler flowmeter. The response of alpha-adrenoceptors in the cutaneous microcirculation was assessed with laser Doppler flowmetry with iontophoresis of phenylephrine into the nailfold. In vitro binding with (125)I-cyanopindolol determined beta-adrenoceptor density in lymphocytes. The cyclic adenosine monophosphate (cAMP) level at baseline and after isoproterenol stimulation reflects lymphocyte beta-adrenergic responsiveness. Results revealed persistently decreased skin perfusion in patients with blackfoot disease. In contrast, there was a transient decrease in skin perfusion in healthy controls after iontophoresis of phenylephrine. Both beta-2 receptor density and isoproterenol-stimulated cAMP levels in lymphocytes decreased. Increased peripheral alpha-adrenergic response and decreased beta-2-adrenergic response are related to increased vascular tone and result in atherosclerosis. Our findings of accentuated alpha-adrenergic response in microcirculation and decreased lymphocyte beta-2-adrenoceptor response play an important role in the pathogenesis of atherosclerosis in blackfoot disease.

International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children

Heart failure (HF) in the United States is well recognized as a major public health problem, with over 900,000 hospital admissions annually in the United States, and greater than 250,000 deaths per year. The great majority of heart failure occurs in adults. In children, the scope of the problem is less well defined, but recent data from the Pediatric Cardiomyopathy Registry suggest an annual incidence of 1.13 cases of cardiomyopathy per 100,000 children. 1 While some of this represents asymptomatic disease, the burden of disease overall is nonetheless quite high. In the Pediatric Cardiomyopathy Registry, the majority of children with cardiomyopathy also had HF, with mortality rates of 13.6% at 2 years in dilated forms of cardiomyopathy. The etiology of heart failure differs greatly between children and adults. Children in the Pediatric Cardiomyopathy Registry had a recognizable syndrome or genetic diagnosis in 27% of cases, with an additional 5% of cases due to myocarditis. Furthermore, a large percentage of children with end-stage HF (between 25% and 75%, depending upon the age group) have an underlying diagnosis of congenital heart disease. 2 In contrast to adult patients, ischemic heart disease is rare in children. There is a large, and rapidly growing literature addressing HF treatment for adult patients, with a much smaller literature concerning HF therapy in children. Excellent guidelines for adult patients have recently been published, but given the significant differences between adult and pediatric patients with HF, there is little reason to believe that these guidelines are directly applicable to children. 3 Accordingly, in this document we have attempted to summarize the relevant literature and synthesize management guidelines for children with HF. The document that follows has been prepared in a consensus fashion, with input from pediatric cardiologists at multiple sites throughout the United States and Canada.

Regulation of the Catecholamine .BETA.-Adrenergic System in Ventricular Remodeling of Hypertension

Differences in structural remodeling are believed to be influenced by hormonal systems in hypertension. The objective of the present study was to investigate the change in the circulating catecholamine beta-adrenergic system in the left ventricle remodeling process in hypertensives. One hundred and thirty-four men (mean age, 53 years) had essential hypertension and underwent echocardiography before treatment. Normal morphology (n = 26) and concentric remodeling (n = 41) were defined by a relative wall thickness at diastole (RWT) of < 0.44 and > or = 0.44, respectively, and concentric hypertrophy (n = 28) and eccentric hypertrophy (n = 39) by a left ventricular mass index (LVMI) of < 150 g/m(2) and > or = 150 g/m(2), respectively. Forty healthy males were studied as normal controls. Plasma levels of norepinephrine (NE) and epinephrine (E) were measured by high performance liquid chromatography. The density of lymphocyte beta-adrenoceptors (beta-AR) and the content of intralymphocyte cyclic AMP (cAMP) in peripheral blood were measured using (3)H-dihydroalpneol as a ligand and protein binding assay, respectively. The plasma levels of NE and E in the 4 groups of patients with essential hypertension were significantly increased compared with the control group. The density of lymphocyte beta-AR and the content of intralymphocyte cAMP of peripheral blood in the normal morphology, concentric remodeling, and concentric hypertrophy groups were significantly higher than those in the control group, while the values in the eccentric hypertrophy group were significantly lower than those in the control group. Among the 4 groups, the plasma levels of NE and E had increased the most in the normal morphology group, followed in decreasing order by the concentric remodeling, concentric hypertrophy, and eccentric hypertrophy groups; the density of lymphocyte beta-AR and the content of intralymphocyte cAMP of peripheral blood in the normal morphology, concentric remodeling, and concentric hypertrophy groups increased while they decreased in the eccentric hypertrophy group in patients with essential hypertension. The catecholamine beta-adrenergic system appears to be related to left ventricular remodeling of hypertension. In this process, catecholamines increased continually. The density of beta-AR and the content of cAMP in peripheral lymphocytes increased at first and then decreased.

