Beta-adrenoceptor Blockade Research Articles

Diagnostic accuracy of early computed tomographic coronary angiography to detect coronary artery disease after out-of-hospital circulatory arrest

AimTo test the diagnostic accuracy of ECG-gated coronary computed tomography angiography (CCTA) to detect coronary artery disease (CAD) among survivors of out-of-hospital circulatory arrest (OHCA). MethodsWe prospectively studied head-to-pelvis computed tomography (CT) scanning (<6 h from hospital arrival) in OHCA survivors. This sub-study tested the primary outcome of CCTA diagnostic accuracy to identify obstructive CAD (≥50% stenosis) compared to clinically-ordered invasive coronary angiography. Patients were not optimized with beta receptor blockade or nitroglycerin. Secondary analyses included CCTA accuracy for CAD in major coronary arteries, obstructive disease at ≥70% stenosis threshold, and where non-evaluable CCTA segments were considered either obstructive or non-obstructive. ResultsOf the 104 enrolled OHCA survivors, 28 (27%) received both CT and invasive angiography in this sub study. All CCTA studies were evaluable although 49/346 (14%) individual coronary segments were unevaluable, primarily due to being too small to evaluate (65%). Patient-level diagnostic accuracy for the ≥50% stenosis threshold was high at 0.93 (95% CI 0.77–0.98) with a specificity of 1.0 (95% CI 0.8–1.0), sensitivity of 0.85 (95%CI 0.58–0.96), negative predictive value of 0.88 (95% CI 0.66–0.97) and positive predictive value of 1.0 (0.74–1.0). When non-evaluable segments were considered obstructive, the sensitivity rose to 0.92 (95% CI 0.67–0.99) with lower specificity of 0.27 (95% CI 0.11–0.52). ConclusionEarly CCTA of OHCA survivors has high diagnostic accuracy to detect obstructive coronary artery disease. However, the number of non-diagnostic coronary segments is high suggesting further CCTA refinement is needed, such as the pre-CCTA use of nitroglycerin. Clinical Trial RegistrationNCT03111043 https://clinicaltrials.gov/ct2/show/record/NCT03111043

Practice Variation in Establishing the Adequacy of Beta-Blockers as an Antiarrhythmic Agent in School-Aged Children and Adolescents

BackgroundBeta-blockers (BBs) are commonly prescribed to manage arrhythmias in children and adolescents without any standardised approach to establish BB adequacy. We invited all Canadian pediatric cardiologists to participate in an anonymous survey to understand practice variation in the assessment of BB adequacy in school-aged children and adolescents with arrhythmia or the potential for arrhythmia. MethodsAn electronic survey approved by the Institutional Ethics Board was distributed by e-mail to 96 Canadian pediatric cardiologists who had been active in practice for at least 1 year. Incomplete surveys were excluded. ResultsForty-one cardiologists (43%) responded to all questions in the survey. Thirteen cardiologists (32%) reported always assessing BB adequacy, 17 (41%) did so only for specific arrhythmias, and 11 (27%) reported never performing such an assessment. A total of 19 cardiologists (46%) and 18 cardiologists (44%) reported using Holter monitoring and exercise testing, respectively, to assess beta receptor blockade adequacy. Thirteen cardiologists (32%) considered BB therapy adequate if Holter demonstrated a 20% decrease in heart rate (HR) from baseline, and 10 respondents (24%) defined adequate BB therapy using exercise testing as a 20% decrease in maximal HR or blood pressure from baseline. ConclusionDespite wide variation in practice, Holter monitoring and exercise testing are commonly used methods to measure the adequacy of BB therapy. There are no standard criteria, but the majority (56%) reported using a 20% decrease in HR or blood pressure from the pretreatment state as a criterion for adequate BB therapy in children and adolescents with arrhythmia or the potential for arrhythmia.

