Β-adrenergic Blockers Research Articles

Efficacy & tolerability of bisoprolol in comparison to metoprolol in Indian patients with stage-1 hypertension: multicentre, parallel group, open labelled, randomised noninferiority clinical study

Abstract Introduction Bisoprolol & Metoprolol are selective β1 adrenergic blockers used in treatment of several diseases, including hypertension (HTN). Unlike Metoprolol, the β1-receptor selectivity of Bisoprolol does not change with increasing dose and Bisoprolol also has a longer half-life. The objective was to compare the efficacy & tolerability of Bisoprolol with Metoprolol in Indian patients with Stage-1 HTN. Method Multicentre, parallel group, open labelled, randomised noninferiority trial was conducted at 6 cardiology centres in India (2010 – 2011). The study was approved by the institutional ethics committee at each centre and was performed in accordance with the good clinical practice guidelines and ICH-GCP. Out 218 adult patients screened, 200 patients between the age group of 18 to 65 years, with systolic blood pressure (SBP) 140–159 mm Hg or diastolic blood pressure (DBP) 90–99 mm Hg were randomly assigned to receive either Bisoprolol 5 mg once daily or Metoprolol-SR 50 mg once daily. Primary outcome measure was the responder rate (% of patients achieving BP <140/90 mm Hg throughout 24 hours) at 12 weeks. The secondary outcome measures were the percentage of patients requiring dose titration at 6 weeks, change in the SBP & DBP from baseline at 6 and 12 weeks, change in the mean night-time blood pressure from baseline at 12 weeks & global efficacy and tolerability assessment on a four-point scale. Results 200 patients (100 each in the 2 arms, 74.5% Males, mean age of 49.55 and 53.39 in the bisoprolol and metoprolol arms respectively) were enrolled in the study. Efficacy analysis was done on 165 patients who completed the study. There was a trend towards a better 24 hr BP control rate with Bisoprolol, responder rates were 68.33% for Bisoprolol and 62.9% for Metoprolol as measured by continuous ambulatory blood pressure measurement. Also Bisoprolol was non-inferior to Metoprolol with respect to percentage of patients requiring dose titration (12.3% vs 11.6%), change in SBP (7.7% vs 7.2%) & DBP (9.6% vs 9.1%), change in mean night-time blood pressure (29.1% vs 25.3%) and reduction in heart rate (9.2% vs 6.7%). The two treatments were also similar with respect to efficacy & tolerability on Global Assessment by doctors & patients respectively. Conclusion Bisoprolol is non-inferior to Metoprolol-SR with respect to efficacy & safety in patients of stage-1 HTN, with a trend towards better control of 24 hr BP in this non-inferiority trial. This study was conducted at a time when β-blockers were considered as first-line therapies for the management of hypertension. Our study supports the use of bisoprolol in Indian patients, based on the non-inferiority (as compared to metoprolol) and with the advantageous profile of the molecule. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The study was supported by a research grant from Merck.

Beta-adrenergic glaucoma drugs reduce lymphatic clearance from the eye: A sequential photoacoustic imaging study

Our study aims to determine whether the beta-adrenergic system is involved in the regulation of lymphatic drainage from the eye. For this purpose, we assessed the effect of 2 topical beta-adrenergic blockers, timolol and betaxolol, commonly used as glaucoma drugs, on lymphatic clearance of albumin from the aqueous humor to neck lymph nodes. Adult mice were treated with either topical timolol, a non-selective β-blocker, 0.5% (n = 8), or topical betaxolol, a selective β1-adrenergic blocker, 0.5% (n = 6) twice daily for 14 days and compared to respective control groups (n = 5 and n = 7). Changes in lymphatic clearance from the eye were assessed using a quantitative in vivo photoacoustic imaging approach. In all subjects, right eye and neck lymph nodes were longitudinally assessed by sequential photoacoustic imaging just prior to near-infrared dye injection into the anterior chamber of the eye, and 20 min, 2 and 4 h after injection. Repeat measurements of mean pixel intensities (MPIs) of right eyes and nodes were performed at all timepoints. The areas under the curves (AUC) were calculated and the AUC of the treated-group was compared to that of controls using the Mann-Whitney U test. The slopes of MPI of each region of interest over time were compared using the linear mixed model after adjusting for IOP decrease after treatment and other parameters such as sex and body weight. In the timolol-treated group, right neck nodes showed significant decrease in AUC signal intensity compared with controls (P = 0.003), and significant decrease in slope of MPI compared with controls (P = 0.0025). In the betaxolol-treated group, right neck nodes showed significant decrease in AUC signal intensity compared with controls (P = 0.02), and significant decrease in slope of MPI compared with controls (P = 0.0069).Topical treatment with timolol and betaxolol reduced lymphatic clearance of albumin from the aqueous humor to the neck lymph nodes. This finding may be relevant for the management of secondary glaucomas and inflammatory eye disease in which the clearance of accumulated proteins and antigen from the eye is important to disease recovery and sight protection. This study suggests that the beta-adrenergic system plays a role in the regulation of lymphatic clearance from the eye.

