Beta-adrenergic drugs and risk of Parkinson's disease: A systematic review and meta-analysis.

BACKGROUND: Parkinson's Disease (PD) is a neurodegenerative disorder manifested by rest tremor, rigidity, bradykinesia, and postural instability. Recent pharmaco-epidemiological studies evaluating beta-adrenergic drug use and risk of PD have reported conflicting findings. OBJECTIVES: This systematic review and meta-analyses evaluate the association between beta-adrenergic (agonists and antagonists) drugs' use and PD. METHODS: An electronic literature search of eight databases was performed from inception to July 2021 to identify pharmaco-epidemiological studies (case-control and cohort) reporting the risk of PD in beta-adrenergic users compared to non-users. We used the generic inverse variance method and RevMan (5.3.5) to estimate pooled adjusted risk ratios (aRRs) of PD using a random-effects model. RESULTS: Of 3168 records, 15 studies (10 case-control; five cohort) with 6508,877 participants, including 87,011 PD cases, were included. In the pooled analysis (n = 10) including any beta-antagonist users, compared with non-users, the aRR for PD was 1.19 (CI: 1.05,1.35); for any beta-agonist users (n = 8) aRR for PD was 0.87 (CI: 0.78,0.97). Propranolol users had a significantly increased risk of PD (aRR:1.91; CI:1.20,3.06), whereas salbutamol use was associated with reduced risk of PD (aRR:0.95; CI:0.92,0.99). Significant heterogeneity (I2 >87%) was observed, but the majority (n = 13) of the studies were of high quality, based on the JBI tool. CONCLUSIONS: Beta-antagonist use was associated with a modestly increased risk of PD, whereas beta-agonist use was associated with a modest decreased risk of PD. Future epidemiological studies should address the issues of protopathic bias and indirect association using appropriate epidemiological methods.

NT3/TrkC Pathway Modulates the Expression of UCP-1 and Adipocyte Size in Human and Rodent Adipose Tissue.

Neurotrophin-3 (NT3), through activation of its tropomyosin-related kinase receptor C (TrkC), modulates neuronal survival and neural stem cell differentiation. It is widely distributed in peripheral tissues (especially vessels and pancreas) and this ubiquitous pattern suggests a role for NT3, outside the nervous system and related to metabolic functions. The presence of the NT3/TrkC pathway in the adipose tissue (AT) has never been investigated. Present work studies in human and murine adipose tissue (AT) the presence of elements of the NT3/TrkC pathway and its role on lipolysis and adipocyte differentiation. qRT-PCR and immunoblot indicate that NT3 (encoded by NTF3) was present in human retroperitoneal AT and decreases with age. NT3 was also present in rat isolated adipocytes and retroperitoneal, interscapular, perivascular, and perirenal AT. Histological analysis evidences that NT3 was mainly present in vessels irrigating AT close associated to sympathetic fibers. Similar mRNA levels of TrkC (encoded by NTRK3) and ß-adrenoceptors were found in all ATs assayed and in isolated adipocytes. NT3, through TrkC activation, exert a mild effect in lipolysis. Addition of NT3 during the differentiation process of human pre-adipocytes resulted in smaller adipocytes and increased uncoupling protein-1 (UCP-1) without changes in ß-adrenoceptors. Similarly, transgenic mice with reduced expression of NT3 (Ntf3 knock-in lacZ reporter mice) or lacking endothelial NT3 expression (Ntf3flox1/flox2;Tie2-Cre+/0) displayed enlarged white and brown adipocytes and lower UCP-1 expression. Conclusions: NT3, mainly released by blood vessels, activates TrkC and regulates adipocyte differentiation and browning. Disruption of NT3/TrkC signaling conducts to hypertrophied white and brown adipocytes with reduced expression of the thermogenesis marker UCP-1.

Blunted beta-adrenoceptor-mediated inotropy in valvular cardiomyopathy: another piece of the puzzle in human aortic valve disease.