Stem Cell–Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy

BackgroundAlthough cardiomyopathy has emerged as a leading cause of death in Duchenne muscular dystrophy (DMD), limited studies and therapies have emerged for dystrophic heart failure. ObjectivesThe purpose of this study was to model DMD cardiomyopathy using DMD patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and to identify physiological changes and future drug therapies. MethodsTo explore and define therapies for DMD cardiomyopathy, the authors used DMD patient-specific hiPSC-derived cardiomyocytes to examine the physiological response to adrenergic agonists and β-blocker treatment. The authors further examined these agents in vivo using wild-type and mdx mouse models. ResultsAt baseline and following adrenergic stimulation, DMD hiPSC-derived cardiomyocytes had a significant increase in arrhythmic calcium traces compared to isogenic controls. Furthermore, these arrhythmias were significantly decreased with propranolol treatment. Using telemetry monitoring, the authors observed that mdx mice, which lack dystrophin, had an arrhythmic death when stimulated with isoproterenol; the lethal arrhythmias were rescued, in part, by propranolol pre-treatment. Using single-cell and bulk RNA sequencing (RNA-seq), the authors compared DMD and control hiPSC-derived cardiomyocytes, mdx mice, and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized after propranolol treatment in the mdx model. The authors also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived cardiomyocytes have dysregulated pathways similar to the human DMD heart. The authors further determined that relatively few patients with DMD see a cardiovascular specialist or receive β-blocker therapy. ConclusionsThe results highlight mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. These results may serve as a prelude for an adequately powered clinical study that examines the impact of β-blocker therapy in patients with dystrophinopathies.

Haemodynamic Balance in Acute and Advanced Heart Failure: An Expert Perspective on the Role of Levosimendan.

Acute and advanced heart failure are associated with substantial adverse short- and longer-term prognosis. Both conditions necessitate complex treatment choices to restore haemodynamic stability and organ perfusion, relieve congestion, improve symptoms and allow the patient to leave the hospital and achieve an adequate quality of life. Among the available intravenous vasoactive therapies, inotropes constitute an option when an increase in cardiac contractility is needed to reverse a low output state. Within the inotrope category, levosimendan is well suited to the needs of both sets of patients since, in contrast to conventional adrenergic inotropes, it has not been linked in clinical trials or wider clinical usage with increased mortality risk and retains its efficacy in the presence of beta-adrenergic receptor blockade; it is further believed to possess beneficial renal effects. The overall haemodynamic profile and clinical tolerability of levosimendan, combined with its extended duration of action, have encouraged its intermittent use in patients with advanced heart failure. This paper summarises the key messages derived from a series of 12 tutorials held at the Heart Failure 2019 congress organised in Athens, Greece, by the Heart Failure Association of the European Society of Cardiology.

Cardiogenic shock secondary to phaeochromocytoma: adrenalectomy on multiple mechanical circulatory support devices

Introduction Phaechromocytoma is a neuroendocrine tumour of the chromaffin cells of the adrenal medulla. Tumours secrete catecholamines and typically present with hypertensive crisis or, in rare circumstances, cardiogenic shock. Case Presentation A 33 year old male presented with hypertensive crisis and fulminant cardiogenic shock. He required mechanical ventilation for hypoxaemia secondary to acute pulmonary oedema. A CT aortogram was performed for presumed aortic dissection which revealed a necrotic, enhancing adrenal mass. Due to severe left ventricular dysfunction, he was referred to our hospital for mechanical circulatory support (MCS). Peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was established in the referral hospital and he was transferred to our intensive care unit. An Impella-CP was then inserted to offload an increasingly dilated left ventricle. Hypertensive crises continued to occur despite maximum medical therapy, and it was determined the only viable option to control these paroxysms of hypertension was to perform adrenalectomy. Surgery was successfully performed whilst on dual MCS devices (VA-ECMO and Impella). Preoperatively the patient had intravenous alpha and beta adrenoceptor blockade and fluid status was optimised to address the chronic circulating volume depletion. Glucose and electrolyte imbalances were corrected. Intra-operative management focused on blood pressure control, heart rate and arrhythmia control. Agents that induce catecholamine release were avoided and tumour manipulation was minimised. Hypotension after tumour removal was anticipated and developed relatively quickly requiring infusions of noradrenaline, adrenaline and vasopressin to support an adequate arterial pressure. His post-operative recovery was initially favourable and myocardial function had improved to the point of planning ECMO explanation. Despite cardiovascular stability the patient suffered a catastrophic intracranial haemorrhage and treatment was withdrawn. Discussion Cardiogenic shock secondary to phaeochromoctyoma can be difficult to manage and has high mortality. The evolution of short to medium term MCS devices has provided clinicians with additional therapeutic options to manage refractory cases of this uncommon cause of cardiogenic shock. The authors hope this case will add to an expanding library of practice of using MCS in phaeochromocytoma.