The β-adrenergic receptor blocker and anti-inflammatory drug propranolol mitigates brain cytokine expression in a long-term model of Gulf War Illness

AimsGrowing evidence suggests that Gulf War Illness (GWI) is the result of underlying neuroimmune dysfunction. For example, previously we found that several GWI-relevant organophosphate acetylcholinesterase inhibitors produce heightened neuroinflammatory responses following subchronic exposure to stress hormone as a mimic of high physiological stress. The goal of the current study was to evaluate the potential for the β-adrenergic receptor inhibitor and anti-inflammatory drug, propranolol, to treat neuroinflammation in a novel long-term mouse model of GWI. Main methodsAdult male C57BL/6J mice received a subchronic exposure to corticosterone (CORT) at levels mimicking high physiological stress followed by exposure to the sarin surrogate, diisopropyl fluorophosphate (DFP). These mice were then re-exposed to CORT every other week for a total of five weeks, followed by a systemic immune challenge with lipopolysaccharide (LPS). Animals receiving the propranolol treatment were given a single dose (20 mg/kg, i.p.) either four or 11 days prior to the LPS challenge. The potential anti-neuroinflammatory effects of propranolol were interrogated by analysis of cytokine mRNA expression. Key findingsWe found that our long-term GWI model produces a primed neuroinflammatory response to subsequent immune challenge that is dependent upon GWI-relevant organophosphate exposure. Propranolol treatment abrogated the elaboration of inflammatory cytokine mRNA expression in the brain instigated in our model, having no treatment effects in non-DFP exposed groups. SignificanceOur results indicate that propranolol may be a promising therapy for GWI with the potential to treat the underlying neuroinflammation associated with the illness.

Cardioluminescence in Transgenic Zebrafish Larvae: A Calcium Imaging Tool to Study Drug Effects and Pathological Modeling.

Zebrafish embryos and larvae have emerged as an excellent model in cardiovascular research and are amenable to live imaging with genetically encoded biosensors to study cardiac cell behaviours, including calcium dynamics. To monitor calcium ion levels in three to five days post-fertilization larvae, we have used bioluminescence. We generated a transgenic line expressing GFP-aequorin in the heart, Tg(myl7:GA), and optimized a reconstitution protocol to boost aequorin luminescence. The analogue diacetyl h-coelenterazine enhanced light output and signal-to-noise ratio. With this cardioluminescence model, we imaged the time-averaged calcium levels and beat-to-beat calcium oscillations continuously for hours. As a proof-of-concept of the transgenic line, changes in ventricular calcium levels were observed by Bay K8644, an L-type calcium channel activator and with the blocker nifedipine. The β-adrenergic blocker propranolol decreased calcium levels, heart rate, stroke volume, and cardiac output, suggesting that larvae have a basal adrenergic tone. Zebrafish larvae treated with terfenadine for 24 h have been proposed as a model of heart failure. Tg(myl7:GA) larvae treated with terfenadine showed bradycardia, 2:1 atrioventricular block, decreased time-averaged ventricular calcium levels but increased calcium transient amplitude, and reduced cardiac output. As alterations of calcium signalling are involved in the pathogenesis of heart failure and arrhythmia, the GFP-aequorin transgenic line provides a powerful platform for understanding calcium dynamics.

