beta 2 adrenoreceptor desensitization

Inhaled β2-adrenoreceptor agonists are widely used in asthma and chronic obstructive pulmonary disease (COPD) for bronchoconstriction relief. β2-Adrenoreceptor agonists relax airway smooth muscle cells via cyclic adenosine monophosphate (cAMP) mediated pathways. However, prolonged stimulation induces functional desensitization of the β2-adrenoreceptors (β2-AR), potentially leading to reduced clinical efficacy with chronic or prolonged administration. ASM-024, a small synthetic molecule in clinical stage development, has shown activity at the level of nicotinic receptors and possibly at the muscarinic level and presents anti-inflammatory and bronchodilator properties...

The relationship between β(2)-adrenoreceptor gene Arg16Gly polymorphism and bronchial cold reactivity has been studied. Genotype Arg16Arg and allele Arg16 carriership is associated with the development of cold bronchospasm in asthmatics. In addition, a significant reduction of 3,5'-cyclic adenosine monophosphate (cAMP) level has been recorded in Arg16Arg homozygotes on minute 30 after cold provocation in comparison with Gly16Gly genotype carriers. These data indicate the influence of primary dysfunction of β(2)-adrenoreceptors for the formation of bronchial cold hyperreactivity in the patients...

PURPOSE: In a mouse model of oxygen-induced retinopathy (OIR), a well-established model of retinopathy of prematurity (ROP), blocking beta-adrenoreceptors (β-ARs), and, in particular, β2-ARs, counteracts retinal responses to hypoxia. In the present work, we determined the effects of the β-AR agonist isoproterenol on retinal angiogenesis and β-AR signaling to better clarify the role of sympathetic transmission in ROP. METHODS: Isoproterenol was administered subcutaneously...

The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is generally transient because its accompanying effects (for example, immunosuppression, growth inhibition and enhanced catabolism) can be harmful in the long term. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders, and epidemiological studies strongly indicate that chronic stress leads to DNA damage...

Catecholamines play a key role in the regulation of cardiovascular function, classically through ß(1/2)-adrenoreceptors (AR) activation. After ß(3)-AR cloning in the late 1980s, convincing evidence for ß(3)-AR expression and function in cardiovascular tissues recently initiated a reexamination of their involvement in the pathophysiology of cardiovascular diseases. Their upregulation in diseased cardiovascular tissues and resistance to desensitization suggest they may be attractive therapeutic targets. They may substitute for inoperant ß(1/2)-AR to mediate vasodilation in diabetic or atherosclerotic vessels...

Catecholamines released by the orthosympathetic system play a major role in the short- and long-term regulation of cardiovascular function. Beta1- and beta2-adrenoreceptors (ARs) have classically been considered as mediating most of their effects on cardiac contraction. After their initial cloning and pharmacologic characterization in the late 1980s, beta3-ARs have been mostly thought of as receptors mediating metabolic effects (e.g., lipolysis) in adipocytes. However, definitive evidence for their expression and functional coupling in cardiovascular tissues (including in humans) has recently initiated a re-examination of their implication in the pathophysiology of cardiovascular diseases...

Former studies on net rate of liquid absorption from small Ringer or 1% albumin-Ringer hydrothoraces in rabbits indicated that Na+ transport and solute-coupled liquid absorption by mesothelium is increased by pleural liquid dilution, and stimulation of β2-adrenoreceptors (β2AR). In this research we tried to provide molecular evidence for β2AR in visceral and parietal mesothelium of rabbit pleura. Moreover, because prolonged stimulation of β2AR may lead to desensitization mediated by G-protein-coupled receptor kinase 2 (GRK2), we also checked whether GRK2 is expressed in pleural mesothelium...

INTRODUCTION: Alpha(1)-adrenergic receptor (alpha(1)-AR) stimulation produces smooth muscle contraction, vasoconstriction, and myocyte hypertrophy, suggesting a potential therapeutic role for alpha(1)-AR antagonists to reduce cardiac workload and myocardial hypertrophy. Preliminary reports suggest that vascular alpha(1)-ARs are desensitized in heart failure (HF) in a manner similar to myocardial beta(1)-ARs. We examined alpha(1)-AR signal transduction by repeat phenylephrine (PE) infusions in patients with HF receiving chronic carvedilol therapy...

OBJECTIVE: To report a case of confirmed beta(16) Arg/Arg polymorphism (Arg/Arg) in a patient with uncontrolled asthma. CASE SUMMARY: A 49-year-old black female presented to the emergency department with acute shortness of breath with subsequent intubation. After extubation, she reported multiple hospitalizations for asthma with one prior intubation, adherence to asthma medications, and very frequent use of her short-acting beta(2)-agonist (SABA). Because of her asthma history, self-reported adherence, and race, she was tested for beta(2)-adrenoreceptor genotype, which revealed Arg/Arg...

In cardiac muscle the sarcoplasmic reticulum (SR) plays a key role in the control of contraction, releasing Ca(2+) in response to Ca(2+) influx across the sarcolemma via voltage-gated Ca(2+) channels. Here we report evidence for an additional distinct Ca(2+) store and for actions of nicotinic acid adenine dinucleotide phosphate (NAADP) to mobilize Ca(2+) from this store, leading in turn to enhanced Ca(2+) loading of the SR. Photoreleased NAADP increased Ca(2+) transients accompanying stimulated action potentials in ventricular myocytes...

