Beta-adrenoceptor Sensitivity Research Articles

Autonomous regulation of heart rate in conditions of blocking the beta 1-adrenergic receptors in associative cortex of young rats with hypoxic exposure

<p>The literature discusses modulation of beta-adrenergic receptors sensitivity of the cerebral cortex under changed<br />conditions for the functioning of the body. However, very little data on the effect of the hypoxic environment to the<br />sensitivity of beta-adrenergic receptors of the cerebral cortex in a young body, which possible to investigate in<br />experiments on rats. The aim of the experiment was to determine the functional consequences of the exclusion of<br />beta1-adrenergic receptors in the associative cortex in young rats after incubation in hypoxic environment under<br />conditions of low atmospheric pressure. Blocking the beta1-adrenergic receptors in young rat’s associative cortex<br />can significantly offset the regulatory effects on heart rate that occurred during incubation in the hypoxic environment<br />under conditions of low atmospheric pressure. Hypoxic effect in young rats resulted in a significant decrease in<br />sensitivity beta1-adrenergic receptors in the associative cortex.</p>

Norepinephrine exerts an inotropic effect at the early phase of human septic shock

Norepinephrine (NE) is recognized as a potent vasopressor used in septic shock to reverse hypotension. Whether NE still exerts a positive effect on cardiac contractility through beta-adrenergic stimulation is unclear since the sensitivity of beta-adrenergic receptors can be abnormally reduced in septic conditions. Our study was designed to address this issue at the early phase of septic shock.

Adrenergic Activation, Fuel Substrate Availability, and Insulin Resistance in Patients With Congestive Heart Failure

This study sought to investigate plasma levels of glucose and free fatty acids (FFA) and their relationship with adrenergic activation and insulin resistance (IR) in patients with advanced congestive heart failure (CHF). Adrenergic activation and IR are hallmarks of advanced heart failure. The resulting changes in fuel substrate availability and their implications for exercise capacity have not been elucidated. Subjects with CHF underwent maximal exercise testing. Plasma glucose, FFA, insulin, and norepinephrine (NE) levels were measured at rest and at peak exercise. Beta-receptor sensitivity to NE was assessed using the Chronotropic Responsiveness Index (CRI). Homeostasis Model Assessment Index >2.5 defined IR. Left ventricular ejection fraction was estimated by 2-dimensional echocardiography. Ninety-six subjects were enrolled. CHF subjects without IR (CHF/No-IR), but not those with IR (CHF/IR), significantly increased glucose and insulin in response to exercise. Only CHF/No-IR subjects increased FFA in response to exercise (0.14 ± 0.27 mmol/l; p = 0.027). NE increased significantly less with exercise, and CRI was lower in CHF/IR subjects compared with CHF/No-IR subjects (1.3 ± 1.4 vs. 2.5 ± 2.1; 6.4 ± 2.6 vs. 8.5 ± 3.4; p = 0.069). CRI correlated with the exercise-induced increase in FFA (r = 0.41; p < 0.005). These results stayed the same after excluding diabetic patients from the CHF/IR group. Circulating FFA levels increased during exercise in CHF subjects without IR, but not in those with IR or DM. Increased FFA availability during exercise may represent a catecholamine-dependent compensatory fuel shift in CHF.