Development and Evaluation of Micro Emulsion Formulations of Nebivolol for Solubility Enhancement

Nebivolol HCl is a newer drug of β1-adrenergic blocker category, basically used as anti-hypertensive. It is a 3rd generation, antagonist, having NO (nitric oxide) enhancing vasodilator properties. It has 12% oral bioavailability, because of its pre systemic metabolism by the means of cytochrome P450 2D6 enzymes. Its log P value is 4.03 and 5mg is its daily dose. It is highly lipophilic drug and belongs to class BCS II, with slow dissolution. Bioavailability of any drug can be improved by avoiding its first pass metabolism and promoting solubility. Several researchers have worked on the development of ME formulations on different poor water-soluble drugs, to increase their solubility. The purpose of this study is an attempt to enhance the solubility to improve the bioavailability of nebivolol drug by developing a novel delivery system that is microemulsion (ME) .ME formulations were developed using different oil, surfactant and co-surfactants in different ratio and studied on various parameters. Different preformulation tests done on received sample of Nebivolol. FTIR study was performed in order to find out any interactions between the ingredients. Based on the solubility Capmul Pg-12 was finalized oil, Tween 80 as surfactant, propylene glycol as the cosurfactant based on solubility and emulsification efficiency. Five Nebivolol ME formulations were successfully developed by use of oil, water, SA and Co-SA different ratio. Prepared formulations were studied for different properties- transmittance (%), pH, refractive index, viscosity, drug content, and solubility. It was seen that after 4 hours of diffusion, the drug released from the formulation ME5 is faster and more than that of the other i.e., 90.2±0.06%. It was found that ME5 was more stable and Soluble than other prepared formulations. With the better solubilty the bioavailability of Nebivolol will increased and helps in faster absorption and High diffusion in systemic circulation with lower or no risk of degradation. It somehow also reduced frequent intake of drug.
 Keywords: Nebivolol, micro emulsion, Ternary phase diagram, surfactant, co-surfactant.

Antihypertensive and cardioprotective effects of different monotherapies and combination therapies in young spontaneously hypertensive rats - A pilot study.

Spontaneously hypertensive rats (SHR) are an established animal model for antihypertensive treatment. The aim of this pilot study was a systematic search for two lines of antihypertensive treatment – a monotherapy and a combination of two drugs – to be applied in a future study on old SHR. Originally, representatives of three drug classes recommended for antihypertensive therapy in humans should be applied, namely captopril (CAP) as an antagonist of the renin-angiotensin-aldosterone system, nifedipine (NIF) as calcium channel blocker and propranolol (PROP) as β-adrenergic blocker. As we observed that PROP had been poorly ingested, all groups with PROP therapy were excluded from the study. CAP (60 mg kg−1 d-1), NIF (10 mg kg−1 d-1) or both were administered orally to seven-week-old SHR over 3 weeks. A further group of SHR received no treatment (SHR/CTRL). Age-matched normotensive Wistar-Kyoto rats served as normotensive controls. We examined the effect of the antihypertensive therapies on systolic blood pressure, heart weight and on histological and biochemical markers of cardiac hypertrophy and fibrosis.CAP proved to be the most effective treatment reducing blood pressure and relative heart weight significantly compared to SHR/CTRL without reaching normotensive values. Beginning cardiac fibrosis observed in SHR/CTRL was completely abrogated with CAP treatment. Similar effects were achieved with a combination of CAP and NIF. CAP as monotherapy and CAP + NIF as combination therapy were chosen for the forthcoming study on old SHR.