OBJECTIVES: Heart failure induced by valvular cardiomyopathy occurs in a substantial proportion of patients undergoing heart valve surgery. We aimed (i) to quantify beta-adrenoceptor (beta-AR) function by measuring the inotropic effect of isoprenaline in left ventricular (LV) tissue and (ii) to correlate beta-AR-mediated inotropy with clinical markers of heart failure. METHODS: A total of 179 LV myocardial samples were obtained from 104 consecutive patients who underwent aortic valve (AV) surgery between 2017 and 2019. Beta-ARs were stimulated by increasing the concentrations of isoprenaline, followed by a single high concentration of forskolin and calcium. Beta-AR sensitivity was estimated as the concentration to achieve half maximum effects (EC50). Maximum effect size was calculated as the relative beta-AR-mediated inotropic response compared to the force in the presence of high calcium [FISO/Ca (%)]. In vitro data were correlated with the clinical indicators of LV disease. RESULTS: FISO/Ca was independent of age and sex and amounted to 79.6 ± 20.5%. In a multivariate regression model, we found a significant inverse association between FISO/Ca and preoperative left ventricular end-diastolic diameter increase per 10 mm (OR -9.24, 95% CI -16.66 to -1.82; P = 0.015). Furthermore, patients with end-stage heart failure showed a strong tendency towards more severe reduction of max beta-AR response, as indicated by reduced FISO/Ca in a multivariate model (OR -29.60, 95% CI -61.92 to 2.72; P = 0.055). CONCLUSIONS: Our study indicates that in vitro myocardial contractility testing can quantify beta-AR dysfunction in patients with AV disease. We found a significant association between reduced beta-AR sensitivity and increased LV diameter, which may indicate a role of beta-AR dysfunction in the development of heart failure in patients with AV disease.

Functionality of beta-adrenergic receptors in patients with cirrhosis treated chronically with non-selective beta-blockers.

BACKGROUND: In patients with cirrhosis, beta-adrenoceptors expressed on peripheral blood mononuclear cells have a reduced response to catecholamine stimulation. This study aimed to determine if chronic treatment with beta-blockers influences these changes. METHODS: Blood samples were collected from patients with cirrhosis treated in outpatient clinics. Differences in cyclic AMP production before and after stimulation of mononuclear cells with epinephrine and/or N-Formylmethionine-leucyl-phenylalanine (fMLP) was used as a marker of beta-adrenoceptors activity in patients treated (N = 19) versus not treated (N = 55) with beta-blockers. In addition, we studied the gene expression of different types of adrenoceptors and possible associations with the activity of beta-adrenoceptors, the serum concentrations of catecholamines and cytokines, and the presence of bacterial antigens such as DNA or gram-negative bacterial endotoxin in patients' blood. RESULTS: The increase in intracellular cAMP concentrations after stimulation of adrenergic receptors with epinephrine was significantly higher in samples from patients treated with beta-blockers. Older patients showed lower responses to epinephrine stimulus, while the response increased linearly with the duration of the beta-blocker treatment. mRNA expression levels of adrenoceptors ß1, ß2, ß3 and α1-A, B and D showed no significant differences according to treatment with beta-blockers. Neither serum cytokines nor catecholamines levels were significantly associated with the intracellular production of cAMP after adrenergic stimulation. CONCLUSION: Chronic treatment with beta-blockers in patients with cirrhosis enables beta-adrenoceptors to respond to catecholamine stimulation irrespective of the degree of systemic adrenergic or immune activations of the patient at the time of sampling.

Beta1- and Beta2-Adrenoceptors Expression Patterns in Human Non-small Cell Lung Cancer: Relationship with Cancer Histology.