110. Beta-Adrenergic sensitivity and somatic symptoms of depression in heart failure patients

Background: Depression is prevalent in heart failure (HF) and is considered a powerful predictor of rehospitalization and mortality. Dysregulated sympathetic activity associated with depression may be one pathway. We investigated the relationship between depressive symptoms and alterations in leukocyte beta-adrenergic sensitivity in response to an acute exercise task in HF-patients. Methods: NYHA II–III HF-patients ( n = 13) were assessed for symptoms of depression using the Beck’s Depression Inventory (BDI), sub-categorized into somatic (BDI-s) and cognitive (BDI-c) symptoms. Participants underwent a 15 min bicycle ergometry task using a modified Bruce protocol. Beta-adrenergic receptor sensitivity was measured by quantifying leukocyte cyclic-AMP levels pre- and post-isoproterenol stimulation. Repeated measures analysis-of-variance (MANOVA) was used to measure changes in beta- adrenergic sensitivity in relation depressive symptoms. Results: There was a significant time effect ( p = .006) with increases in stimulated cAMP levels in response to exercise in the HF-patients. Moreover,there was a time x-somatic symptoms interactions ( p = .016) for stimulated cAMP. Although HF-patients with elevated somatic symptoms of depression appeared to have elevated basal stimulated cAMP levels, they responded less to the exercise task then those with low somatic symptoms of depression. Conclusions: HF-patients with low BDI-s had an increase in beta-receptor sensitivity due to exercise. However in HF-patients with high BDI-s, elevated basal and reduced stimulated cAMP level response to exercise suggest sympathetic dysregulation. This is consistent with the hypothesis that depression is related to over-activation of the sympathetic–adrenal–medullary system, causing dysregulation of beta-adrenergic activity. Further study is needed to identify clinical implications and HF-disease prognosis.

Isoprenaline-induced changes in activity of the endogenous inhibitor of cAMP-dependent protein kinases under conditions of beta-adrenoceptor supersensitivity.

Isoprenaline-induced changes in activity of an endogenous, specific inhibitor of cAMP-dependent protein kinases (type I inhibitor) under conditions of experimental supersensitivity of beta-adrenoceptors were investigated in rat hippocampus and brain stem. Both subchronic administration of reserpine (2.5 mg kg-1, i.p., 4 days, once daily) and i.c.v injections of 6-hydroxydopamine (250 micrograms/ventricle, bilaterally, 48 h apart), which are known to increase beta-adrenoceptor sensitivity in the rat brain, markedly enhanced the response of the type I inhibitor activity to isoprenaline. To obtain a significant decrease of type I inhibitor activity in the examined brain structures of these animals, doses of isoprenaline 2-5 times lower than in control groups had to be used. It is suggested that the isoprenaline-induced decrease of type I inhibitor activity might be used as an index of central beta-adrenoceptor reactivity in-vivo.

Chronotropic incompetence, beta‐blockers, and functional capacity in advanced congestive heart failure: Time to pace?

Chronotropic incompetence (CI) is often seen in subjects with chronic congestive heart failure (CHF). The prevalence of CI, its mechanisms and association with beta-blocker use as well as exercise capacity have not been clearly defined. Cardiopulmonary exercise tolerance testing data for 278 consecutive patients with systolic CHF was analyzed. CI, defined as the inability to reach 80% of maximally predicted heart rate was present in 128 of 278 subjects (46%). The prevalence of CI was highest in those with most impaired exercise capacity (72, 48, and 24% for subjects with a VO(2) of <14.0, 14.0-20.0, and >20.0 ml/kg/min respectively; p=0.001). While subjects with CI had lower peak exercise heart rate (114 vs. 152 bpm), and lower peak VO(2) (15.4 vs. 19.9 ml/kg/min), they were equally likely to be on chronic beta-blocker therapy (74% vs. 71%; p=0.51). Heart rate and norepinephrine (NE) levels were measured during exercise in a separate cohort of 24 subjects with CHF. There was no difference in beta-blocker dose between subjects with and without CI, however, exercise induced NE release and Chronotropic Responsiveness Index, a measure of post-synaptic beta-receptor sensitivity to NE, were lower in subjects with CI (1687+/-911 vs. 2593+/-1451 pg/ml p=0.08; CRI 12.7+/-5.7 vs. 22.1+/-4.7, p=0.002). CI occurs in >70% of subjects with advanced systolic CHF irrespective of beta-blocker use and is associated with a trend toward impaired NE release, post-synaptic beta-receptor desensitization and reduced exercise capacity.

