Β-adrenergic Receptor Activity Research Articles

Manipulating cardiac contractility in heart failure: data from mice and men.

In the year 1990, cardiovascular disease surpassed infectious diseases as the leading cause of death worldwide, and by the year 2020 it is predicted to be the leading cause of all disability.1,2 In the United States, cardiovascular disease has been estimated to account for 44% of the nation’s mortality and is a leading cause of morbidity.3,4 Heart failure afflicts an estimated 5 million Americans, with ≈400 000 new individuals diagnosed each year at an annual cost of more than $20 billion.4–6 The alarming reality behind these statistics is our current lack of an effective therapy to repair or otherwise reverse severe forms of cardiac dysfunction and pathological remodeling associated with heart failure. Typically, heart failure is the final culmination of protracted disease states precipitated by underlying hypertension, ischemic disease and atherosclerosis, valvular insufficiency, viral myocarditis, or mutations in genes encoding sarcomeric proteins.6 Given these diverse etiologies, it is not surprising that the final phenotypic manifestations of heart failure can also vary considerably, although dilated cardiomyopathy is the most common. This syndrome is characterized by a progressive loss in contractility and ejection fraction, ventricular chamber dilatation, ventricular wall thinning, increased peripheral vascular resistance, and dysregulated fluid homeostasis. The predominant therapeutic strategy used over the past two decades for treating such patients has been based in pharmacological manipulation of cardiac contractility.7–9 Initially, positive inotropic agents were used as a means of enhancing cardiac pump function aimed at alleviating congestive symptomology. However, use of positive inotropes is now indicated only as a means of acutely bridging patients in severe heart failure because these agents actually worsen prognosis in individuals with somewhat more stable heart failure.8 More recently, pharmacological blockade of β-adrenergic receptors has emerged as the favored treatment for individuals in heart failure. β-Adrenergic receptor antagonists initially …

β-Adrenergic and endothelin receptor interaction in dilated human cardiomyopathic myocardium

Background: Although end-stage dilated cardiomyopathy (DCM) is characterized by defects in β-adrenergic receptor (β-AR) activity and increased endothelin-1 (ET-1), possible interactions between these 2 systems remain to be defined. Accordingly, the goal of this study was to determine the effects of ET receptor activation on β-AR signaling through measurement of cyclic adenosine monophosphate (cAMP) in normal and DCM myocardium. Methods and Results: Myocardial sarcolemmal preparations were prepared from normal human (n = 6), dilated cardiomyopathic (n = 10), and ischemic cardiomyopathic (ICM, n = 10) tissue. Basal cAMP production was measured in the presence of ET-1 alone (10−6 to 0−9 mol/L) as well as after (−)isoproterenol (10−6 to 10−2 mol/L) or forskolin (0.05 to 30.0 μmol/L) stimulation. β-AR and ET receptor profiles were determined by radiolabeled ligand assays. ET-1 inhibited basal cAMP production in all preparations in a concentration-dependent manner. However, β-AR-stimulated cAMP production by either isoproterenol or forskolin was not significantly affected by ET-1. β-AR receptor density was reduced, and a selective reduction of the ETB receptor occurred in both forms of DCM. Conclusions: Under basal conditions, ET receptor stimulation reduced cAMP levels, which may influence contractility, particularly with DCM.

Alterations in β-adrenergic receptor density and adenylate cyclase activity in the rat brain treated chronically with lead

Behavioral and memory impairment resulting from lead exposure is well known but the mechanism is not. We utilized the brain of lead exposed rats to investigate this problem. In an effort to elucidate the mechanism responsible for this alteration we examined blood and brain lead levels, brain β-adrenoceptor density and cyclic AMP production in lead exposed rats. Wistar rats used in these trials were divided into six groups of ten animals each. Five groups were given drinking water containing 0.05, 0.1, 0.5, 1 and 2% lead acetate for a period of 60 days. One group (control group, 0% lead acetate) was given pure water. Application of a trend test indicated that both blood and brain lead levels increased significantly from group 0% to group 2% (group 0% <group 0.05% <group 0.1% <group 0.5%<group 1%<group 2%), but that brain β-adrenoceptor density and cyclic AMP levels stimulated by isoproterenol decreased (group 2%<group 1%<group 0.5%<group 0.1%<group 0.05%<group 0%). Kd did not vary among the six groups and this indicated that the affinity of the remaining β-adrenoceptors for [ 125I]iodocyanopindolol was not changed. Linear regression analysis showed that β-adrenoceptor density and stimulated cyclic AMP level in brain was found to be negatively correlated with brain lead level ( P<0.001). The results show lead exposure that may be the result of an alteration of β-adrenergic receptor and adenylate cyclase activity in brain.