Assessment of Beta-AR protein expression on tumour tissues might be a plausible strategy to select cancer patients who can benefit from Beta-blockers therapy. The aim of this study is to evaluate the differences between resected tissue specimens from primary lung cancer (adenocarcinoma (ADC) and squamous cell carcinoma (SCC)) in terms of expression pattern of Beta1- and Beta2-AR in both tumour and adjacent surrounding non-tumour tissue. This retrospective study was based on the analysis of 80 patients with histologically confirmed diagnosis of primary Non-Small Cell Lung Cancer (NSCLC) who received surgical treatment. The cases were carefully selected in order to obtain the most homogeneous sample in terms of histologic subtype (40 ADCs and 40 SCCs) and clinical stage (10 each). Beta1- and Beta2-AR expression was determined by immunohistochemistry and the staining evaluated by semi-quantitative scoring using the H-score method. In our NSCLC series, Beta1- and Beta2-AR are differentially expressed. Beta1-AR expression is present at low levels in both SCC and ADC. Likewise, when compared with the matched surrounding non-tumour tissues, Beta1-AR expression level was significantly lower in both histologic subtypes. Conversely, Beta2-AR is highly expressed in both histologic subtypes, but clearly highly expressed in ADC when compared with SCC and with their matched surrounding non-tumour tissue. Overall, this clinicopathological study highlights the differential expression of Beta1- and Beta2-AR in ADC and SCC. Repurposing non-selective Beta-blockers in oncologic setting might be a suitable therapeutic strategy for lung ADC. Graphical abstract.

Brain cholesterol metabolite 24-hydroxycholesterol modulates inotropic responses to ß-adrenoceptor stimulation: The role of NO and phosphodiesterase.

AIMS: 24-Hydroxycholesterol (24HC) is the main brain cholesterol metabolite, which level in the circulation is significantly changed under physiological and pathological conditions. Here, we have studied the effect of 24HC on the inotropic responses to ß-adrenoceptor (AR) stimulation. MAIN METHODS: Electrical stimulation-evoked contractions were recorded in isolated atria from mice. Fluorescent dyes, Fluo-4 and DAF-FM, were used for estimation of Ca2+ transient and NO production, respectively. KEY FINDINGS: We revealed that 24HC in the submicromolar range attenuated ß-AR-induced positive inotropy in isolated atria. This was accompanied by a decrease in Ca2+ transient and unchanged nitric oxide (NO) production. However, ß1-AR-induced positive inotropy and enhancement of Ca2+ transient were increased by 24HC due to suppression of NO production. Only ß2-AR-dependent inotropy and enhancement of Ca2+ transient were decreased by 24HC in a NO-independent manner. Inhibition of phosphodiesterase (PDE) suppressed effect of 24HC on ß2-AR-dependent contractility as well as on non-subtype specific ß-AR activation. Moreover, 24HC counteracted positive inopropic action of PDE inhibitors, IBMX and rolipam. Thus, 24HC modulates the effects of ß1- and ß2-AR stimulation via different mechanisms linked with change in activity of NO synthase or PDE, respectively. Under conditions of non-selective activation of ß-ARs, the depressant effect of 24HC related with ß2-AR-dependent signaling dominates. SIGNIFICANCE: We suggest that 24HC could serve as a modulator of atrial ß-AR signaling, contributing to regulation of contractility.

Organic chemicals from diesel exhaust particles affects intracellular calcium, inflammation and ß-adrenoceptors in endothelial cells.