Mood states, sympathetic activity, and in vivo β-adrenergic receptor function in a normal population

The purpose of this study was to examine the relationship between mood states and beta-adrenergic receptor function in a normal population. We also examined if sympathetic nervous system activity is related to mood states or beta-adrenergic receptor function. Sixty-two participants aged 25-50 years were enrolled in this study. Mood states were assessed using the Profile of Mood States (POMS). Beta-adrenergic receptor function was determined using the chronotropic 25 dose isoproterenol infusion test. Level of sympathetic nervous system activity was estimated from 24-hr urine norepinephrine excretion. Higher tension-anxiety, depression-dejection, and anger-hostility were related to decreased beta-adrenergic receptor sensitivity (i.e., higher chronotropic 25 dose values), but tension-anxiety was the only remaining independent predictor of beta-adrenergic receptor function after controlling for age, gender, ethnicity, and body mass index (BMI). Urinary norepinephrine excretion was unrelated to either mood states or beta-adrenergic receptor function. These findings replicate previous reports that anxiety is related to decreased (i.e., desensitized) beta-adrenergic receptor sensitivity, even after controlling for age, gender, ethnicity, and body mass index.

Mechanisms of exercise‐induced ST‐segment depression in patients without typical angina pectoris

To evaluate if exercise-induced ST-segment depression without typical angina pectoris is related to increases in sympatho-adrenal activity or beta-adrenoceptor sensitivity. Thirteen patients (four men) aged 35-62 years with ST-segment depression during exercise but atypical symptoms and normal myocardial scintigraphy, and 13 matched controls. Patients and controls were compared regarding responses with: (i) exercise testing without treatment, (ii) exercise testing following beta-adrenoceptor blockade by propranolol (0.15 mg kg(-1) i.v.), (iii) incremental adrenaline infusions (0.1, 0.2, 0.4 and 0.8 nmol kg(-1) min(-1)) and (iv) adrenaline infusions during alpha-adrenoceptor blockade by phentolamine (0.5 mg min(-1)). ST-segment depression and tissue Doppler parameters reflecting contractility. Exercise lowered the ST-segment by 2.44 mm without and 0.87 mm with beta-adrenoceptor blockade (P < 0.001 for difference) amongst patients, but not amongst controls. Maximal heart rate was slightly higher amongst patients (P < 0.05), despite similar loads and plasma catecholamine responses to exercise in the two groups; this difference disappeared after beta-adrenoceptor blockade with propranolol. ST-segment depression during adrenaline infusion was greater in patients compared with controls (P < 0.01) despite similar increases in heart rate. alpha-Blockade enhanced the ST-segment depression (P < 0.001) and heart rate (P < 0.001) responses to adrenaline infusion more markedly amongst patients. Tissue Doppler imaging showed similar contractility and diastolic relaxation responses of patients and controls to adrenaline, but early diastolic movements did not increase amongst patients after phentolamine (P < 0.01). Exercise-induced ST-segment depression in patients with a low likelihood of ischaemic heart disease is related to increased beta-adrenergic sensitivity regarding chronotropic and electrophysiological, but not inotropic responses.

β-Receptor Response to Noradrenaline in Cluster Headache. A Study of Adipose Tissue Lipolysis

We have previously shown decreased lipolysis in both phases of cluster headache (CH), as an indication of a sympathetic dysregulation. Reduced lipolysis could be a result of diminished beta-receptor sensitivity in adipose tissue. The aim of this study was to measure the lipolytic response to noradrenaline in 10 CH patients in remission and in 10 healthy subjects, to estimate beta-receptor function. Microdialysis technique was used to measure the increase of glycerol, the end-product of lipolysis, during infusion of noradrenaline into the adipose tissue. Noradrenaline infusion resulted in a distinct elevation of glycerol. The average glycerol increase was significantly higher in CH patients (121% +/- 48) than in healthy subjects (77% +/- 41) (P < 0.05), which indicates increased beta-receptor response to noradrenaline in CH patients in remission. This may be due to up-regulated beta-receptor sensitivity, secondary to reduced sympathetic outflow and a primary autonomic disturbance in CH.