Changes and significance of subtype function of beta-adrenoreceptors in left ventricular remodeling of hypertension.

Changes in the density of myocardium and blood lymphocyte beta-adrenoceptors (beta-AR) in left ventricular (LV) geometry have been found in patients with essential hypertension (EH). However, it is not known whether intrinsic beta-AR subtype function changes during left ventricular remodeling of hypertension. The purpose of this study was to further investigate the changes and clinical significance of beta-AR subtype function in LV remodeling in patients with EH. One hundred and thirty-four men (mean age, 53 years) with EH as defined in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure grades 1 to 2 and 40 normotensives were studied. Based on the echocardiographic LV mass index and relative wall thickness, four patterns of LV geometry, ie, normal left ventricle, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy were identilied. beta-Adrenoreceptor subtype responsiveness was measured by a treadmill exercise test (to measure cardiac beta1-adrenoreceptor responsiveness) and by Salbutamol injection test (to measure cardiac beta2-adrenoreceptor responsiveness) in 134 male patients with EH. Forty normotension subjects were also studied as controls. In patients with EH in the groups of concentric remodeling, concentric hypertrophy, and eccentric hypertrophy, heart rate in response to the treadmill test (peak exercise-resting rate) was significantly higher (P < 0.05, P < 0.01. P < 0.01, respectively) than that in the control group. In the concentric remodeling and concentric hypertrophy group, the chronotropic doses of salbutamol required to increase the heart rate by 30 beats/min (CD30) were significantly lower (P < 0.05, P < 0.01, respectively) than that in the control group. However, in the eccentric hypertrophy group. CD30 was higher significantly (P < 0.01) than that in the control group. In the concentric remodeling, concentric hypertrophy, and eccentric hypertrophy groups, beta1-AR responsiveness significantly increased them in the normotensive group, whereas beta2-AR responsiveness significantly increased in the concentric remodeling and concentric hypertrophy groups them in the normotensive group, and significantly decreased in the eccentric hypertrophy them in the normotensive group. The results suggest that non-beta-selective blocker may be beneficial for normal morphology, concentric remodeling and concentric hypertrophy, while beta1-selective blockers may be beneficial for eccentric hypertrophy in patients with EH.

Regulation of equine lymphocyte beta-adrenoceptors under the influence of clenbuterol and dexamethasone.

In 12 healthy horses, the effects of the beta2-agonist clenbuterol and the glucocorticoid dexamethasone on the lymphocyte beta2-adrenoceptor density and affinity (determined by (-)-[125I]-iodocyanopindolol binding) as well as its responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 micromol/l (-)-isoprenaline) were studied. Clenbuterol treatment, 2 x 0.8 microg/kg/day i.v. for 12 days, decreased significantly ICYP binding sites by approximately 30-40%; concomitantly, lymphocyte cAMP response to (-)-isoprenaline was reduced. After withdrawal of clenbuterol, beta2-adrenoceptor density and responsiveness gradually increased, reaching predrug levels after 4 days. The effects of dexamethasone on clenbuterol-induced desensitisation were further investigated. Administration of dexamethasone (1 x 0.1 mg/kg/day, i.v. for 5 days) immediately after clenbuterol withdrawal accelerated beta2-adrenoceptor recovery: only 24 h after administration dexamethasone restored the number of binding sites and cAMP response to (-)-isoprenaline to levels statistically indistinguishable from values before clenbuterol treatment. Three days after dexamethasone administration, lymphocyte beta2-adrenoceptors were further increased about 2-fold the pretreatment values, and this increase declined gradually after dexamethasone withdrawal, reaching baseline values after 4 days. Furthermore, in groups exposed simultaneously to both drugs, dexamethasone completely prevented clenbuterol-induced decrease in lymphocyte beta2-adrenergic receptor density and responsiveness. No significant change was observed in the dissociation constant for ICYP in any of the situations. We conclude that dexamethasone (glucocorticoids) can reverse and prevent Clenbuterol-induced desensitisation (down-regulation) of the lymphocyte beta2-adrenoceptors and therefore, a combined therapy with clenbuterol and dexamethasone may be potentially beneficial in horses suffering from chronic obstructive pulmonary disease (COPD).