Exposure to diesel exhaust particles (DEP) may contribute to endothelial dysfunction and cardiovascular disease. DEP, extractable organic material from DEP (DEP-EOM) and certain PAHs seem to trigger [Ca2+]i increase as well as inflammation via GPCRs like ßARs and PAR-2. In the present study we explored the involvement of ßARs and PAR-2 in effects of DEP-EOM on [Ca2+]i and expression of inflammation-associated genes in the endothelial cell-line HMEC-1. We exposed the human microvascular endothelial cell line HMEC-1 to DEP-EOM fractionated by sequential extraction with solvents of increasing polarity: n-hexane (n-Hex-EOM), dichloromethane (DCM-EOM), methanol (Methanol-EOM) and water (Water-EOM). While Methanol-EOM and Water-EOM had no marked effects, n-Hex-EOM and DCM-EOM enhanced [Ca2+]i (2-3 times baseline) and expression of inflammation-associated genes (IL-1α, IL-1ß, COX-2 and CXCL8; 2-15 times baseline) in HMEC-1. The expression of ßARs (60-80% of baseline) and ßAR-inhibitor carazolol suppressed the increase in [Ca2+]i induced by both n-Hex- and DCM-EOM. Carazolol as well as the Ca2+-channel inhibitor SKF-96365 reduced the DCM-EOM-induced pro-inflammatory gene-expression. Overexpression of ßARs increased DCM-EOM-induced [Ca2+]i responses in HEK293 cells, while ßAR-overexpression suppressed [Ca2+]i responses from n-Hex-EOM. Furthermore, the PAR-2-inhibitor ENMD-1068 attenuated [Ca2+]i responses to DCM-EOM, but not n-Hex-EOM in HMEC-1. The results suggest that ßAR and PAR-2 are partially involved in effects of complex mixtures of chemicals extracted from DEP on calcium signalling and inflammation-associated genes in the HMEC-1 endothelial cell-line.

Oxytocin modulates the expression of norepinephrine transporter, ß3-adrenoceptors and muscarinic M2 receptors in the hearts of socially isolated rats.

Social stress produces behavioral alterations, and autonomic and cardiac dysfunction in animals. In addition to the well-known roles of oxytocin on birth and maternal bonding, recent evidence shows that this neuropeptide possesses cardio-protective properties. However less is known about its role in the regulation of the autonomic nervous system. The direct influence of oxytocin on the cardiac catecholamine synthesizing enzyme, transport beta-adrenoceptors and muscarinic receptors in animals exposed to chronic social isolation stress has not yet been studied. In this study, we examined the influence of peripheral chronic oxytocin treatment on anxiety-related behavior, the morphology and content of epinephrine and norepinephrine, mRNA and protein levels of tyrosine hydroxylase (TH), norepinephrine transporter (NET) and receptors  3 (ß3-AR) and muscarinic 2 (M2 MR) in the right and left cardiac atrium and ventricle of chronically socially isolated male rats. Our results show that oxytocin treatment exhibits an anxiolytic effect, decreases the heart/body weight ratio and prevents the hypertrophy of cardiomyocytes in the wall of the left ventricle of stressed rats. Epinephrine and TH protein levels were unchanged after prolonged oxytocin treatment. Peripheral oxytocin administration led to the enhancement of gene expression of ß3-AR in both atria, NET protein in the left ventricle and gene expression of M2 MR in the right atrium and the left ventricle of chronically socially isolated rats. The study provides evidence that oxytocin treatment in chronically socially isolated animals enhances norepinephrine uptake and expression of cardio-inhibitory receptors in cardiac tissues, which could have a beneficial effect on the cardiovascular system under the increased activity of the sympathoneural system.

Influence of ß2- and ß3-adrenoceptor agonists on contractile activity of the porcine myometrium in the luteal phase and the first days of pregnancy.

This study analysed the relaxant properties of salbutamol (ß2-adrenoceptors agonist) and BRL 37344 (ß3-adrenoceptors agonist) regarding the contractility of porcine myometrium on days 10-14 of the oestrous cycle (cyclic group; n = 10) and on days 3-5 of pregnancy (early pregnant group; n = 6). The activity of myometrial strips (tension, frequency and amplitude) was recorded under isometric conditions using force transducers. The contractility was assessed further following the administration of increasing concentrations of the agonists (10-9-10-4 M), both with and without ß-adrenoceptor antagonists (butaxamine - a selective ß2- adrenoceptor antagonist, propranolol- a non-selective ß1- and ß2-adrenoceptor antagonist and bupranolol - a non-selective ß1-, ß2- and ß3-adrenoceptor antagonist) at a concentration of 10-4 M. Although neither salbutamol nor BRL 37344 caused changes in the tension, at the highest concentrations they decreased the frequency and amplitude of contractions. These changes were more evident after salbutamol treatment and in the early pregnant group. Antagonists given alone did not cause changes in the parameters examined but changed some activity of the agonists. Butoxamine reduced the decrease in frequency and amplitude induced by salbutamol and produced a decrease in the tension after BRL 37344 treatment in the early pregnant group. Propranolol reduced the decrease in frequency and amplitude induced by salbutamol in both examined groups and did not cause significant changes in BRL 37344 activity. The administration of bupranolol before salbutamol treatment caused an increase in the tension and reduced the decrease in the frequency in the cyclic group. Moreover, bupranolol eliminated a decrease in frequency and induced an increase in amplitude caused by BRL 37344 in both groups and these changes were more evident in the early pregnant group. The data indicates that both ß2- and ß3-adenoreceptors are involved in the regulation of the contractility in both groups, but the changes after agonists and antagonists treatment are more evident in the early pregnant myometrium.