Estrogen regulates adrenal medullary function producing sexual dimorphism in nociceptive threshold and β2‐adrenergic receptor‐mediated hyperalgesia in the rat

Epinephrine produces sexually dimorphic beta(2)-adrenergic receptor-mediated mechanical hyperalgesia, with male rats exhibiting greater hyperalgesia. Because female rats have higher plasma epinephrine levels, and beta-adrenergic receptor sensitivity is affected by chronic exposure to agonists, we tested the hypothesis that this sexual dimorphism is due to epinephrine-induced desensitization of beta(2)-adrenergic receptors. Following gonadectomy, epinephrine hyperalgesia, as measured by the Randall-Selitto paw-withdrawal test, was unchanged in male rats while in females it was increased. Prepubertal male and female rats do not demonstrate sexual dimorphism in either plasma epinephrine level or epinephrine-induced hyperalgesia. Adrenal medullectomy and adrenal denervation both significantly enhanced epinephrine hyperalgesia, but only in females. In contrast, the sexually dimorphic hyperalgesia induced by prostaglandin E(2), another agent that acts directly to sensitize primary afferent nociceptors, was not enhanced by adrenal medullectomy or denervation. Chronic administration of epinephrine in male rats, to produce plasma levels similar to those of gonad-intact females, significantly attenuated epinephrine-induced hyperalgesia, making it similar to that in females. These results strongly support the suggestion that estrogen regulates plasma epinephrine in female rats and differential sensitivity to beta(2)-adrenergic agonists accounts for the sexual dimorphism in epinephrine-induced hyperalgesia. Unexpectedly, regulation of adrenal medullary function by estrogen was also found to modulate baseline nociceptive threshold such that females had a lower nociceptive threshold.

Differences in beta-adrenergic receptor sensitivity between women and men with panic disorder

This study was conducted on patients with panic disorder (PD) to examine the gender differences in the pathophysiology of PD by evaluating and comparing the value of CD 25/wt, the chronotropic 25 dose of isoproterenol (CD 25) divided by the body weight, which reflects the in vivo index of β-adrenergic receptor sensitivity. This study included a total of 70 subjects, including 35 patients with PD (female: 13, male: 22) along with 35 healthy control subjects (female: 13, male: 22). There were significant differences in the mean value of CD 25/wt (0.073±0.045 μg/kg vs. 0.032±0.019 μg/kg; p=0.006) and the serum epinephrine (EPI) level (77.3±64.1 pg/ml vs. 31.6±10.3 pg/ml; p=0.001) between the female panic patients and the female control subjects. However, there were no differences in either the CD 25/wt value or the EPI level between the male panic patients and the male control subjects. These results suggest that the β-adrenergic receptor sensitivity decreased in the female patients, but not in the male patients, which provides evidence for the possible existence of a gender difference in the pathophysiology of PD.

Changes in the receptor profile of the aging bladder

Future demographic developments will challenge urology with a steadily increasing incidence of lower urinary tract symptoms (LUTS) derived from the aging bladder. Obstruction, instability and hypocontractility, which may be caused by changes in the receptor profile of the detrusor, are typical pathophysiologic findings in geriatric bladder dysfunction. Benign prostatic hyperplasia and diabetes mellitus are age-associated comorbidities with an additional influence on bladder receptors. Muscarinic (M(2), M(3)), purinergic (P2X, P2Y) and adrenergic receptors (alpha(1), beta(3)) are targets of efferent sympathetic and parasympathetic bladder innervation. Although the results from animal experiments are somewhat inconsistent, aging and bladder outlet obstruction (BOO) probably cause partial cholinergic denervation of the detrusor with a subsequent upregulation of muscarinic receptor sensitivity leading to bladder instability. The non-cholinergic (atropine-resistant) component of the detrusor contraction rises with aging and BOO to 50%, emphasizing the increasing impact of purinergic receptors in geriatric LUTS. alpha(1)-adrenergic receptors are modulated in the aging bladder by a shift from the predominant alpha(1a) subtype to the alpha(1d) subtype, which shows 100-fold higher affinity towards norepinephrine and increases alpha-adrenergic bladder susceptibility. No data are available on the changes in beta(3) receptor density or sensitivity with aging. Moreover, the role of sensory C-fiber receptors in geriatric LUTS remains completely unclear, although specific C-fiber blockers are already under clinical evaluation (capsaicin, resiniferatoxin).

P.3.019 Differences in beta-adrenergic receptor sensitivity between female and male with panic disorder

P.3.019 Differences in beta-adrenergic receptor sensitivity between female and male with panic disorder

Melatonin response to atenolol administration in depression: indication of beta-adrenoceptor dysfunction in a subtype of depression.