Диабетическая кардиомиопатия: лечение

В обзоре проведен анализ литературных источников, посвященных некоторым ключевым аспектам со­временного состояния проблемы лечения диабетической кардиомиопатии. На первом плане лечения диабетической кардиомиопатии должны быть мероприятия, направленные на уменьшение инсулиновой резистентности, коррекцию гипергликемии, дислипопротеинемий, нарушений метаболизма миокарда, предупреждение и лечение тромбообразования; симптоматическую терапию сопутствующих заболеваний и синдромов артериальной гипертензии, ишемической болезни сердца, сердечной недостаточности и аритмий. В этом направлении необходимо проводить следующие лечебно-профилактические мероприятия: рациональное питание и физическая активность, коррекция ожирения, ограничение употребления соли до 2–4 г/сут, исключение курения, употребления алкоголя, продуктов, содержащих кофеин. В частности, анализируются вопросы, связанные с особенностями рационального питания и физической активности; оптимизации контроля гликемии (инсулин и/или секретагоги инсулина, аналоги глюкагоноподобного пептида-1, ингибиторы натрий-глюкозного котранспортера-2); коррекции метаболических нарушений в миокарде (препараты, улучшающие энергетическое состояние клеток (потенциальные средства энергообеспечения выживания ишемизированного миокарда), модуляторы метаболизма (метаболические препараты — триметазидин, пергекселин, ранолазин), L-карнитин); ограничения поступления внеклеточного ионизированного кальция в клетки (блокаторы кальциевых каналов), применения блокаторов β-адренорецепторов; модуляции оксидантного стресса (альфа-липоевая кислота, бенфотиамин); назначения длинноцепочечных ω-3 полиненасыщенных жирных кислот; сульфорафана, коэнзима Q10; магния; рассмотрены перспективные пути в лечении диабетической кардиомиопатии (пептиды-миметики, мишенью для которых является L-тип Ca2+-каналов; некодирующие микроРНК и длинные некодирующие РНК).

Carvedilol inhibits Aβ25-35 fibrillation by intervening the early stage helical intermediate formation: A biophysical investigation

Self-assembly of disordered amyloid-beta (Aβ) peptides results in highly ordered amyloid fibrils. The structural information of the early-stage events and also in the presence of inhibitors is of great significance. It is challenging to acquire due to the nature of the amyloids and experimental constraints. Here, we demonstrate the cascade of aggregation (early to late) of the Aβ25-35 peptide in the absence and presence of carvedilol, a nonselective β-adrenergic receptor blocker. The aggregation process of Aβ25-35 peptide is monitored using Thioflavin T (ThT) fluorescence, dynamic light scattering (DLS), circular dichroism (CD), Raman spectroscopic techniques, and imaging experiments. We find that the Aβ25-35 peptide undergoes an early-stage (3-6 h) helical intermediate formation across the fibrillation pathway using CD and Raman measurements. Carvedilol obstructs the helical intermediate formation of Aβ25-35 peptide resulting in inhibition. CD spectra and deconvolution of the Raman bands suggest the β-sheet formation (24-100 h) in the absence of carvedilol. Spectroscopic results indicate a disordered structure for the peptide in the presence of carvedilol (24-100 h). Electron microscopy (EM) shows the formation of polymorphic fibrils for the peptide alone and non-amyloidal aggregates in the presence of carvedilol. Molecular docking study suggests that the plausible mode of interaction with carvedilol involves the C-terminal residues of the peptide.

Mechanisms of beta-blockers antihypertensive action

This article presents an analysis of data on the mechanisms of antihypertensive effect of β-adrenergic receptor blockers. The article describes the effectiveness of cardiotropic action of drugs to reduce high blood pressure (BP) with short-term and long-term action of compounds, the effect of blockers on the activity of plasma renin. The influence of β-blockers on the central mechanisms of blood circulation regulation is considered. Information on the effect of β-blockers on myogenic mechanisms of vascular tone regulation is presented. The possibilities of blockade of β-adrenergic receptors of endothelium-dependent hyperpolarization of smooth muscles of resistive arteries, violation of the NO-cGMP pathway and blockade of Ca2+ channel currents as factors providing expansion of resistive vessels and reduction of high BP are analyzed.

A Review on Pharmacokinetic and Pharmacodynamic Drug Interactions of Adrenergic β-blockers with Clinically Relevant Drugs-An Overview

Adrenergic β-blockers are used to treat many conditions, including hypertension, cardiac arrhythmias, heart failure, angina pectoris, migraine, and tremors. The majority of the β-blockers including Propranolol, Metoprolol, Acebutolol, Alprenolol, Betaxolol, Carvedilol, Nebivolol and Oxprenolol are metabolised majorly by CYP2D6, and Bisoprolol is primarily metabolised by CYP3A4 enzymes. The drugs inhibiting or inducing them may alter the pharmacokinetics of those β-blockers. The plasma concentrations of Propranolol might be elevated by the concomitant use of drugs, such as SSRIs (Fluoxetine, Paroxetine), SNRIs (Duloxetine) and Cimetidine, while the plasma concentrations of Metoprolol increased by the concurrent use of SSRIs (Fluoxetine, Paroxetine), Amiodarone, Celecoxib, Cimetidine, Terbinafine, and Diphenhydramine. β-blockers can also interact pharmacodynamically with drugs, including fluoroquinolones, antidiabetic agents and NSAIDs. In addition, β-blockers may interact with herbs, such as curcumin, Ginkgo biloba, Schisandra chinensis, green tea, guggul, hawthorn, St. John's wort and Yohimbine. This article focuses on clinically relevant drug interactions of β-blockers with commonly prescribed medications. In addition to Pharmacokinetics and Pharmacodynamics of the drug interactions, recommendations for clinical practice are highlighted. The prescribers and the pharmacists are needed to be aware of the drugs interacting with β-blockers to prevent possible adverse drug interactions.