Lymphocyte glucocorticoid receptor mRNA correlates negatively to serum leptin in normal weight subjects.

The aim of the present study was to test the hypothesis that glucocorticoid receptor mRNA concentrations decreased with increasing fatness in normal subjects. Serum leptin concentrations, fat distribution parameters, lymphocyte glucocorticoid (GCR) mRNA, beta2-adrenoceptor mRNA and c-fos mRNA concentrations measured by RT-PCR-HPLC. Fifteen healthy non-obese young subjects with a mean body mass index (BMI) of 23. 5+/-0.3 (+/-s.e.m.) kg/m2. Lymphocyte GCR and beta2-adrenoceptor mRNA concentrations averaged 4.2+/-0.2 (+/-s.e.m. ) amol/microg total RNA and 1.4+/-0.1 amol/microg total RNA, respectively. There was a significant negative correlation between serum leptin and lymphocyte GCR mRNA (P<0.01). Serum leptin correlated positively with the waist-hip ratio (P<0.03), whereas lymphocyte GCR mRNA correlated negatively to the waist-hip ratio (P<0.04). Serum cortisol correlated with the weight of the subjects but not the waist-hip ratio or GCR mRNA. It is suggested that the decrease in lymphocyte GCR mRNA concentration with increasing serum leptin concentrations is a counterregulatory response to an increased body fat content. Further studies are warranted, especially to elucidate the relationship between GCR mRNA in lymphocytes and in fat cells and to clarify the mechanism of the decrease in GCR mRNA.

Apoptosis of peripheral blood lymphocytes is induced by catecholamines.

We explored the mechanism through which patients sometimes show immunosuppression after cardiac surgery. To test the hypothesis that commonly used drugs could cause apoptosis of immune cells, the proapoptotic effects of heparin and catecholamines (dopamine and dobutamine) on peripheral blood lymphocytes were evaluated. Peripheral blood lymphocytes were purified from blood samples of normal healthy volunteers. These cells were cultured in the presence of heparin, dobutamine or dopamine. The apoptosis was quantified by Annexin V fluorescent assay, by DNA content and by morphological assessment. Lymphocytes did not show significant levels of apoptosis induction after 24 hours of incubation with heparin. Both dopamine and dobutamine demonstrated a clear apoptosis inducing effect on lymphocytic population after 24 and 48 hours of culture, in concentrations comparable with the clinically used levels. Apoptosis was time and concentration dependent for both catecholamines. The dopamine and dobutamine effect on lymphocyte viability was due, at least partially, to lymphocyte beta receptor engagement, as proved by blocking the receptor with propranolol. These results suggest that catecholamines could induce apoptosis of lymphocytes. This finding may be associated with immunosuppression observed in patients undergoing cardiac surgery.

A Bolus of Inhaled Budesonide Rapidly Reverses Airway Subsensitivity and β2-Adrenoceptor Down-regulation After Regular Inhaled Formoterol