To investigate peripheral beta-adrenoceptor sensitivity in depression by assessing urinary melatonin pre- and post-administration of atenolol. Overnight urinary melatonin pre- and post-administration of 100 mg oral atenolol was assessed in 36 depressed subjects and 47 controls. Baseline melatonin was significantly lower in depressed patients than controls (P=0.004). Melatonin following atenolol administration was strongly reduced in both groups (P < 0.0001). This reduction depends on whether the subject is a high or low (cutoff: 0.25 nmol/l) baseline melatonin excretor (P=0.025) and on whether he is depressed being a low excretor (P=0.048). A negative correlation (P=0.007) was found between melatonin decrease after atenolol and the Montgomery-Asberg Depression Rating Scale score. Atenolol strongly reduces melatonin in depressed and control subjects; this decrease relates inversely to the severity of depressive symptoms. Furthermore, responsiveness to atenolol differs between low melatonin depressed patients and low excretor controls, alluding to beta-adrenoceptor up-regulation in a subtype of depression.

β2-Adrenoceptor desensitization in human alveolar macrophages induced by inhaled terbutaline in vivo is not counteracted by budesonide

In vitro studies suggest that glucocorticoids may counteract beta-agonist-induced desensitization of beta-adrenoceptors by actions at the transcriptional level, but the clinical relevance of such findings is not clear. Oral terbutaline treatment decreases beta-adrenoceptor sensitivity in alveolar macrophages in vivo. This effect is not counteracted by inhaled or orally taken steroids. We therefore examined whether inhaled terbutaline elicited a similar effect on beta(2)-adrenoceptor sensitivity in alveolar macrophages, and if co-treatment with an inhaled steroid, budesonide, would prevent such down-regulation. Bronchoalveolar lavage (BAL) and lung function tests, including bronchodilator responses to inhaled terbutaline, were performed before and after 2 weeks of regular inhalation of terbutaline, 0.5 mg three times daily, and budesonide, 400 microg twice daily, or placebo, in 24 healthy volunteers. Four untreated subjects served as controls. A marked, approx. 90%, decrease in isoprenaline-induced cAMP accumulation in alveolar macrophages was found in both treatment groups after 2 weeks, with no difference between placebo and budesonide (P = 0.45). In the untreated control group, cAMP responses to both isoprenaline and prostaglandin E(1) tended to be lower on the second occasion. A limited, non-specific desensitization of adenylate cyclase activity thus contributed to the marked desensitization elicited by terbutaline inhalations. The bronchodilator response to inhaled terbutaline did not change after treatment in any of the three groups (F = 0.9, P = 0.50). In conclusion, inhalation of a beta-agonist induced marked down-regulation of beta(2)-adrenoceptor sensitivity in alveolar macrophages in vivo without influencing the bronchodilator response to a beta(2)-agonist in healthy subjects. Co-treatment with an inhaled steroid failed to counteract the desensitization of alveolar macrophage beta(2)-adrenoceptors.

Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: a pilot study in fibromyalgia.