Bbeta-adrenergic receptor kinase-1 levels in catecholamine-induced myocardial hypertrophy: regulation by beta- but not alpha1-adrenergic stimulation.

Pressure overload ventricular hypertrophy is accompanied by dysfunctional beta-adrenergic receptor signaling due to increased levels of the beta-adrenergic receptor kinase-1, which phosphorylates and desensitizes beta-adrenergic receptors. In this study, we examined whether increased beta-adrenergic receptor kinase 1 expression is associated with myocardial hypertrophy induced by adrenergic stimulation. With use of implanted mini-osmotic pumps, we treated mice with isoproterenol, phenylephrine, or vehicle to distinguish between alpha1- and beta-adrenergic stimulation. Both treatments resulted in cardiac hypertrophy, but only isoproterenol induced significant increases in beta-adrenergic receptor kinase-1 protein levels and activity. Similarly, in isolated adult rat cardiac myocytes, 24 hours of isoproterenol stimulation resulted in a significant 2.8-fold increase in beta-adrenergic receptor kinase-1 protein levels, whereas 24 hours of phenylephrine treatment did not alter beta-adrenergic receptor kinase-1 expression. Our results indicate that increased beta-adrenergic receptor kinase-1 is not invariably associated with myocardial hypertrophy but apparently is controlled by the state of beta-adrenergic receptor activation.

Changes in the sympathetic nervous system induced by 42 days of head-down bed rest.

Changes in autonomic nervous system activity could be linked to the orthostatic intolerance (OI) that individuals suffer after a spaceflight or head-down bed rest (HDBR). We examined this possibility by assessing the sympathetic nervous system activity during 42 days of HDBR in seven healthy men. Heart rate variability was studied with the use of power spectral analysis, which provided indicators of the sympathetic (SNSi) and parasympathetic (PNSi) nervous system influences on the heart. Urinary catecholamines and the spontaneous baroreflex sensitivity were measured. Urinary catecholamines decreased by 21.3%, showing a decrease in SNSi. Heart rate variability was greatly reduced during 42 days of HDBR with a drop in PNSi but with no significant changes in SNSi. The baroreflex sensitivity was greatly reduced (30.7%) on day 42 of HDBR. These results suggest a dissociation between the catecholamine response and the SNSi of the heart rate. This dissociation could be the consequence of an increase in beta-adrenergic receptor density and/or activity induced by a decrease in catecholamines during HDBR. The subjects who suffered from OI also had a greater sympathetic response and much lower baroreflex sensitivity when supine than those who finished the stand test. However, the mean response of all subjects indicated that the sympathetic activity (catecholamine excretion) was probably slightly inhibited during HDBR and could contribute to OI.

Is epinephrine contraindicated during cardiopulmonary resuscitation?

Why pulmonary gas exchange deteriorates after administration of epinephrine during cardiopulmonary resuscitation (CPR) is unclear. Forty-four anesthetized swine received an infusion of six inert gases. Animals underwent ventricular fibrillation with CPR and intravenous administration of saline (control), epinephrine (15 microg/kg), or methoxamine (150 microg/kg). Cardiac output, aortic blood pressure, pH, and arterial oxygen saturation were recorded. Distributions of VA and Q were determined by the multiple inert gas elimination technique. Ventricular fibrillation and CPR caused significant decreases in cardiac output, aortic blood pressure, and arterial pH. With epinephrine (versus saline), diastolic blood pressure was significantly higher (23+/-7 versus 8+/-4 mm Hg), but the increase in shunt (from 7+/-4% to 29+/-17%) and the reduction in SaO2 (from 99.7% to 76.8%) were significantly larger. Also, the increase in dead space was greater and elimination of CO2 less. There were no differences between animals given methoxamine or saline, except for increased diastolic blood pressure. During experimental ventricular fibrillation and CPR, epinephrine increased intrapulmonary shunt approximately 300% more than saline or methoxamine and significantly reduced arterial oxygen saturation. We suspect that the beta-adrenergic receptor activity of epinephrine attenuated hypoxic pulmonary vasoconstriction. Methoxamine is as effective a pressor as epinephrine for CPR and devoid of beta-adrenergic activity. We recommend that such an agent be considered, instead of epinephrine, for CPR.