MP48-16 ATENOLOL REDUCES INCIDENT LOW AND INTERMEDIATE RISK PROSTATE CANCER

INTRODUCTION AND OBJECTIVES:Recent evidence from pre-clinical models of prostate cancer (PCa) suggests that disruption of adrenergic signaling by beta-adrenergic receptor blockade inhibits PCa prog...

Regulation of blood flow in the pulmonary and systemic circuits during submerged swimming in common snapping turtle (Chelydra serpentina).

Blood flow patterns and heart rate have rarely been investigated in freely swimming turtles and their regulation during swimming is unknown. In this study, we investigated the blood flow patterns and heart rate in surfacing and during graded, submerged swimming activity in common snapping turtles. We further investigated the effects of beta-adrenergic and cholinergic receptor blockade on blood flow and heart rate during these activities. Our findings illustrate that surfacing is accompanied by an increase in heart rate that is primarily due to beta-adrenergic stimulation. During swimming, this mechanism also increases heart rate while vagal withdrawal facilitates a systemic to pulmonary (left to right) shunt. The results indicate there may be important taxonomic effects on the responses of cardiac function to activity in turtle species.

The comparative effects of esmolol and amiodarone on isolated coronary artery bypass grafts

Background/aim: Esmolol and amiodarone are two most commonly used antiarrhythmic drugs in coronary artery bypass grafting (CABG) surgery. Nevertheless, blockade of beta-2 receptors by increasing doses raise concerns about possible vasospasms. We studied the vasoactive effects of amiodarone and esmolol on left internal mammary artery (LIMA), radial artery (RA), and saphenous vein (SV) grafts. Materials and methods: After determining the presence of functional smooth muscle and endothelial layers, the responses of submaximally preconstricted graft samples were recorded in a tissue bath system. A total of 96 graft samples from 40 patients were used: 16 LIMA, 16 RA, and 16 SV grafts for each drug. Esmolol and amiodarone were added to reservoirs separately, starting from a concentration of 10-8 M until a concentration of 10-4 M. Results: Although both drugs caused vasodilatation, amiodarone exhibited a more potent vasodilatory effect than esmolol (P < 0.0001 for LIMA, P = 0.0128 for RA, and P < 0.0001 for SV). The vasodilatation rates with esmolol were 48.99 ± 2.28% in LIMA, 49.77 ± 3.03% in RA, and 41.90 ± 4.05% in SV grafts and with amiodarone they were 71.65 ± 5.18% in LIMA, 58.61 ± 5.87% in RA, and 65.07 ± 4.09% in SV grafts. Conclusion: This in vitro study revealed that even increasing doses of both drugs induce vasodilatation of CABG grafts, with amiodarone having a more potent vasodilatory effect than esmolol.

Abstract 542: Manipulation of Beta Adrenergic Receptor in Pressure-Overloaded Murine Hearts Mimics Adverse Cardiac Remodeling and Reverse Remodeling

Background: Adverse cardiac remodeling (ACR) during pressure overload is a major concern in development of heart failure (HF). Cardiac reverse remodeling (CRR) normally occurs following induction of beta-receptor blockade and is linked to improved prognosis of HF. However, the detailed and regulatory mechanisms of both ACR and CRR remain to be fully elucidated. To solve these issues, a novel highly reproducible model that mimics these pathophysiological conditions is needed. Methods and results: We explored suitable experimental conditions for establishing a highly reproducible model that mimics adverse cardiac remodeling. To examine suitable durations of transverse aortic constriction (TAC) before one-week infusion of ISO (3mg/kg/day), mice were distributed into three groups according to TAC durations. Proportion of adverse cardiac remodeling was 44.4% (4 of 9) in one-week, 60.0% (6 of 10) in two-week, and 91.7% (11 of 12) in three-week TAC groups. Next we examined adequate dose of ISO infusion after three weeks of TAC. Proportion of adverse cardiac remodeling was 37.5% (3 of 8) in 1mg/kg/day, 83.3% (5 of 6) in 3mg/kg/day, and 100% (8 of 8) in 10mg/kg/day group. But infusion of 10mg/kg/day ISO caused an increase in systolic BP. Thus we identified 3-week TAC and subsequent one-week ISO (3mg/kg/day) infusion as a suitable model for ACR. To identify molecular signatures of failing hearts of our ACR model, we performed RNA-Seq analyses. We found the up-regulated genes were mainly related to fibrosis including Fbn1 , C1qtnf6 and Loxl2 and the down-regulated genes associated with mitochondrial functions including, Uqcrc1 , Ndufs3 , and Idh2 . Next, we followed the changes in cardiac function after ceasing ISO to investigate CRR. Decreased LVFS gradually recovered to baseline within 7 weeks after cessation of ISO and exhibited CRR. Gene expression signature of CRR hearts was almost identical to that of TAC hearts without ISO infusion. Conclusions: Our model exhibits a transition to adverse cardiac remodeling and subsequent reverse remodeling with high reproducibility. This novel mouse model might add new insights into these cardiac remodeling.