To determine whether deficient activity of the hypothalamic corticotropin-releasing hormone (CRH) neuron, which stimulates the hypothalamic-pituitary-adrenal (HPA) axis and the central control nuclei of the sympathetic nervous system and inhibits ascending pain pathways, may be pathogenic in patients with fibromyalgia (FM). We administered interleukin-6 (IL-6; 3 microg/kg of body weight subcutaneously), a cytokine capable of stimulating hypothalamic CRH release, and measured plasma levels of adrenocorticotropic hormone (ACTH), cortisol, and catecholamines and their metabolites and precursors. Thirteen female FM patients and 8 age- and body mass index-matched female controls were studied. The diagnosis of FM was made according to American College of Rheumatology criteria. Tender points were quantitated by pressure algometry. All subjects had HPA axis studies. Seven FM patients and 7 controls also had catecholamine measurements. After IL-6 injection, delayed ACTH release was evident in the FM patients, with peak levels at 96.9 +/- 6.0 minutes (mean +/- SEM; control peak 68.6 +/- 10.3 minutes; P = 0.02). Plasma cortisol responses to IL-6 did not differ significantly between patients and controls. Basal norepinephrine (NE) levels were higher in the FM patients than in the controls. While a small, although not significant, rise in NE levels occurred after IL-6 injection in the controls, NE levels dramatically increased over basal levels in the FM patients between 60 and 180 minutes after IL-6 injection. Both peak NE levels (mean +/- SEM 537.6 +/- 82.3 versus 254.3 +/- 41.6 pg/ml; P = 0.0001) and time-integrated NE responses (93.2 +/- 16.6 pg/ml x minutes(-3) versus 52.2 +/- 5.7 pg/ml x minutes(-3); P = 0.038) were greater in FM patients than in controls. Heart rate was increased by IL-6 injection in FM patients and controls, but rose to significantly higher levels in the FM patients from 30 minutes to 180 minutes after IL-6 injection (P < 0.03). Exaggerated NE responses and heart rate increases, as well as delayed ACTH release, were observed among female FM patients compared with age-matched female controls. Delayed ACTH release after IL-6 administration in FM is consistent with a defect in hypothalamic CRH neuronal function. Exaggerated NE release may reflect abnormal regulation of the sympathetic nervous system, perhaps secondary to chronically deficient hypothalamic CRH. The excessive heart rate response after IL-6 injection in FM patients may be unrelated to the increase in NE, or it may reflect an alteration in the sensitivity of cardiac beta-adrenoceptors to NE. These responses to a physiologic stressor support the notion that FM may represent a primary disorder of the stress system.

Beta-adrenergic signalling and threshold adrenaline concentration for induction of fibrillation in the perfused heart pretreated with antihypertensive drugs.

Recent investigations have shown that antihypertensive drug treatment leads to enhanced myocardial beta-adrenoceptor sensitivity. This study was therefore conducted to establish whether or not such hypersensitivity might trigger myocardial arrhythmia subsequent to adrenaline exposure. Adult male Wistar rats (n = 6 per group) were treated with either placebo (vehicle), metoprolol (2.40 mg.kg-1.day-1), timolol (0.075 mg.kg-1.day-1), verapamil (5.50 mg.kg-1.day-1) or enalapril (0.50 mg.kg-1.day-1) for 20 consecutive days. Hearts were excised and perfused ad modum Langendorff in the presence of an adrenaline gradient (0-300 nM) for 20 min with either 3.0 mM or 5.9 mM of potassium in the perfusion buffer. Adrenaline threshold concentration (ATC, nanomolar) at myocardial fibrillation was recorded, as well as tissue cAMP contents, beta-adrenoceptor number, G-protein levels and signalling effector enzyme activities. The main findings were: (1) ATC and cAMP levels were affected in hearts perfused with low-concentration potassium buffer only. In terms of ATC, the beneficial effect of each drug regimen appeared to be in the rank order of: placebo = enalapril > verapamil > timolol > metoprolol. There was an inverse correlation between ATC and myocardial cAMP contents at the start of fibrillation; (2) Subsequent to fibrillation, beta-adrenoceptor number, hormone-elicited adenylate cyclase activities and Gs alpha:Gi2 alpha-ratio were no different from preperfusion values; (3) Significant inverse correlations between beta 1-adrenoceptor numbers and ATC were observed. We conclude that alterations in beta-adrenoceptor number, G proteins and cAMP induced by antihypertensive drugs are predictive of the myocardial sensitivity to adrenaline in terms of time to continuous and irrevocable fibrillation.

Is visceral adiposity a significant correlate of subcutaneous adipose cell lipolysis in men?