Pavlovian Conditioning of Morphine-Induced Alterations of Immune Status: Evidence for Peripheral β-Adrenergic Receptor Involvement

The present studies examined the involvement of peripheral β-adrenergic receptor activity in the establishment and expression of conditioned morphine-induced alterations of immune status. Previous work in our laboratory has shown that morphine′s immunomodulatory effects can become conditioned to environmental stimuli which predict drug administration. These immune alterations include conditioned changes in natural killer cell activity, interleukin-2 production, and mitogen-induced lymphocyte proliferation. During the training phase of these experiments, Lewis rats received two conditioning sessions during which a subcutaneous injection of 15 mg/kg morphine sulfate was paired with exposure to a distinctive environment. On the test day, rats were reexposed to the conditioned stimulus prior to sacrifice. Saline or nadolol (0.002, 0.02, 0.2, or 2.0 mg/kg) was administered either prior to the training sessions or prior to the test session. Administration of nadolol prior to training did not affect the development of conditioned alterations of immune status. Conversely, nadolol administration prior to testing completely attenuated the expression of a subset of the conditioned morphine-induced changes in immune status. Taken together, these studies suggest that whereas peripheral β-adrenergic receptor activity is not required for the establishment of conditioned morphine-induced alterations of immune status, it is involved in the expression of a subset of these conditioned immunomodulatory effects.

S-antigen immunoreactivity in tumors of the choroid plexus

Using monoclonal antibodies (MAbs) directed against retinal S-antigen, the authors demonstrated the presence of S-antigen immunoreactivity in six of six (100%) tumors of the human choroid plexus, a tissue rich in β-adrenergic receptor activity. An anti-retinal S-antigen MAb F4C1, showed S-antigen immunoreactivity in one papilloma of the choroid plexus and in five of five (100%) carcinomas of the choroid plexus. In contrast, a papillary ependymoma of the spinal cord, an astrocytoma, an oligodendroglioma, metastatic oat cell carcinoma and metastatic adenocarcinoma to the brain did not stain. Our study indicates that MAb F4C1 may prove to be a useful immunohistochemical marker of tumors originating from the choroid plexus.

3,5,3′- l-Triiodothyronine regulation of β-adrenergic receptor density and adenylyl cyclase activity in synaptosomal membranes of aged rats

To determine the effect of aging on T 3 up-regulation of β-adrenergic receptor activity of purified synaptosomal membranes (SPM), β-adrenergic receptor density ( B max) and adenylyl cyclase (AC) activity were measured in young (6 months old) and aged (26 months old) male F-344 rats at baseline and after treatment with triiodothyronine (T 3), 15 μg/100 g, intraperitoneally for 10 days. The B max (fmol/mg protein) as measured by 125I-iodocyanopindolol binding was reduced in aged rats (70.8 ± 4.1) compared to young rats (93.5 ± 11.2). T 3 treatment resulted in a significant increase in B max of young rats but not in aged rats ( P < 0.05). The AC activity (pmol cAMP/mg) in response to prostaglandin E 1 (PGE 1) was reduced in aged rats compared to young rats (67.8 ± 2.9 vs 108.3 ± 18.6 P < 0.01). The sodium fluoride (NaF) stimulated AC activity was not altered with age. A net isoproterenol stimulated AC activity could not be demonstrated in any age group. T 3 treatment did not alter AC activity of SPM. It is concluded that aging is associated with reduced responsiveness to T 3-stimulated up-regulation of β-adrenergic receptor number in synaptosomal membranes.