Subsensitivity of airway beta2-adrenoceptors develops readily in asthmatics receiving regular long-acting beta2-agonists. This subsensitivity may be rapidly reversed by using systemic corticosteroids. The purpose of the present study was to investigate whether the same acute facilitatory effects occur when using a bolus dose of inhaled corticosteroid. Ten subjects with stable mild-to-moderate asthma, with a mean age of 27 years, mean (+/- SD) FEV1 of 2.95 L (0.94 L), 81% (15%) of predicted, all receiving inhaled corticosteroids, reactive to adenosine monophosphate (AMP) with a provocative concentration producing a 20% fall in FEV1 (PC20) < 200 mg/mL, were recruited into a randomized double-blind crossover study. The subjects received two separate 1-week treatment periods with formoterol dry powder, 24 microg bid, with an initial 1-week run-in and a 1-week washout period between the treatments. A single dose of placebo or budesonide turbuhaler, 1,600 microg, was taken in conjunction with the last dose of both treatment periods. AMP challenge was performed 2 h after the first and last dose of formoterol. Blood for lymphocyte beta2-adrenoceptor density (Bmax) was also measured before and after treatment with formoterol. There was no significant difference in the geometric mean PC20 after the first dose of formoterol comparing the two treatment periods: 362 mg/mL vs 391 mg/mL. The PC20 after the last dose of formoterol was significantly higher (p < 0.05) in conjunction with budesonide than with placebo: 427 mg/mL vs 99 mg/mL, amounting to a 4.3-fold difference (95% confidence interval [CI], 1.1 to 16.6). For comparison within each treatment period, there was significant subsensitivity (p < 0.05) between the first and last dose of formoterol when the latter was given with placebo: 391 mg/mL vs 99 mg/mL, a 3.9-fold fall (95% CI, 1.0 to 15.2), but not when the latter was given with budesonide: 362 mg/mL vs 427 mg/mL, a 1.2-fold rise (95% CI, 0.5 to 2.8). Lymphocyte 02-adrenoceptor density (geometric mean Bmax: fmol/10(6) cells) also showed significant down-regulation (p < 0.05) by formoterol given with placebo: preformoterol 2.53 vs postformoterol 1.91, but not by formoterol given with budesonide: preformoterol 2.43 vs postformoterol 2.67. The Bmax was significantly higher (p < 0.05) with formoterol + budesonide as compared to formoterol + placebo, amounting to a 1.40-fold difference (95% CI, 1.09 to 1.80). We have shown that a bolus dose of inhaled budesonide rapidly reverses subsensitivity to AMP bronchoprotection and associated beta2-adrenoceptor down-regulation in asthmatics taking regular formoterol. Further studies are indicated to assess whether high-dose inhaled corticosteroids should be administered as soon as possible along with beta2-agonists during an acute episode of bronchoconstriction.

Effects of Genetic Polymorphism on Ex Vivo and In Vivo Function of β2-Adrenoceptors in Asthmatic Patients

Genetic polymorphism determines agonist-induced down-regulation and desensitization of beta2-adrenoceptors. The aim of the present study was to investigate the effects of genetic polymorphism on ex vivo (lymphocytes) and in vivo (bronchoprotection) function of beta2-adrenoceptors in asthmatic patients, having been washed out of previous beta2-agonist exposure. Sixty patients with stable mild-to-moderate asthma were evaluated, with a post hoc analysis of genotype performed at end of study. Having withheld treatment with long-acting beta2-agonists for > or = 48 h and short-acting beta2-agonists for > or = 12 h, measurements of lymphocyte beta2-adrenoceptors were made for binding density, binding affinity, basal cyclic adenosine monophosphate (cAMP), and maximal cAMP response to isoproterenol (Emax). In addition, in 48 of these patients who were methacholine responsive (PD20 < 1,000 microg), the acute protective effect of formoterol as a 24-microg single dose (at 1 h) was also evaluated. Comparisons were made according to homozygous and heterozygous (Het) polymorphisms at codon 16 and codon 27. There were no significant differences in age, FEV1 percent predicted, or inhaled corticosteroid dose, when comparing mean values for polymorphisms at either codon-16 or codon 27. There were also no significant differences between polymorphisms for any of the measured lymphocyte beta2-adrenoceptor parameters apart from basal cAMP between Glu-27 and Het-27. Mean values for Emax (after-before isoproterenol as pmol/10(6) cells) were as follows: Gly-16 (3.4), Arg-16 (3.5), Het-16 (4.0), Glu-27 (3.9), Gln-27 (3.5), and Het-27 (3.7). Polylorphism had no significant effect on formoterol protection as doubling dose shift in methacholine PD20 (geometric mean): Gly-16 (5.3), Arg-16 (5.4), Het-16 (4.6), Glu-27 (5.3), Gln-27 (5.3), Het-27 (4.5). Our results show that genetic polymorphism at codon 16 or 27 does not influence stimulated coupling of lymphocyte beta2-adrenoceptors and similarly did not influence the degree of functional antagonism exhibited by formoterol. Thus, a single dose of beta2-agonist when used on demand affords equal protection against bronchoprotection regardless of genetic polymorphism.