The Effect of Beta‐Adrenergic Receptor Blockade on Sympathetic Vasoconstrictor Responsiveness in Sedentary and Exercise‐Trained Female Rats

Stimulation of the sympathetic nervous system evokes the release of neurotransmitters and produces vasoconstriction that is primarily mediated by the binding of norepinephrine (NE) to alpha‐adrenergic receptors. However, NE may also bind to beta‐ adrenergic receptors and produce vasodilation that opposes vasoconstriction. Therefore, in the present study, we tested the hypothesis that beta‐adrenergic receptor blockade would augment sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle of sedentary and exercise trained female rats, demonstrating beta‐adrenergic receptor mediated opposition of vasoconstriction. We also hypothesized that the increase in sympathetic vasoconstrictor responsiveness in the presence of beta‐adrenergic blockade would be larger in exercise‐trained rats, indicating that exercise training augments beta‐adrenergic receptor mediated opposition of vasoconstriction. Female Sprague‐Dawley rats were randomized to Sedentary (n=8, 265 ± 28 g) and Exercise Trained (n=9, 290 ± 27 g) groups. Exercise Trained rats completed a 4‐week treadmill training regimen (5 d/week, 15 min at 40 m/min, 5% gradient). Subsequently, rats were anaesthetized and instrumented for the measurement of femoral vascular conductance (FVC), stimulation of the lumbar sympathetic chain, and contraction of the triceps surae muscle group. The percentage change of femoral vascular conductance (Δ%FVC) in response to sympathetic chain stimulation delivered at 2 and 5 Hz was determined at rest and during triceps surae muscle contraction (60% maximal contractile force) before (Control) and after beta‐adrenergic blockade (Propranolol; 0.075 mg/kg body mass, I.V.). Sympathetic vasoconstrictor responsiveness (Δ%FVC) was not different (P &gt; 0.05) between Sedentary and Exercise Trained rats at rest or during contraction. At rest, beta‐adrenergic receptor blockade did not increase (P &gt; 0.05) sympathetic vasoconstrictor responsiveness in Sedentary (Control: 2Hz: −34 ± 9 %, 5Hz: −53 ± 8 %; Propranolol: 2Hz: −31 ± 10 %, 5Hz: −49 ± 8 %) or Exercise Trained (Control: 2Hz: −38 ± 9 %, 5Hz: −57 ± 8 %; Propranolol: 2Hz: −34 ± 7 %, 5Hz: −53 ± 8 %) rats. Similarly, beta‐adrenergic receptor blockade did not increase (P &gt; 0.05) sympathetic vasoconstrictor responsiveness during exercise in Sedentary (Control: 2Hz: −7 ± 4 %, 5Hz: −20 ± 11 %; Propranolol: 2Hz: −6 ± 5 %, 5Hz: −18 ± 10 %) or Exercise Trained (Control: 2Hz: −10 ± 8 %, 5Hz: −28 ± 8 %; Propranolol: 2Hz: −6 ± 5 %, 5Hz: −24 ± 12 %) rats. In conclusion, beta‐adrenergic receptor blockade did not augment sympathetic vasoconstrictor responsiveness in resting or contracting skeletal muscle of sedentary or exercise‐trained female rats, suggesting that beta‐adrenergic receptor mediated vasodilation did not oppose vasoconstriction, regardless of training status.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada, Canadian Foundation for Innovation, and Alberta Advanced Education and Technology.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

EFFECTS OF ADVANCED HEART FAILURE TREATMENT ON MORTALITY IN PATIENTS WITH A SYSTEMIC RIGHT VENTRICLE

Patients with a systemic right ventricle are prone to develop heart failure. Beneficial effects of ACE-inhibition, angiotensin- or betareceptor blockade (advanced heart failure treatment, AHFT) are well established for patients with heart failure due to systemic left ventricular dysfunction, however

Left Ventricle Function During Therapeutic Hypothermia with Beta1-Adrenergic Receptor Blockade.