An Overview of Investigational and Experimental Drug Treatment Strategies for Marfan Syndrome.

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by pathogenic variants in the gene coding for the extracellular matrix protein fibrillin-1. While the disease affects multiple organ systems, the most life-threatening manifestations are aortic aneurysms leading to dissection and rupture. Other cardiovascular complications, including mitral valve prolapse, primary cardiomyopathy, and arrhythmia, also occur more frequently in patients with MFS. The standard medical care relies on cardiovascular imaging at regular intervals, along with pharmacological treatment with β-adrenergic receptor blockers aimed at reducing the aortic growth rate. When aortic dilatation reaches a threshold associated with increased risk of dissection, prophylactic surgical aortic replacement is performed. Although current clinical management has significantly improved the life expectancy of patients with MFS, no cure is available and fatal complications still occur, underscoring the need for new treatment options. In recent years, preclinical studies have identified a number of potentially promising therapeutic targets. Nevertheless, the translation of these results into clinical practice has remained challenging. In this review, we present an overview of the currently available knowledge regarding the underlying pathophysiological processes associated with MFS cardiovascular pathology. We then summarize the treatment options that have been developed based on this knowledge and are currently in different stages of preclinical or clinical development, provide a critical review of the limitations of current studies and highlight potential opportunities for future research.

Застосування анксиолітиків та β1-адреноблокаторів в поєднанні з когнітивно-поведінковою терапією для зменшення тривожних розладів при вегето-судинній дистонії в осіб молодого віку

The article is devoted to the problem of the influence of autonomic dysfunction and anxiety disorders on the quality of life and performance of young people. The relevance of the study is beyond doubt, because vegetative-vascular dystonia is the most common pathology among adolescents and young adults. The author of the article emphasizes that functional autonomic (vegetative) disorders without appropriate correction eventually transform into organic nosological diseases, such as coronary heart disease and hypertension. Anxiety disorders and panic attacks often accompany vegetative disorders, especially in young people, and are actually obligate in the development of vegetative crises of the cerebral or cardiac type, which as a result leads to temporary disability and reduced quality of life. In the complex treatment of vegetative-vascular dystonia in young people with anxiety disorders, the use of cognitive-behavioral therapy in combination with pharmacotherapy – anxiolytic (buspirone) and a selective β1-adrenergic blocker (bisoprolol) was proposed. The dynamics of the general condition, clinical and physiological indicators and the level of anxiety in persons with cardiac, cephalic and arrhythmic syndromes are determined. As a result of the treatment of young people with vegetative-vascular dystonia, a positive effect of selective β1-adrenergic blockers on the general condition, clinical and cardiodynamic parameters was revealed in the form of disappearance or significant reduction of pain and heart rhythm disorders, normalization of blood pressure, regression of neurotic, especially anxiety disorders with simultaneous cognitive behavioral and anxiolytic therapy with buspirone, which can be recommended for use in young people, as well as young men and adolescents, in the process of training and acquiring professional skills, to improve the quality of life and prevent the development of behavioral disorders and organic complications in the future.

Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot

BackgroundPatients with Tetralogy of Fallot with pulmonary stenosis (ToF/PS), the most common form of cyanotic congenital heart disease (CHD), develop adverse right ventricular (RV) remodeling, leading to late heart failure and arrhythmia. We recently demonstrated that overactive β-adrenergic receptor signaling inhibits cardiomyocyte division in ToF/PS infants, providing a conceptual basis for the hypothesis that treatment with the β-adrenergic receptor blocker, propranolol, early in life would increase cardiomyocyte division. No data are available in ToF/PS infants on the efficacy of propranolol as a possible novel therapeutic option to increase cardiomyocyte division and potentially reduce adverse RV remodeling. MethodsUsing a randomized, double-blind, placebo-controlled trial, we will evaluate the effect of propranolol administration on reactivating cardiomyocyte proliferation to prevent adverse RV remodeling in 40 infants with ToF/PS. Propranolol administration (1 mg/kg po QID) will begin at 1 month of age and last until surgical repair. The primary endpoint is cardiomyocyte division, quantified after 15N-thymidine administration with Multi-isotope Imaging Mass Spectrometry (MIMS) analysis of resected myocardial specimens. The secondary endpoints are changes in RV myocardial and cardiomyocyte hypertrophy. ConclusionThis trial will be the first study in humans to assess whether cardiomyocyte proliferation can be pharmacologically increased. If successful, the results could introduce a paradigm shift in the management of patients with ToF/PS from a purely surgical approach, to synergistic medical and surgical management. It will provide the basis for future multi-center randomized controlled trials of propranolol administration in infants with ToF/PS and other types of CHD with RV hypertension.Clinical trial registration: The trial protocol was registered at clinicaltrials.gov (NCT04713657).

Alpha- and beta- adrenergic receptors regulate inflammatory responses to acute and chronic sleep fragmentation in mice.

Sleep is a recuperative process, and its dysregulation has cognitive, metabolic, and immunological effects that are largely deleterious to human health. Epidemiological and empirical studies have suggested that sleep fragmentation (SF) as result of obstructive sleep apnea (OSA) and other sleep abnormalities leads to pronounced inflammatory responses, which are influenced by the sympathetic nervous system (SNS). However, the underlying molecular mechanisms contributing to SNS regulation of SF-induced inflammation are not fully understood. To assess the effects of the SNS upon inflammatory responses to SF, C57BL/6j female mice were placed in automated SF chambers with horizontally moving bars across the bottom of each cage at specified intervals to disrupt sleep. Mice were first subjected to either control (no bar movement), acute sleep fragmentation (ASF), or chronic sleep fragmentation (CSF) on a 12:12-h light/dark schedule. ASF involved a bar sweep every 120 s for 24 h, whereas CSF involved a bar sweep every 120 s for 12 h (during 12 L; resting period) over a period of 4 weeks. After exposure to these conditions, mice received an intraperitoneal injection of either phentolamine (5 mg/kg BW; an α-adrenergic receptor blocker), propranolol (5 mg/kg BW; a β-adrenergic receptor blocker), or vehicle (saline). Serum corticosterone concentration, brain and peripheral cytokine (IL1β, TNFα, and TGFβ) mRNA expression, and body mass were assessed. ASF and CSF significantly elevated serum corticosterone concentrations as well as cytokine mRNA expression levels compared with controls, and mice subjected to CSF had decreased body mass relative to controls. Mice subjected to CSF and treated with phentolamine or propranolol had a greater propensity for a decrease in cytokine gene expression compared with ASF, but effects were tissue-specific. Taken together, these results suggest that both α- and β-adrenergic receptors contribute to the SNS mediation of inflammatory responses, and adrenergic antagonists may effectively mitigate tissue-specific SF-mediated inflammation.

Attenuated β-adrenergic response in calcium/calmodulin-dependent protein kinase IV-knockout mice.

In the present study, we examined the importance of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) in the regulation of cardiac function using genetically modified CaMKIV-null mice. RT-PCR analysis revealed decreased expression of voltage-dependent calcium channels in the cardiac myocytes of CaMKIV-null mice compared with wild-type mice. CaMKIV-null mice showed shortened QT time on electrocardiograms. Pharmacological analysis revealed decreased responsiveness to the β-adrenergic blocker propranolol in CaMKIV-null mice, whereas the plasma norepinephrine level was not affected. CaMKIV-null mice showed decreased baroreflex on electrocardiograms. Heart rate variability analysis showed unstable R-R intervals, a decreased low frequency power/high frequency power (LF/HF) ratio, and increased standard deviation of the normal to normal R-R intervals (SDNN) in CaMKIV-null mice, suggesting decreased responsiveness to β-adrenergic stimulation in CaMKIV-null mice. Atrial contraction analysis and cardiac action potential recording showed a decreased response to the β-adrenoceptor agonist isoproterenol in CaMKIV-null mice. Furthermore, fluorescence imaging in a CRE-hrGFP assay revealed a decreased response to isoproterenol in CaMKIV-null cardiac myocytes. Taken together, our data strongly suggest a significant effect of CaMKIV gene ablation on cardiac β-adrenergic signal transduction.