β2-Adrenoceptor Regulation and Function in Female Asthmatic Patients Receiving the Oral Combined Contraceptive Pill

Previously it has been shown that there is abnormal hormonal control of beta2-adrenoceptors in asthmatic women. Exogenous progesterone but not estradiol produces paradoxic downregulation and desensitization of beta2-adrenoceptors in asthmatic women when compared with nonasthmatic subjects. This study investigates the effect of the oral combined contraceptive pill (OCP) on beta2-adrenoceptor regulation and function in female asthmatic patients. The study population was comprised of 11 women with stable mild to moderate asthma. The mean age was 25 years; the FEV1 was 89% of predicted, and the forced expiratory flow, mid-expiratory phase (FEF25-75%) was 69% of predicted. Patients were evaluated while on (day 20 to 21) and off (day 5 to 7) the OCP during a 28-day calendar period. Serum sex hormones, lymphocyte beta2-adrenoceptor parameters, and bronchodilator and systemic dose-response curves (DRCs) to albuterol (Salbutamol) (100 to 1,600 microg) were measured at both on and off periods. Serum levels of endogenous estradiol and progesterone were both suppressed by the OCP. Baseline FEV1 were not different while patients were on (2.70 L) and off (2.72 L) the OCP. There were no significant differences in lymphocyte beta2-adrenoceptor parameters between the two phases of the cycle. Receptor density (geometric mean Bmax) was 1.78 (on OCP) vs 1.86 (off OCP) fentomole/10(6) cells, maximal cyclic adenosine monophosphate response to isoprenaline was 6.60 (on OCP) vs 7.58 (off OCP) pmol/10(6) cells, and binding affinity was 14.0 (on OCP) and 13.6 (off OCP) pmol/L. Likewise, there were no significant differences in the bronchodilator and systemic DRCs constructed at both phases of the cycle as evaluated: area-under-curve (AUC) FEV1 was 0.53 (on OCP) vs 0.56 (off OCP) L.h; and AUC FEF25-75% was 3,130 (on OCP) vs 3,640 (off OCP) L. Potassium (K) and finger tremor responses were unaltered between the two periods: AUC K was 0.50 (on OCP) vs 0.44 (off OCP) mmol . h/L and AUC tremor was 0.72 (on OCP) vs 0.89 (off OCP) log units.h. The OCP did not alter beta2-adrenoceptor regulation and function in stable female asthmatic patients. Further studies are required in patients who have premenstrual asthma.

Chronic terbutaline treatment desensitizes beta-adrenergic inhibition of lymphocyte activation in healthy volunteers.

1. A substantial body of evidence has accumulated that beta-adrenoceptor mediated increases in human lymphocyte cyclic AMP can inhibit activation of resting lymphocytes. The aim of this study was to determine whether this effect might desensitize during chronic beta-adrenoceptor agonist treatment. We assessed the effects of 2 weeks treatment with the beta 2-adrenoceptor agonist terbutaline (3 x 5 mg day-1 p.o.) on isoprenaline-induced inhibition of concanavalin A-evoked lymphocyte activation in nine healthy male volunteers. Lymphocyte activation was determined by [3H]-thymidine incorporation (as a measure of proliferation), and inositol phosphate formation was assessed in [3H]-myo-inositol prelabelled lymphocytes in the presence of 10 mM LiCl. 2. Terbutaline treatment caused a significant reduction in isoprenaline (1 nM-10 microM)-induced increases in lymphocyte cyclic AMP content; the maximal increase was 14 +/- 3 pmol/10(6) cells before and 7 +/- 2 pmol/10(6) cells (n = 9, P < 0.05) after terbutaline treatment. 3. The mitogen concanavalin A (Con A, 1-32 micrograms ml-1)-induced increase in inositol phosphate formation was significantly enhanced after terbutaline treatment (max. increase before treatment: 255 +/- 25% above basal; after treatment 453 +/- 16% above basal; n = 9, P < 0.001), while isoprenaline (1 nM-10 microM)-induced inhibition of Con A (16 micrograms ml-1)-evoked increases in inositol phosphate formation was significantly reduced after the terbutaline treatment (max. inhibition before treatment: 22 +/- 4%; after treatment 9 +/- 1%, n = 9, P < 0.01). 4. Con A (1.25-10 micrograms ml-1)-induced increases in [3H]-thymidine incorporation into the lymphocytes (as a measure of proliferation) was not affected by the terbutaline treatment. On the other hand, isoprenaline (1 nM-1 microM)-induced inhibition of Con A (5 micrograms ml-1)-evoked lymphocyte proliferation (max. inhibition: 33 +/- 7%, n = 9) was almost completely abolished after the terbutaline treatment. 5. We conclude that chronic treatment with terbutaline desensitizes lymphocyte beta 2-adrenoceptors and, therefore, the inhibitory effect of cyclic AMP on lymphocyte activation.