Therapeutic hypothermia is an established treatment in patients resuscitated from cardiac arrest. It is usually well-tolerated circulatory, but hypothermia negatively effects myocardial contraction and relaxation velocities and increases diastolic filling restrictions. A significant proportion of resuscitated patients are treated with long-acting beta-receptor blocking agents' prearrest, but the combined effects of hypothermia and beta-blockade on left ventricle (LV) function are not previously investigated. We hypothesized that beta1-adrenergic receptor blockade (esmolol infusion) exacerbates the negative effects of hypothermia on active myocardial motions, affecting both systolic and diastolic LV function. A pig (n = 10) study was performed to evaluate the myocardial effects of esmolol during hypothermia (33°C) and during normothermia, at spontaneous and pacing-increased heart rates (HRs). LV function was assessed by a LV pressure transducer, an epicardial ultrasonic transducer (wall thickness, wall thickening/thinning velocity) and an aortic ultrasonic flow-probe (stroke volume, cardiac output). The data were compared using a paired two-tailed Students t-test, and also analyzed using a linear mixed model to handle dependencies introduced by repeated measurements within each subject. The significance level was p ≤ 0.05. The effects of hypothermia and beta blockade were distinct and additive. Hypothermia reduced myocardial motion velocities and increased diastolic filling restrictions, but end-systolic wall thickness increased, and stroke volume and dP/dtmax (pumping function) were maintained. In contrast, esmolol predominantly affected systolic pumping function, by a negative inotropic effect. In combination, hypothermia and esmolol reduced myocardial velocities in systole and diastole by ∼40%, compared with normothermia without esmolol, inducing in combination both systolic and diastolic LV function impairment. The cardiac dysfunction deteriorated at increased HRs during hypothermia. Beta1-adrenergic receptor blockade (esmolol) exacerbates the negative effects of hypothermia on active myocardial contraction and relaxation. The combination of hypothermia with beta-blockade induces both systolic and diastolic LV function impairment.

Beta adrenoceptor blockade ameliorates impaired glucose tolerance and alterations of the cerebral ceramide metabolism in an experimental model of ischemic stroke.

Background:Sphingolipids are versatile signaling molecules derived from membrane lipids of eukaryotic cells. Ceramides regulate cellular processes such as proliferation, differentiation and apoptosis and are involved in cellular stress responses. Experimental evidence suggests a pivotal role of sphingolipids in the pathogenesis of cardiovascular diseases, including ischemic stroke. A neuroprotective effect has been shown for beta-adrenergic antagonists in rodent stroke models and supported by observational clinical data. However, the exact underlying pathophysiological mechanisms are still under investigation. We aimed to examine the influence of propranolol on the ceramide metabolism in the stroke-affected brain.Methods:Mice were subjected to 60 or 180 min transient middle cerebral artery occlusion (tMCAO) and infarct size, functional neurological deficits, glucose tolerance, and brain ceramide levels were assessed after 12, 24, and 72 h to evaluate whether the latter two processes occur in a similar time frame. Next, we assessed the effects of propranolol (10 mg/kg bw) at 0, 4 and 8 h after tMCAO and FTY720 (fingolimod; 1 mg/kg) on infarct size, functional outcome, immune cell counts and brain ceramide levels at 24 h after 60 min tMCAO.Results:We found a temporal coincidence between stroke-associated impaired glucose tolerance and brain ceramide accumulation. Whereas propranolol reduced ischemic lesion size, improved functional outcome and reduced brain ceramide accumulation without an effect on circulating immune cells, FTY720 showed the known neuroprotective effect and strong reduction of circulating immune cells without affecting brain ceramide accumulation.Conclusions:Propranolol ameliorates both stroke-associated impairment of glucose tolerance and brain ceramide accumulation which are temporally linked, strengthening the evidence for a role of the sympathetic nervous system in regulating post-stroke glucose metabolism and its metabolic consequences in the brain.

Dysregulated myelopoiesis and hematopoietic function following acute physiologic insult.