Цукровий діабет і хронічний коронарний синдром

Хронічний коронарний синдром (ХКС) характеризується розвитком епізодів ішемії внаслідок дисбалансу між потребами та кровопостачанням міокарда. Зазвичай такі епізоди провокуються фізичними або емоційними навантаженнями чи іншими стресовими ситуаціями, проте можуть виникати й спонтанно. Класичним проявом ішемії міокарда є напади стенокардії. У деяких випадках захворювання певний час може бути безсимптомним і дебютувати одразу гострим коронарним синдромом. ХКС може мати довготривалий доклінічний період на тлі підтвердженого коронарного атеросклерозу. В огляді проведений аналіз літературних джерел, присвячених сучасному стану проблеми цукрового діабету (ЦД) і ХКС. Зокрема, аналізуються питання, пов’язані з особливостями оцінки ризику, основних чинників, що зумовлюють дуже високий ризик атеросклеротичних серцево-судинних захворювань, класифікацією, основними характеристиками ХКС та його особливостями при ЦД, діагностикою ХКС (дозоване фізичне навантаження (велоергометрія, тредміл-тест) або стрес-тести, однофотонна емісійна комп’ютерна томографія, стрес-ехокардіографія; стрес-магнітно-резонансна томографія, позитронно-емісійна томографія із застосуванням радіоактивних маркерів). Аналізуються питання консервативної терапії ХКС на тлі ЦД (призначення антиагрегантів, блокаторів β-адренорецепторів, блокаторів кальцієвих каналів, нітратів, інгібіторів ангіотензинперетворювального ферменту, міокардіальних цитопротекторів, статинів). Лікування пацієнта з поєднанням ЦД і ХКС буде успішним лише в тому випадку, якщо призначено адекватну, безпечну в плані гіпоглікемій і можливих серцево-судинних ризиків цукрознижувальну терапію, з одного боку, і метаболічно нейтральну антиангінальну терапію— з іншого. Без сумніву, необхідно звернути увагу на корекцію факторів ризику ССЗ, АГ і ХСН.

Nebivolol is more effective than atenolol for blood pressure variability attenuation and target organ damage prevention in L-NAME hypertensive rats.

β-Adrenergic blockers are no longer recommended as first-line therapy due to the reduced cardioprotection of traditional β-blockers compared with other antihypertensive drugs. It is unknown whether third-generation β-blockers share the limitations of traditional β-blockers. The aim of the present study was to compare the effects of nebivolol or atenolol on central and peripheral systolic blood pressure (SBP) and its variability and target organ damage (TOD) in N-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. Male Wistar rats were treated with L-NAME for 8 weeks together with oral administration of nebivolol 30 mg/kg (n = 8), atenolol 90 mg/kg (n = 8), or vehicle (n = 8). The control group was composed of vehicle-treated Wistar rats. SBP and its variability, as well as echocardiographic parameters, were assessed during the last 2 weeks of treatment. Tissue levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor β (TGF-β), and histopathological parameters were evaluated in the left ventricle and aorta. Nebivolol had a greater ability than atenolol to decrease central SBP and mid-term and short-term blood pressure variability (BPV) in L-NAME rats. Echocardiographic analysis showed that nebivolol was more effective than atenolol on E/A wave ratio normalization. Compared with atenolol treatment, nebivolol had a greater protective effect on different TOD markers, inducing a decrease in collagen deposition and a reduction in the proinflammatory cytokines IL-6 and TNF-α in the left ventricle and aorta. Our findings suggest that the adverse hemodynamic profile and the reduced cardiovascular protection reported with traditional β-blockers must not be carried forward to third-generation β-blockers.

Rosuvastatin Reduces L-Type Ca2+ Current and Alters Contractile Function in Cardiac Myocytes via Modulation of β-Adrenergic Receptor Signaling.