Autonomic nervous system and adrenergic receptors in chronic hypotensive haemodialysis patients.

The pathophysiology of chronic hypotension (CH) in uraemia is not elucidated. The possible role of autonomic nervous system dysfunction and adrenoceptor alterations in the pathophysiology of CH in uraemia was evaluated in this study. Seventeen hypotensive haemodialysis (HD) patients, 17 normotensive HD patients, and 17 control subjects were studied. We evaluated the integrity of the baroreflex arc (Valsalva manoeuvre), the parasympathetic efferent pathway ('deep-breathing test') and the sympathetic efferent pathway ('hand-grip test'). We also evaluated platelet alpha 2-adrenoceptor and lymphocyte beta 2-adrenoceptor densities (radioligand binding assay), and beta 2-adrenoceptor response (intracellular cAMP generation after isoproterenol stimulation in lymphocytes). Responses to the Valsalva manoeuvre and the deep-breathing test were altered in all HD patients (P < 0.05). Valvalva ratio was lower in hypotensive patients than in normotensive patients (P < 0.01), whereas the pressor response to the hand-grip test was reduced only in hypotensive HD patients (P < 0.01). In haemodialysed patients, basal mean blood pressure (MBP) correlated with MBP increases during the hand-grip exercise (r = 0.59, P < 0.01). Plasma catecholamine levels were elevated in both groups of patients (P < 0.025). Plasma adrenaline levels were higher in hypotensive HD patients than in normotensive patients (P < 0.05). alpha 2- and beta 2-adrenoceptor densities and beta 2-adrenoceptor response were reduced in hypotensive patients (P < 0.05 vs normotensive patients). MBP correlated with alpha 2-adrenoceptor (r = 0.46, P < 0.01) and beta 2-adrenoceptor (r = 0.43, P < 0.025) densities in HD patients. Normotensive haemodialysed patients have increased plasma catecholamine levels with preserved alpha 2- and beta 2-adrenoceptor numbers, as well as beta 2-adrenoceptor responses. In hypotensive patients, plasma adrenaline levels were even higher; the increased plasma catecholamine levels induced an alpha 2- and beta 2-adrenoceptor downregulation. This downregulation may play a role in the reduced cardiovascular responses to adrenergic stimuli reported in hypotensive HD patients.

Alterations of cardiac and lymphocyte β- adrenoceptors in rat with chronic heart failure

The alterations of cardiac and lymphocyte beta-adrenoceptors were observed in the rats with chronic heart failure produced by constriction of both abdominal aorta and renal artery. The results showed that beta(1)-adrenoceptor density and mRNA levels were increased, whereas these levels remained unchanged for beta(2). The concentrationcontractile response curve for isoproterenol was shifted m the right in cardiac atrium, whereas the concentration-CAMP accumulation response curve for isoproterenol in myocardium was not changed. The number of beta-adrenoceptom in blood lymphocyte was markedly reduced. Thus in the heart-failure rats the density of cardiac beta-adrenoceptor was increased accompanying reduced beta-adrenoceptormediated positive inotropic response, suggesting a post adenylate cyclase dysfunction or impaired contractile components. In contrast, the alteration of beta-adrenoceptor in lymphocyte is consistent with the reduced beta-adrenoceptor-mediated inotropic response in heart.