The purpose of this review is to describe recent findings in the context of previous work regarding dysregulated myelopoiesis and hematopoietic function following an acute physiologic insult, focusing on the expansion and persistence of myeloid-deriver suppressor cells, the deterioration of lymphocyte number and function, and the inadequacy of stress erythropoiesis. Persistent myeloid-derived suppressor cell (MDSC) expansion among critically ill septic patients is associated with T-cell suppression, vulnerability to nosocomial infection, chronic critical illness, and poor long-term functional status. Multiple approaches targeting MDSC expansion and suppressor cell activity may serve as a primary or adjunctive therapeutic intervention. Traumatic injury and the neuroendocrine stress response suppress bone marrow erythropoietin receptor expression in a process that may be reversed by nonselective beta-adrenergic receptor blockade. Hepcidin-mediated iron-restricted anemia of critical illness requires further investigation of novel approaches involving erythropoiesis-stimulating agents, iron administration, and hepcidin modulation. Emergency myelopoiesis is a dynamic process with unique phenotypes for different physiologic insults and host factors. Following an acute physiologic insult, critically ill patients are subject to persistent MDSC expansion, deterioration of lymphocyte number and function, and inadequate stress erythropoiesis. Better strategies are required to identify patients who are most likely to benefit from targeted therapies.

The Beta Adrenergic Receptor Blocker Propranolol Counteracts Retinal Dysfunction in a Mouse Model of Oxygen Induced Retinopathy: Restoring the Balance between Apoptosis and Autophagy.

In a mouse model of oxygen induced retinopathy (OIR), beta adrenergic receptor (BAR) blockade has been shown to recover hypoxia-associated retinal damages. Although the adrenergic signaling is an important regulator of apoptotic and autophagic processes, the role of BARs in retinal cell death remains to be elucidated. The present study was aimed at investigating whether ameliorative effects of BAR blockers may occur through their coordinated action on apoptosis and autophagy. To this aim, retinas from control and OIR mice untreated or treated with propranolol, a non-selective BAR1/2 blocker, were characterized in terms of expression and localization of apoptosis and autophagy markers. The effects of propranolol on autophagy signaling were also evaluated and specific autophagy modulators were used to get functional information on the autophagic effects of BAR antagonism. Finally, propranolol effects on neurodegenerative processes were associated to an electrophysiological investigation of retinal function by recording electroretinogram (ERG). We found that retinas of OIR mice are characterized by increased apoptosis and decreased autophagy, while propranolol reduces apoptosis and stimulates autophagy. In particular, propranolol triggers autophagosome formation in bipolar, amacrine and ganglion cells that are committed to die by apoptosis in response to hypoxia. Also our data argue that propranolol, through the inhibition of the Akt-mammalian target of rapamycin pathway, activates autophagy which decreases retinal cell death. At the functional level, propranolol recovers dysfunctional ERG by recovering the amplitude of a- and b-waves, and oscillatory potentials, thus indicating an efficient restoring of retinal transduction. Overall, our results demonstrate that BAR1/2 are key regulators of retinal apoptosis/autophagy, and that BAR1/2 blockade leads to autophagy-mediated neuroprotection. Reinstating the balance between apoptotic and autophagic machines may therefore be viewed as a future goal in the treatment of retinopathies.

Divergent profile between hypothalamic and plasmatic aminopeptidase activities in WKY and SHR. Influence of beta-adrenergic blockade

AimsWistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) differ in their renin-angiotensin system function and sympathetic tone. The metabolism of angiotensins and vasopressin depends on the action of certain aminopeptidases whose activity may be influenced by the autonomic nervous system. Their regulation may differ between WKY and SHR in hypothalamus and plasma according to the sympathetic tone. We analyzed aminopeptidases responsible for the hydrolysis of certain angiotensins, vasopressin, cholecystokinin or enkephalins in hypothalamus and plasma of WKY and SHR in untreated controls rats and under beta-adrenoceptor blockade. Systolic blood pressure, food intake, water intake and diuresis were measured as parameters modulated by the autonomic nervous system and the above mentioned peptides. Main methodsGlutamyl-, aspartyl-, cystinyl- and alanyl-aminopeptidase activities were analyzed fluorimetrically in plasma and hypothalamus of control and propranolol-treated (100mg/kg/day administered in drinking water for 1month) WKY and SHR, using arylamide derivatives as substrates. Key findingsAn opposite response of aminopeptidases to propranolol treatment between plasma and hypothalamus was observed in either WKY and SHR. Furthermore, the behavior of aminopeptidases was inversed between WKY and SHR either in hypothalamus and plasma: while the activity increased in hypothalamus and decreased in plasma of WKY, it decreased in hypothalamus and increased in plasma of SHR. SignificanceThese results revealed an inverse response of aminopeptidases between hypothalamus and plasma and also an opposite behavior of these enzymes between WKY and SHR in hypothalamus and plasma. These observations support the involvement of the sympathetic system in the modulation of aminopeptidase activities.

Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control.

The evoked cardiac response to bipolar cervical vagus nerve stimulation (VNS) reflects a dynamic interaction between afferent mediated decreases in central parasympathetic drive and suppressive effects evoked by direct stimulation of parasympathetic efferent axons to the heart. The neural fulcrum is defined as the operating point, based on frequency-amplitude-pulse width, where a null heart rate response is reproducibly evoked during the on-phase of VNS. Cardiac control, based on the principal of the neural fulcrum, can be elicited from either vagus. Beta-receptor blockade does not alter the tachycardia phase to low intensity VNS, but can increase the bradycardia to higher intensity VNS. While muscarinic cholinergic blockade prevented the VNS-induced bradycardia, clinically relevant doses of ACE inhibitors, beta-blockade and the funny channel blocker ivabradine did not alter the VNS chronotropic response. While there are qualitative differences in VNS heart control between awake and anaesthetized states, the physiological expression of the neural fulcrum is maintained. Vagus nerve stimulation (VNS) is an emerging therapy for treatment of chronic heart failure and remains a standard of therapy in patients with treatment-resistant epilepsy. The objective of this work was to characterize heart rate (HR) responses (HRRs) during the active phase of chronic VNS over a wide range of stimulation parameters in order to define optimal protocols for bidirectional bioelectronic control of the heart. In normal canines, bipolar electrodes were chronically implanted on the cervical vagosympathetic trunk bilaterally with anode cephalad to cathode (n=8, 'cardiac' configuration) or with electrode positions reversed (n=8, 'epilepsy' configuration). In awake state, HRRs were determined for each combination of pulse frequency (2-20Hz), intensity (0-3.5mA) and pulse widths (130-750μs) over 14months. At low intensities and higher frequency VNS, HR increased during the VNS active phase owing to afferent modulation of parasympathetic central drive. When functional effects of afferent and efferent fibre activation were balanced, a null HRR was evoked (defined as 'neural fulcrum') during which HRR≈0. As intensity increased further, HR was reduced during the active phase of VNS. While qualitatively similar, VNS delivered in the epilepsy configuration resulted in more pronounced HR acceleration and reduced HR deceleration during VNS. At termination, under anaesthesia, transection of the vagi rostral to the stimulation site eliminated the augmenting response to VNS and enhanced the parasympathetic efferent-mediated suppressing effect on electrical and mechanical function of the heart. In conclusion, VNS activates central then peripheral aspects of the cardiac nervous system. VNS control over cardiac function is maintained during chronic therapy.

Imaging-Guided Cardioprotective Treatment in a Community Elderly Population of Stage B Heart Failure

ObjectivesThe purpose of the study was to evaluate the benefit of care guided by the detection of stage B heart failure (SBHF) using advanced echocardiography for the reduction of new HF in the community. BackgroundThe detection of nonischemic SBHF has been facilitated by advanced echocardiographic imaging modalities. However, improved outcomes have not been proven as they are predicated on benefit of treatment. MethodsBetween September 13, 2013 and November 6, 2015, 618 asymptomatic community-based patients with HF risks (age 71 ± 5 years) were randomized to care guided by advanced echocardiography (myocardial deformation and detailed diastolic function) versus usual care. Evidence of SBHF led to advice to the patients and their primary physicians to initiate treatment with angiotensin-converting enzyme inhibition and beta-adrenoceptor blockade. The trial followed the PROBE (Prospective Randomized Open Blinded Endpoint) design. Participants were followed for 1 year for the primary composite endpoint of death from cardiovascular causes and new HF. ResultsAdvanced echocardiography identified 219 as having SBHF and treatment was advised. Over a mean follow-up of 13 ± 6 months, 67 reached the primary endpoint. The incidence rate of HF was no different between the 2 arms (p = 0.47), likely because only 43% initiated therapy, and only 9% achieved target dose. Among subjects needing therapy on the basis of imaging and adherence to therapy, imaging-guided care showed a 77% lower hazard for the primary outcome (p = 0.04). ConclusionsThe detection of SBHF from strain and diastolic function evaluation was associated with a higher incidence of incidence HF and death. The efficacy of pharmacological intervention with angiotensin-converting enzyme inhibition and beta-adrenoceptor blockade is limited by its uptake, and alternative strategies should be considered. (Tasmanian Study of Echocardiographic Detection of Left Ventricular Dysfunction [TAS-ELF]; ACTRN12614000080628)

Preoperative β-blockade and hypertension in the first hour of functional endoscopic sinus surgery.