Desensitization of the beta-adrenoreceptors (beta-AR) may contribute to a post-exercise reduction in left ventricular (LV) function. However, attenuation of the chronotropic and inotropic responses to a beta-AR agonist may depend upon alterations in parasympathetic tone. Furthermore, changes in cardiac output and LV diastolic function in response to a beta-AR agonist, pre- to post-prolonged exercise, remain unclear. Seven trained males (mean+/-s.d., age 27+/-6 years) performed 4 h of ergometer rowing. Peak heart rate (HR) and LV systolic and diastolic functional responses to incremental isoproterenol (isoprenaline) infusion (2, 4 and 6 microg kg min-1) were assessed after vagal blockade (glycopyrrolate, 1...

Prolonged strenuous exercise has been associated with transient impairment in left ventricular (LV) systolic and diastolic function that has been termed 'cardiac fatigue'. It has been postulated that cardiac beta-adrenoreceptor desensitization may play a central role; however, data are limited. Accordingly, we assessed the cardiovascular response to progressive dobutamine stimulation after prolonged strenuous exercise (2 km swim, 90 km bike, 21 km run). Nine experienced male athletes were studied: PRE (2-3 days before), POST (after) and REC (1-2 days later)...

Long-term oxygen deficiency in vivo leads to the progressive blunting of responsiveness to sympathetic stimulation and blood catecholamines in many human and animal tissues. In order to better understand the molecular processes that underlie this phenomenon we examined the effect of hypobaric hypoxia (290 mm Hg, pO2 = 40 mM Hg) on the--beta-adrenoreceptor (beta-AR) density and the activity of adenylate cyclase (AC) and phosphoinositide turnover (PI-turnover) in cultures of human pulmonary artery and umbilical vein cells...

AIM: To evaluate norepinephrine (NE) and epinephrine (E) plasma concentration and lymphocyte beta-2-adrenoceptor dependent cAMP synthesis in primary pulmonary hypertension (PPH) patients in comparison with healthy controls. MATERIAL AND METHODS: Seven volunteers and fifteen patients with PPH were included in the study. NE and E plasma levels were measured by high performance liquid chromatography. Basal and stimulated (isoproterenol and forskolin) adenylyl cyclase activity in lymphocytes was measured by cAMP production using an enzyme immunoassay (Biotrak, Amersham UK)...

Arrestins play a key role in the homologous desensitization of G protein-coupled receptors (GPCRs). These cytosolic proteins selectively bind to the agonist-activated and GPCR kinase-phosphorylated forms of the GPCR, precluding its further interaction with the G protein. Certain mutations in visual arrestin yield "constitutively active" proteins that bind with high affinity to the light-activated form of rhodopsin without requiring phosphorylation. The crystal structure of visual arrestin shows that these activating mutations perturb two groups of intramolecular interactions that keep arrestin in its basal (inactive) state...

BACKGROUND: We investigated the combination of selective serotonin reuptake inhibitors (SSRIs) with the beta-adrenoceptor/serotonin 1A (5-HT(1A)) antagonist pindolol, based on the concept that 5-HT(1A) receptor blockade would eliminate the need for desensitization of presynaptic 5-HT(1A) receptors and therefore hasten the onset of action and improve the efficacy of SSRIs. However, since pindolol plasma levels after 2.5 mg three times a day are about 60 nmol/L, and the K(i) for the 5-HT(1A) receptor is 30 nmol/L, it is questionable whether pindolol levels in the brain would be sufficient to antagonize 5-HT(1A) receptors...

The involvement of adrenergic signaling and sarcoplasmic calcium regulatory proteins in the development of heat acclimation-induced adaptations in cardiac mechanics was studied in heat-acclimated (34 degrees C) rats for 2, 5, and 30 days (AC(2), AC(5), and AC(30), respectively). Control (C) rats were held at 24 +/- 1 degrees C. Systolic pressure (LVP) and velocities of contraction (dP/dt/P) and relaxation (-dP/dt/P) were measured using a Langendorff system. For adrenergic signaling, beta-adrenoreceptor (AR) density and affinity (Scatchard plots) and cardiac inotropic response to norepinephrine (10(-7) mM, +/- 10(-6) mM propranolol) were measured...

Prolonged treatment with the beta(2)-adrenergic agonist clenbuterol (0.25 mg kg(-1) s.c. once daily for 10 days) produced a reduction of the relaxant response and cAMP production mediated by stimulation of beta-adrenoceptors in oestrogen-treated rat uterus. Substantial decreases in the relaxant effect of isoproterenol is observed in uterine rings precontracted with 50 mM KCl from clenbuterol-treated rats. The recovery of the relaxant response was also studied and significant differences were seen between acute and prolonged treatment with clenbuterol (P<0...

The beta adrenergic agonist isoprenaline inhibited the IgE-triggered release of the preformed mediator histamine from human lung mast cells (HLMC) in a dose-dependent fashion. After prolonged (> or = 4 h) preexposure of HLMC to isoprenaline, there was a subsequent diminution in the effectiveness of a second exposure of isoprenaline to inhibit the release of histamine from activated HLMC. This induced hyporesponsiveness to isoprenaline was both concentration and time dependent. Although maximal levels of desensitization were obtained after an initial prolonged (14-h) preincubation with a high (10(-5) M) concentration of isoprenaline, exposure of HLMC for a shorter (4-h) time period with a lower (3 x 10(-7) M) concentration of isoprenaline was also effective at inducing a functional desensitization to isoprenaline...

To assess the physiological relevance of the changes in adrenergic receptor observed in adipocyte membranes after in vitro exposure to catecholamines, hamster white adipocytes, which possess both beta- and alpha-adrenergic receptors, were studied after a 6-day in vivo epinephrine administration (1 mg/kg, daily). This treatment resulted in a 3-fold increase in total plasma catecholamine levels and in the following changes in the adipocytes. The lipolytic and cAMP responses to beta-agonists, ACTH, and theophylline were decreased by 55-60%, but the sensitivity of these responses to (-)isoproterenol was unchanged...