Paradoxical Down-Regulation and Desensitization of β2-Adrenoceptors by Exogenous Progesterone in Female Asthmatics

We have demonstrated previously that exogenous progesterone, but not estrogen, up-regulated lymphocyte beta2-adrenoceptors (beta2-AR) when given during the follicular phase in healthy women. Female asthmatics exhibit loss of the cyclical pattern of beta2-AR regulation seen in healthy women, in that there is no luteal phase rise in beta2-AR. It has been postulated that abnormal cyclical regulation of beta2-AR might be a possible mechanism for premenstrual asthma. In this study, we were interested to see how exogenous female sex-steroid hormones altered beta2-AR regulation in female asthmatics during the follicular phase, when endogenous hormone levels are normally low. Seven nonsmoking female subjects with mild asthma, with a mean (SEM) age of 26 (2) years and FEV1 of 94.7% (6.4) of predicted, completed this randomized, double-blind, crossover study. They were evaluated at two successive menstrual cycles, during the follicular phase (day 1 to 6). They were randomized to receive single oral doses of either ethinyl estradiol (ethinyloestradiol), 50 microg, or medroxyprogesterone, 10 mg. Lymphocyte beta2-AR parameters were evaluated at baseline (T0), 24 h (T24), and 72 h (T72) after ingestion. Baseline levels of progesterone and estradiol were comparable on both cycles. Receptor binding density (log Bmax; fmol/10(6) cells) decreased significantly after progesterone but not after estrogen at T24: amounting to a 1.34-fold mean difference (95% confidence interval [CI], 1.01 to 1.78) between T24 vs T0 with progesterone. Comparing Bmax for progesterone with estrogen at T24 amounted to a 1.25-fold significant difference (95% CI, 1.00 to 1.56). This was associated with a trend (p=0.06) toward a lower cyclic-adenosine monophosphate (AMP) response to isoproterenol hydrochloride (isoprenaline) 10(-4) M (Emax) at T24 vs T0 with progesterone. Receptor binding affinity (Kd) was not altered by either treatment. These results show that exogenous progesterone, but not estrogen, given during the follicular phase, decreased beta2-AR density and cyclic-AMP response in female asthmatics, in contrast to the previously observed up-regulating effect of progesterone seen in healthy women. This paradoxical effect of progesterone in female asthmatics suggests an abnormal regulation of beta2-AR and might be a possible mechanism for premenstrual asthma when progesterone levels are high during this period of the cycle.

Circulating noradrenaline and beta-adrenergic receptors in children with congestive heart failure.

This study was designed to investigate changes in plasma catecholamine concentrations and the number of beta-adrenoceptors (beta-AR) of circulating lymphocyte in 94 noncyanotic congenital heart patients. In 43 patients with congestive heart failure, beta-AR density was significantly lower (p < 0.001) and plasma noradrenergic levels were significantly higher (p < 0.001) compared with corresponding values in 51 patients without heart failure. A significant negative correlation between lymphocyte beta-AR density and plasma noradrenergic levels was observed (r = -0.61, p < 0.001). The degree of left-to-right shunt and pulmonary pressure was correlated directly with noradrenaline level and inversely with lymphocyte beta-AR density. Both plasma noradrenaline level and lymphocyte beta-AR density return to normal in children with heart failure after surgical repair. Our results support the idea that changes in noradrenaline level and lymphocyte beta-adrenoceptor density occur concurrently with the presence and severity of heart failure in children.

Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients

In view of current concerns about use of regular beta-2 agonists, and the place of the newer long-acting drugs, we decided to evaluate whether continuous exposure to twice daily salmeterol results in a blunting of the acute bronchodilator response to repeated doses of salbutamol, as might be administered in the management of an acute asthma attack. After a 2 week run-in without beta-2 agonists, 17 asthmatic patients (mean [SE] age 34 [3] years, mean forced expiratory volume in 1 s [FEV 1] 64 [2·7]% of predicted) were randomised to receive salmeterol 50 μg twice daily or placebo for 4 weeks in a double-blind crossover fashion. A histamine challenge test was done 12 h after the last dose of each treatment period, and dose-response curves to inhaled salbutamol (200-3200 μg) were constructed 36 h after the last dose. Patients treated with salmeterol had reduced bronchodilator responses to salbutamol in terms of FEV 1 and peak expiratory flow rate (PEFR) than those treated with placebo. The reduction in response equated with a 2·5-fold and a fourfold greater dose of salbutamol being required to produce a given FEV 1 and PEFR, respectively. There was a significant reduction in lymphocyte beta-2 adrenoceptor density after salmeterol compared with placebo and run-in. Salmeterol remained effective in terms of disease control, with a significant improvement in morning PEFR compared with placebo that was maintained over the 4 week treatment period. Continuous exposure to salmeterol 50 μg twice daily results in subsensitivity to the acute bronchodilator response to repeated doses of inhaled salbutamol. Thus patients receiving regular treatment with salmeterol might require higher doses of salbutamol when used for relief of acute bronchoconstriction.