β-adrenergic receptor activity of cerebral microvessels in experimental diabetes mellitus

The effect of diabetes mellitus on beta-adrenergic receptor number (B(max)), receptor-cyclase coupling and adenylate cyclase (AC) activity was determined in cerebral microvessels isolated from control and streptozotocin induced diabetic rats after 5 weeks of induction of diabetes. Scatchard analysis of [125I]iodocyanopindolol (ICYP) binding indicated that the B(max) (fmol/mg) in diabetic rat cerebral microvessels (63.8 +/- 4.8) (mean +/- S.E.M.) was not significantly different from the B(max) in control rats (56.5 +/- 6.9). Isoproterenol competition of [125I]ICYP binding sites indicated that the percentage of beta-receptors expressing high affinity binding was 53.9 +/- 0.45% in control rats and 47.5 +/- 2.3% in diabetic rats. The total isoproterenol-stimulated AC activity (pmol cAMP/mg) in diabetic rats (76.7 +/- 6.1) was significantly lower than that in control rats (118.4 +/- 11.2) (P less than 0.01). However, the net isoproterenol-stimulated AC activity (i.e. total minus GTP-stimulated AC activity) was not altered in diabetes. The net sodium fluoride (NaF) stimulated AC activity in diabetic rats (109.5 +/- 11.4) was significantly lower than the control rats (154.3 +/- 16.3) (P less than 0.05). It is concluded that diabetes mellitus in rats is associated with reduced post receptor activation of adenylate cyclase in cerebral microvessels while the beta-adrenergic receptor density, affinity and receptor-cyclase coupling are not significantly altered.

β-Adrenergic receptor activity in ponies with recurrent obstructive pulmonary disease

Summary Pulmonary function measurements were made in control ponies and in ponies with recurrent obstructive pulmonary disease (principals) during clinical remission and during an attack of acute airway obstruction. The ponies were given β-adrenergic antagonists and agonists to determine the role of β receptors in recurrent obstructive pulmonary disease, and to determine the subtypes of β receptors mediating bronchodilation in ponies. Aerosol administration of the β antagonists, propranolol (β1 and β2), atenolol (β1), and butoxamine (β2) decreased dynamic compliance (Cdyn) and increased pulmonary resistance (RL) in the principal ponies during airway obstruction, but were without effect when the ponies were in clinical remission. Intravenous administration of atropine reversed the effect of atenolol on Cdyn and RL, but was without effect on the decrease in Cdyn and increase in RL observed after butoxamine administration. The β antagonists did not affect airway function in the control ponies. The effect of β blockade on Cdyn and RL suggests β-adrenergic activation in the central and peripheral airways of principal ponies, mediated through both β2- and β1-adrenergic receptors. The aerosol β agonists, isoproterenol (β1 and β2), and clenbuterol (β2) attenuated histamine-induced airway obstruction to a similar extent in control ponies that were given histamine iv. In addition, the β1 antagonist, atenolol, did not attenuate the bronchodilation observed with isoproterenol. We concluded that, although β1- and β2-adrenergic receptors exist in pony airways and are activated during acute airway obstruction, bronchodilation in response to β agonists in ponies seems to be mediated primarily by β2-adrenergic receptors.

Plasma cyclic AMP in non-abstinent chronic alcoholics. Relation to clinical parameters

Plasma cyclic AMP levels were determined in a group of 36 male chronic alcoholics during a period of their usual alcohol intake and compared to 29 normal controls. Significantly lower values ( P < 0.005) were found in the patient group. The possible influence of age, chronicity of drinking, family history of alocholism, dementia and liver injury on plasma cAMP levels was examined by multiple regression analysis. No influence of those factors could be established except that demented alcoholics showed a trend toward higher levels than a non-demented subgroup. The role of reduced β-adrenergic receptor activity during chronic alcohol ingestion is discussed in relation to the above findings.