Sex-difference in expression and function of beta-adrenoceptors in macrovessels: role of the endothelium.

Estrogen modulates adrenergic reactivity of macrovessels, resulting in weaker α-adrenergic vasoconstriction in females than males. However, the mechanisms governing this important sex-specific difference are not well understood. We hypothesized that vessels of females express more dilatory ß-adrenoceptors, which counteract constrictive effects of α-adrenoceptors. This hypothesis was tested using aortas of normotensive (WKY) and hypertensive rats (SHR), along with human mammary artery. Selective blockade of ß1 (CGP20712) or ß3 (SR59230A), but not ß2 (ICI118,551) adrenoceptors, greatly increased α-adrenergic constriction (norepinephrine) of aorta in female SHRs, but not in male SHRs at 12 weeks of age. Consistently, the selective ß1/ß2 (isoproterenol) and ß3-adrenergic (BRL37344) relaxation was stronger in female SHRs than in males. Removal of endothelium and use of L-NMMA abolished sex-difference in α-adrenergic constriction and ß-adrenergic relaxation. Immunostainings revealed endothelial localization of ß1- and ß3-adrenoceptors. mRNA levels of aortic ß1- and ß3-, but not ß2-adrenoceptors were markedly higher in female than in male SHRs. The sex-specific differences in α-adrenergic constriction and ß-adrenoceptor mRNA levels were age-dependent, predominantly present up to 29 weeks and disappeared at 36 weeks of age. The sex-specific difference was not strain-dependent and was similarly present in normotensive WKY rats. Human mammary artery of women showed a weaker α-adrenergic constriction than arteries of men. This sex-specific difference was prominent at 45-65 years and disappeared with aging. Our results convincingly demonstrate that female macrovessels express more dilatory ß1- and ß3-adrenoreceptors than male vessels with a predominant endothelial localization. This sex-specific difference is functionally relevant in young adults and is attenuated with aging.

Insulin therapy normalizes reduced myocardial ß-adrenoceptors at both the onset and after sustained hyperglycemia in diabetic rats.

AIMS: Reduced cardiac ß-adrenoceptors (ß-AR) and cardiovascular (CV) dysfunction occur in diabetes mellitus (DM) and can be normalized by insulin. It is unclear how the duration of untreated hyperglycemia prior to intervention impacts insulin's effects. This study assesses insulin's effect on reduced myocardial ß-AR and CV function, comparing insulin therapy at the onset of hyperglycemia and after a sustained period of hyperglycemia in streptozotocin (STZ) rats. MAIN METHODS: Ex vivo biodistribution experiments with [(3)H]CGP12177 were performed in high-fat fed STZ rats after 8 weeks of hyperglycemia evaluating cardiac ß-AR expression. Western blotting of ß-AR subtypes was completed in parallel. Serial echocardiography at 0, 6, and 8 weeks post-STZ investigated CV function. Sub-groups of hyperglycemic rats were treated with insulin early, at 1 week post-STZ (InsE) for 7 weeks, or late at 6 weeks post-STZ (InsL) for 2 weeks to observe how the duration of hyperglycemia prior to insulin impacts its effects. KEY FINDINGS: Reduced myocardial [(3)H]CGP12177 binding occurred 8 weeks post-STZ in hyperglycemics, but was normal in both insulin treatments. Western blotting supported reduced ß1-AR in hyperglycemics, but not in either treatment. InsE and InsL treatments improved prolonged mitral valve deceleration (MVD) observed in hyperglycemic animals, but hyperglycemic and InsL still displayed reduced heart rates (HR). SIGNIFICANCE: This work supports that glycemic control with insulin normalizes cardiac ß-AR effectively regardless of prior hyperglycemia but HR may not recover as readily, indirectly supporting the utility of [(11)C]CGP12177 positron emission tomography (PET) in assessing cardiac ß-AR and their modulation with glycemic therapy.