Plasma Catecholamines, Thrombocyte Alpha 2- and Lymphocyte Beta 2-Adrenoceptor Densities in Hypertensive Patients with Low or Normal Plasma Renin Concentrations

The sympathetic nervous system is unique in the regulation of plasma renin, for it can stimulate or suppress renin release by activation of either renal beta- or alpha 2-adrenoceptors. The authors studied plasma renin concentration (PRC), noradrenalin and adrenalin levels in plasma, and the densities of lymphocyte beta 2-adrenoceptors and thrombocyte alpha 2-adrenoceptors in 25 hypertensive patients with either normal (11-40 mU/L; n = 9) or low PRC (0-10 mU/L; n = 14). There were no differences in plasma catecholamine levels and adrenoceptor densities between the two patient groups. A positive correlation (r = 0.66; P < 0.005) between beta 2-adrenoceptor density and PRC in the patient group with low PRC, and a negative correlation (r = -0.72; P < 0.01) between alpha 2-adrenoceptor density and plasma renin in patients with normal PRC were found. They conclude that adrenoceptor densities on blood elements and plasma catecholamines do not differ in low and normal renin hypertension. The significant correlations between adrenoceptor densities and PRCs may indicate that adrenoceptors on blood elements mirror adrenoceptor densities in the kidney and that tonic suppression of renin release through alpha 2-adrenoceptors is preserved in hypertensive patients with normal plasma renin levels.

The relationship between changes in lymphocyte and myocardial beta-adrenoceptor function in volume overloaded patients

The relationship between changes in lymphocyte and myocardial beta-adrenoceptor function in volume overloaded patients

Effects of energy restriction on acute adrenoceptor and metabolic responses to exercise in obese subjects.

This study was intended to investigate the effects of energy restriction on the acute responses of platelet alpha 2- and lymphocyte beta 2-adrenoceptors to exercise in obese female subjects. Seven obese females were restricted to a low-energy formula diet (2.0 MJ/day) for 4 wk. As result of the diet, there was a 7.8-kg weight loss. No significant changes could be detected in sleeping and resting metabolic rate expressed per kilogram fat-free mass. Basal venous glucose, insulin, and norepinephrine levels decreased as a result of the diet, whereas free fatty acid values increased. Before the diet, 60 min of exercise (45% peak mechanical power) caused no alteration in the density of lymphocyte beta 2-adrenoceptors. At the end of 4 wk of dieting, the density was significantly increased in response to exercise, together with a higher thermogenic and lipolytic response and decreased venous insulin levels. Energy restriction resulted in an increased basal platelet alpha 2-adrenoceptor density, whereas exercise did not modify density and affinity of platelet alpha 2-adrenoceptors. The results indicate that adrenoceptor numbers can be modulated by energy restriction in obesity. Modulation of adrenoceptor density may play a role in increased exercise-induced lipolysis during energy restriction.

Effects of chronic stress on beta-adrenergic receptors in the homeless.

This study examined the role of chronic life stress (homelessness), coping style, and hypertension on beta-adrenergic receptors in a sample of homeless men. Sixteen healthy normotensive subjects and nine untreated hypertensive subjects were studied. Life stress was measured with the Brown and Harris categorization; coping style was measured with the Ways of Coping Scale. Lymphocyte beta-adrenergic receptors were characterized in terms of receptor density (Bmax). Individuals with high life stress had lower Bmax (p < .005). In multiple regression analyses, 50% of the variance in Bmax was accounted for by life stress and coping style (p = .01). Receptor measures may be useful for characterizing the physiological response to continuing life adversity.