The interaction of dietary fatty acid and cholesterol on catecholamine-stimulated adenylate cyclase activity in the rat heart

Diets supplemented with high levels of saturated or unsaturated fatty acids supplied by addition of sheep kidney fat or sunflower seed oil, respectively, were fed to rats with or without dietary cholesterol. The effects of these diets on cardiac membrane lipid composition, catecholamine-stimulated adenylate cyclase and β-adrenergic receptor activity associated with cardiac membranes, were determined. The fatty acid-supplemented diets, either with or without cholesterol, resulted in alterations in the proportion of the ( n − 6) to ( n − 3) series of unsaturated fatty acids, with the sunflower seed oil increasing and the sheep kidney fat decreasing this ratio, but did not by themselves significantly alter the ratio of saturated to unsaturated fatty acids. However, cholesterol supplementation resulted in a decrease in the proportion of saturated and polyunsaturated fatty acids and a dramatic increase in oleic acid in cardiac membrane phospholipids irrespective of the nature of the dietary fatty acid supplement. The cholesterol/phospholipid ratio of cardiac membrane lipids was also markedly increased with dietary cholesterol supplementation. Although relatively unaffected by the nature of the dietary fatty acid supplement, catecholamine-stimulated adenylate cyclase activity was significantly increased with dietary cholesterol supplementation and was positively correlated with the value of the membrane cholesterol/phospholipid ratio. Although the dissociation constant for the β-adrenergic receptor, determined by [ 125I](−)-iodocyanopindolol binding, was unaffected by the nature of the dietary lipid supplement, the number of β-adrenergic receptors was dramatically reduced by dietary cholesterol and negatively correlated with the value of the membrane cholesterol/phospholipid ratio. These results indicate that the activity of the membrane-associated β-adrenergic/adenylate cyclase system of the heart can be influenced by dietary lipids particularly those altering the membrane cholesterol/phospholipid ratio and presumably membrane physico-chemical properties. In the face of these dietary-induced changes, a degree of homeostasis was apparent both with regard to membrane fatty acid composition in response to an altered membrane cholesterol/phospholipid ratio, and to down regulation of the β-adrenergic receptor in response to enhanced catecholamine-stimulated adenylate cyclase activity.

Progesterone in rat brain: Modulation of β-adrenergic receptor activity

Cytosolic proteins binding specifically the progesterone analogue 3H R5020 can be detected in various areas of the central nervous system (CNS) of rat. Our study demonstrates that the concentration of progesterone receptors in the brain of adult, ovariectomized, female rats is maximal in frontal cortex and midbrain and lowest in the cerebellum. Short term administration of the hormone does not alter the β-adrenergic receptor system, while a prolonged administration of progesterone results in an up-regulation of 3H-DHA binding in the frontal cortex. Such increase in binding activity is due to an increased number of β-adrenergic receptors. Furthermore, high doses of progesterone can also increase the number of β-adrenergic binding sites in an “in vitro” system where brain slices are incubated for few hours in a physiological medium.

The effect of estrogen and progesterone on β-adrenergic receptor activity in rabbit lung tissue

Study of the effect of sex steroids on the development of β-adrenergic receptors may be essential to an understanding of the mechanisms of both lung maturation and the initiation of labor, (3H)Dihydroalprenolol (DHA) was used to quantify β-adrenergic receptor sites in mature and immature rabbit lung tissue. DHA binding was rapid, saturable, of high affinity (dissociation constant = 2 nM), and of low capacity (246 to 576 fmoles/mg of protein), and adrenergic competitors demonstrated both stereoselectivity ([−]isomer ⪢ [+]isomer) and a rank order of potency (isoproterenol ⪢ norepinephrine > epinephrine) characteristic of the β-adrenergic receptor. β-Adrenergic receptors in the lung tissue of both mature and immature female New Zealand White rabbits were investigated under various sex steroid situations. Estrogen (diethylstilbestrol, 5 μg/day for 10 days) increased the β-adrenergic receptor site number in immature rabbits compared to matched controls (435 versus 339 fmoles/mg of protein, p < 0.02 by paired t test). Addition of progesterone (diethylstibestrol, 5 μg/day for 10 days, plus progesterone, 5 mg/day for 3 days) returned the β-adrenergic receptor site number to control values (321 fmoles/mg of protein, p < 0.01). In mature rabbits, treatment with progesterone alone (10 mg/day for 4 days) caused a significant reduction in β-adrenergic receptor site numbers compared to untreated, matched controls (357 versus 493 fmoles/mg of protein, p < 0.05 by paired t test). In the presence of estrogen, β-adrenergic receptor activity is enhanced in both mature and immature rabbit lung tissue. Addition of progesterone restores this activity to control values.

Characterization of adenylate cyclase activity in asthmatic neutrophil sonicates.