Rosuvastatin is one of the most used statins to lower plasma cholesterol levels. Although previous studies have reported remarkable cardiovascular effects of rosuvastatin (RSV), the mechanisms of these effects are largely unknown. In this study, we investigated the acute effects of RSV on L-type Ca2+ currents and contractile function of ventricular myocytes under basal conditions and during β-adrenergic stimulation. The effects of RSV were investigated in freshly isolated adult rat ventricular myocytes. L-type Ca+2 currents and myocyte contractility were recorded using patch-clamp amplifier and sarcomere length detection system. All experimental recordings were performed at 36 ± 1°C. L-type Ca+2 currents were significantly reduced with the administration of 1μM RSV (~ 24%) and this reduction in Ca2+ currents was observed at almost all potential ranges applied. Suppression of L-type Ca2+ current by RSV was prevented by adenylyl cyclase (AC) and protein kinase A (PKA) inhibitors SQ 22536 and KT5720, respectively. However, inhibition of Rho-associated kinases (ROCKs) by Y-27632 or nitric oxide synthase (NOS) by L-NAME failed to circumvent the inhibitory effect of RSV. Finally, we examined the effect of RSV during β-adrenergic receptor stimulation by isoproterenol and observed that RSV significantly suppresses the β-adrenergic responses in both L-type Ca2+ currents and contraction parameters. In conclusion, RSV modulates the β-adrenergic signaling cascade and thereby mimics the impact of β-adrenergic receptor blockers in adult ventricular myocytes through modulation of the AC-cAMP-PKA pathway.

Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models.

Propranolol, a pleiotropic β-adrenergic blocker, has been anecdotally reported to reduce cerebral cavernous malformations (CCMs) in humans. However, propranolol has not been rigorously evaluated in animal models, nor has its mechanism of action in CCM been defined. We report that propranolol or its S(-) enantiomer dramatically reduced embryonic venous cavernomas in ccm2 mosaic zebrafish, whereas R-(+)-propranolol, lacking β antagonism, had no effect. Silencing of the β1, but not β2, adrenergic receptor mimicked the beneficial effects of propranolol in a zebrafish CCM model, as did the β1-selective antagonist metoprolol. Thus, propranolol ameliorated cavernous malformations by β1 adrenergic antagonism in zebrafish. Oral propranolol significantly reduced lesion burden in 2 chronic murine models of the exceptionally aggressive Pdcd10/Ccm3 form of CCM. Propranolol or other β1-selective antagonists may be beneficial in CCM disease.

Norepinephrine inhibits migration and invasion of human glioblastoma cell cultures possibly via MMP-11 inhibition

PurposeGrowing evidence has shown that the stress hormones affect tumor progression. Patients with surgery to remove tumor often have increased norepinephrine during the perioperative period. However, the effect of norepinephrine on the progression of glioblastoma has not yet studied. Therefore, the present study aimed at investigating the effects of norepinephrine on the migration and invasion of the human glioblastoma U87 and U251 cell lines and the mechanism for the effects. MethodsThe U87 and U251 cells were treated with 0, 0.1, 1, 5, 10 or 50 μM norepinephrine. A scratch wound healing assay and a transwell invasion assay were used to investigate cell migration and invasion, respectively. The Human Tumor Metastasis RT2 Profiler PCR Array was used to detect the expression of 84 genes known to be involved in metastasis. ResultsFollowing norepinephrine treatment, the ability of the U87 and U251 cells to migrate and invade was significantly decreased. Human Tumor Metastasis RT2 Profiler PCR Array assay showed that matrix metallopeptidase-11 (MMP-11) was decreased following norepinephrine treatment. The β-adrenergic receptor blocker (AR) propranolol blunted the suppressive effect of norepinephrine on the migration and invasion of U251 cells but did not have such an effect on the invasion of U87 cells. MMP-11 silencing inhibited the migration and invasion of U87 and U251 cells. The Cancer Genome Atlas data showed that patients with higher expression of MMP-11 in the glioblastoma tissues had poorer prognosis. ConclusionOur results indicate that norepinephrine inhibits the migration and invasion of human glioblastoma cells. This effect may be mediated by the decrease of MMP-11. β-AR may be a regulatory factor for this effect in U251 cells.