Local anesthetic with epinephrine is commonly injected into the nasal mucosa during functional endoscopic sinus surgery (FESS). Systemic absorption of epinephrine following local injection may occur, resulting in a mild sympathetic response. This study seeks to determine whether an exaggerated sympathetic response to epinephrine is demonstrated in patients undergoing FESS treated preoperatively with established pharmacologic beta (β) adrenoceptor blockade. A retrospective analysis of adult patients undergoing FESS at a tertiary care university hospital. The primary outcome was the occurrence of an exaggerated hypertensive response within the first hour of surgical time defined by a relative increase (>20%) in the first measured intraoperative systolic blood pressure (SBP) prior to induction of anesthesia, or a single SBP value above 200 mm Hg. A mixed effects logistic regression model was developed to identify independent predictors of an exaggerated hypertensive response and describe the variance in the outcome attributable to the surgeon and anesthesiologist. There were 2,051 patients identified. Independent predictors of an exaggerated intraoperative hypertensive event included: preoperative β-blocker use (adjusted odds ratio [AOR]: 3.33), female gender (AOR: 1.92), body mass index (AOR: 1.03), lower baseline SBP (AOR: 0.93), and advanced age (AOR: 1.03). The C statistic for the model was 0.8881. Preoperative β-blocker use is an independent predictor of an exaggerated hypertensive response within the first hour of operative time. An exaggerated hypertensive effect should be anticipated in patients presenting for FESS with established pharmacologic β-blockade, and caution should be applied to use of epinephrine-containing solutions. 4. Laryngoscope, 127:1496-1505, 2017.

Pharmacological Effects of Gemfibrozil on Some Isolated Smooth Muscle Preparations of Experimental Animals

Background: Gemfibrozil is a member of fibrates (gemfibrozil, fenofibrate, ceprofibrate, and benzafibrate) which is employed for treatment of dyslipidemia particularly hypertriglyceridemiae through its action on peroxisome proliflator activated receptors (PPAR-α). Objective: The aim of this work was to study the site of action and pharmacololgical effects of different doses of gemfibrozil on some isolated smooth muscles preparations of experimental animals. Materials and Methods: The experiments were conducted on isolated jejunum of rabbits, isolated spiral tracheal and urinary bladder strips of guinea pigs. Results: I- On isolated rabbit jejunum, gemfibrozil produced a dose-dependent reduction on the amplitude of jejunal contractions. The inhibitory effect of gemfibrozil was not abolished after complete blockade of alpha and beta adrenergic receptors, while it was completely abolished after inhibition of nitric oxide synthase by N-methyl L-arginine. On the other hand the stimulatory effects of nicotine small dose, acetylcholine, calcium gluconate, histamine and serotonin were not abolished after administration of gemfibrozil. II- On isolated tracheal spiral strips of ginea pigs, gemfibrozil produced a dose- dependent relaxation on the basal tone and a dose-dependent reduction on the amplitude of acetylcholine-induced tracheal contractions of the tracheal strips. The inhibitory effect of gemfibrozil was completely abolished after inhibition of nitric oxide synthase by N-methyl L-arginine. Gemfibrozil completely abolished also serotonin-induced contraction, while it has no effect on histamine or calcium-induced tracheal contractions. III- On isolated urinary bladder strips of guinea pigs, gemfibrozil produced a dose-dependent reduction on the amplitude of urinary bladder contractions. The inhibitory effect of gemfibrozil was not abolished after complete blockade of beta adrenergic receptors, while it was completely abolished after inhibition of nitric oxide synthase by N-methyl L-arginine. On the other hand the stimulatory effects of acetylcholine and serotonin were not abolished after administration of gemfibrozil. Conclusion: Gemfibrozil (antidyslipidemic, PPAR-α agonist) reduced jejunal and urinary bladder contractions and has a relaxant effect on tracheal basal tone. So it has a beneficial effect in obstructive airway diseases and cases of urgency and frequency of micturation and urinary incontinence. However, it may be used cauciously in cases of ,GIT disturbances as constipation and prostatic hypertrophy.