It has been postulated that bronchial asthma is associated with a defect of the β-adrenergic receptor. Previous studies using intact neutrophil (polymorphonuclear) preparations have shown decreased cyclic adenosine monophosphate responses to isoproterenol and histamine in active bronchial asthma. Using the β-adrenergic antagonist 3H-dihydroalprenolol, we have recently reported normal numbers and affinity of β-adrenergic receptors in homogenates of polymorphonuclear leukocytes from patients with bronchial asthma. In the present study using polymorphonuclear sonicates from 25 patients with bronchial asthma and 23 normal control subjects, we assessed several steps distal to receptor binding, including adenylate cyclase coupling to the β-adrenergic receptor and adenylate cyclase catalytic activity after hormonal (isoproterenol, histamine, and prostaglandin E1) and NaF stimulation. The mean ± SEM concentration of isoproterenol that displaced 50 % 3H-dihydroalprenolol (Kd) was 2.31 ± 0.33 eM for the asthmatic s...

Effects of cold-acclimation on β-adrenergic receptors of rabbit carotid artery

1. 1. Isolated, perfused segments of adult rabbit carotid arteries were used to determine if cold acclimation (17 weeks, 5°C) alters vascular β-adrenergic receptor sensitivity. 2. 2. Concentration-response relationships to a series of catecholamines having graded β-adrenergic receptor agonistic potencies were tested. 3. 3. The concentration-response relationship to norepinephrine was determined before and after β-adrenergic blockade with propranolol. 4. 4. The results indicate that cold-acclimation causes an increased β-adrenergic receptor activity in vascular smooth muscle.

Effects of adrenergic blockers on the relaxation of the guinea-pig ileum by bradykinin and adrenaline

α- and β-adrenergic blockers have been examined on the bradykinin- and adrenaline-induced relaxation of the acetylcholamine contracted guinea-pig ileum. The α-adrenergic blocker piperoxan potentiated, while phentolamine reduced the bradykinin relaxation. Both reduced the acetylcholamine contraction, but had no effect on the adrenaline relaxation. The bradykinin relaxation of the guinea-pig ileum was about 10 times more sensitive to phentolamine than the rat duodenum. The β-adrenergic blocker propranolol potentiated the bradykinin relaxation and reduced the acetylcholine contraction. Sotalol was in these respects less potent than propranolol. The adrenaline relaxation was partially blocked by propranolol, but almost completely by satalol. A combination of phentolamine and propranolol slightly potentiated the bradykinin relaxation, and partially blocked the adrenaline relaxation. The bradykinin relaxation is not due to a direct action on either the α- and β-adrenergic receptors of the guinea-pig ileum. The potentiation of the 0radykinin relaxation is probably indirect via the reduction of the acetylcholine contraction. The action of phentolamine cannot be explained by this mechanism. Seemingly only β-adrenergic receptor activity mediates relaxation with adrenaline.

Effect of beta-adrenergic receptor blockade on coronary haemodynamics in the resting unanaesthetized dog.

In the unanaesthetized dog propranolol 1 mg/kg intravenously failed to alter significantly coronary or systemic haemodynamics. These results suggest that in the supine, unanaesthetized dog, β-adrenergic receptor activity is minimal in the coronary arteries.

Adrenergic receptor activity in the coronary arteries of the unanesthetized dog.

Both α- (vasoconstrictor) and β- (vasodilator) receptor activity was demonstrated in the coronary arteries of the unanesthetized dog independent of adrenergic receptors in the myocardium. In the β-receptor blocked animal, α-adrenergic receptor activity was demonstrated after intravenous and intracoronary injections of epinephrine and norepinephrine by the occurrence of coronary vasoconstriction which could be eliminated by blocking α-adrenergic receptors as well. Coronary vasoconstriction was also seen prior to β-receptor blockade after intravenous phenylephrine and, on occasion, after intracoronary injections of norepinephrine. β-adrenergic receptor activity was demonstrated in several instances after intravenous or intracoronary injections of catecholamines by an initial vasodilatation which could be eliminated by β-adrenergic receptor blockade and which occurred before there was any change in myocardial or systemic hemodynamics. The role of this independent adrenergic receptor activity in the control of the coronary circulation remains to be determined.