The aim of the present study was to examine whether site differences in s.c. adipose tissue (AT) lipolysis may be considered a contributing factor to the altered metabolic risk profile of visceral compared to peripheral obese men once the concomitant variation in adipose cell size is taken into account. For this purpose, sc abdominal and femoral fat cell lipolytic responses were investigated in two groups of men (body mass index, 28 +/- 2 kg/m2), aged 36 +/- 3 yr, who were matched for both s.c. abdominal AT area (256 +/- 64 cm2) and s.c. abdominal adipose cell weight (0.55 +/- 0.08 microg lipid/cell) but were characterized by either a high (162 +/- 29 cm2; n = 18) or a low (101 +/- 21 cm2; n = 18) visceral AT deposition. The maximal lipolytic response to epinephrine or to isoproterenol (beta-adrenergic agonist) as well as the maximal antilipolytic effect of either epinephrine or clonidine (alpha2-adrenergic agonist) assessed in s.c. adipocytes were similar among men with low vs. high levels of visceral AT. However, the beta-adrenoceptor sensitivity was increased in s.c. abdominal adipose cells of individuals with a high visceral AT accumulation compared to those with a low intraabdominal fat deposition. Positive relationships were also found between the lipolytic sensitivity of s.c. abdominal adipocytes and plasma insulin concentrations measured in the fasting state and after an oral glucose load. These results suggest that variation in the degree of visceral adiposity in men does not seem to be associated with differences in regional adipose cell maximal lipolytic capacity once fat cell size is taken into account. However, the greater beta-adrenoceptor lipolytic sensitivity of s.c. abdominal adipocytes could be considered a significant correlate of the increased insulinemia observed among men characterized by high levels of visceral AT.

The Effects of Hypoxia and Sleep Apnea on Isoproterenol Sensitivity

To determine the effects of both apnea and hypoxia on beta-adrenergic receptor sensitivity. Cross-sectional study. A clinical research center. Forty-five normotensive and hypertensive sleep apnea patients (respiratory disturbance index >20) and non-apneic controls. The chronotropic 25 dose (CD25), an in vivo measure of beta-adrenergic receptor sensitivity derived from the heart rate response to a graded infusion of isoproterenol, was determined while subjects breathed either a normoxic (21% O2, 79% N2) or a hypoxic (15% O2, 85% N2) gas mixture. Under normoxic conditions, apnea patients showed a significantly higher CD25 (lower beta-adrenergic receptor sensitivity) as compared to controls (5.9 microg, SD=2.1 versus 4.6 microg, SD=1.2, respectively; p=0.018). In response to hypoxia, apnea patients showed no change in CD25, while controls showed a significant increase in CD25 (beta-adrenergic receptor desensitization) (p=0.002), to a value comparable to the apneics' (5.6 microg, SD=2.0). The in vivo finding of reduced beta-adrenergic receptor sensitivity in sleep apnea patients is consistent with previous in vitro assessments of the beta-adrenergic receptor. The finding that apnea patients do not respond to hypoxia with a further receptor desensitization suggests that sleep apnea patients may have reached a threshold effect of hypoxia on the beta-adrenergic receptor. These findings may be relevant to the greater incidence of hypertension seen in patients with sleep apnea syndrome.

Simulated microgravity increases beta-adrenergic lipolysis in human adipose tissue.

The effect of a sustained decrease in sympathetic nervous activity, achieved through 5-day head-down bed rest (HDBR), on the beta-adrenergic lipolytic activity of s.c. adipose tissue was studied in eight healthy men. The in situ beta-adrenoceptor (AR) sensitivity was studied using the microdialysis method. Local perfusion of increasing concentrations of isoprenaline showed an increased beta-AR sensitivity to lipolysis (assessed by extracellular glycerol concentration) and to vascular tone (assessed by the ethanol clearance). The adrenergic sensitivity of isolated adipocytes was studied in vitro. Basal lipolysis and the response to nonselective (isoprenaline) or selective (dobutamine, terbutaline, and CGP 12177) beta-AR agonists were increased after HDBR as was the lipolytic effect of dibutyryl cAMP. When data were expressed as a percentage of the dibutyryl cAMP effect to rule out the postreceptor events, basal and lipolytic responses to beta-AR agonists where similar before and during HDBR. The alpha 2-AR-mediated antilipolytic effects of adrenaline were not modified. Lymphocyte beta-AR number was unchanged during HDBR. Our results demonstrate that a sustained sympathoinhibition induces an increase in the lipolytic beta-adrenergic response in adipose tissue and suggest that this hypersensitization is linked to an increase in the postreceptor steps of the lipolytic cascade in the adipocyte rather than to changes in beta-adrenoceptors.