Noradrenaline-induced release of newly-synthesized accumbal dopamine: differential role of alpha- and beta-adrenoceptors.

Previous studies have shown that intra-accumbens infusion of isoproterenol (ISO), a beta-adrenoceptor-agonist, and phenylephrine (PE), an alpha-adrenoceptor-agonist, increase the release of accumbal dopamine (DA). In the present study we analyzed whether the ISO-induced release of DA is sensitive to pretreatment with the DA synthesis inhibitor alpha-methyl-para-tyrosine (AMPT). Earlier studies have shown that the PE-induced release of DA is derived from DA pools that are resistant to AMPT. In addition to PE, the alpha-adrenoceptor-antagonist phentolamine (PA) was also found to increase accumbal DA release. Therefore, we investigated whether similar to the DA-increasing effect of PE, the DA increase induced by PA is resistant to AMPT. Pretreatment with AMPT prevented the ISO-induced increase of accumbal DA. The accumbal DA increase after PA was not reduced by the DA synthesis inhibitor, independently of the amount of DA released. These results show that mesolimbic beta-, but not alpha-adrenoceptors, control the release of accumbal newly-synthesized DA pools. The DA-increasing effects of PE have previously been ascribed to stimulation of presynaptic receptors located on noradrenergic terminals, whereas the DA-increasing effects of PA and ISO have been ascribed to an action of these drugs at postsynaptic receptors on dopaminergic terminals. The fact that AMPT did not affect the accumbal DA response to PE and PA, whereas it did prevent the accumbal DA increase to ISO, supports our previously reported hypothesis that the noradrenergic neurons of the nucleus accumbens containing presynaptic alpha-adrenoceptors impinge upon the dopaminergic terminals in the nucleus accumbens containing postsynaptic adrenoceptors of the alpha but not of the beta type. The putative therapeutic effects of noradrenergic agents in the treatment of DA-related disorders are shortly discussed.

Positive emotional arousal increases duration of memory traces: different role of dopamine D1 receptor and ß-adrenoceptor activation.

We investigated the effects of post-training administration of dopamine D1 receptor antagonist SCH 23390 and ß-adrenergic receptor antagonist Propranolol on memory retention of an object sampled in a state of positive emotional arousal. Saline-treated mice trained and tested under high emotional/motivational arousal (High) showed discrimination of a novel object both 24 and 96 h post-training. Instead, mice trained and tested under low motivational arousal (Low) were unable to discriminate the novel object 96 h post-training. Both a high (2 mg/kg) and a low (1 mg/kg) dose of Propranolol reduced object discrimination in High mice tested 24 h post-training, whereas neither dose was effective in Low mice. A high dose of SCH 23390 (0.025 mg/kg) reduced discrimination of the novel object in High mice tested both 24 and 96 h post-training, whereas a low dose of the D1 antagonist (0.01 mg/kg) reduced discrimination in High mice tested 96 h post-training and abolished discrimination in Low mice tested 24h after training.

Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?

Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received increasing attention. Blockage of ß-adrenoceptors in the intestinal mucosa and gut lymphatic tissue together with changes in type and virulence of the intestinal microbiota lead to reduced bacterial translocation and a subsequent decrease in the portal load of pathogen-associated molecular patterns. This may reduce hepatic inflammation. Blockage of ß-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow-up. Observational studies carry a high risk of bias. The meta-analytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient.