Adrenergic Blockade Research Articles

The effects of normoxic endurance exercise on erythropoietin (EPO) production and the impact of selective β1 and non-selective β1 + β2 adrenergic receptor blockade

Habitual endurance exercise results in increased erythropoiesis, which is primarily controlled by erythropoietin (EPO), yet studies demonstrating upregulation of EPO via a single bout of endurance exercise have been equivocal. This study compares the acute EPO response to 30min of high versus 90min of moderate-intensity endurance exercise and whether that response can be upregulated via selective adrenergic receptor blockade. Using a counterbalanced, cross-over design, fifteen participants (age 28 ± 8) completed two bouts of running (30-min, high intensity vs 90-min, moderate intensity) matched for overall training stress. A separate cohort of fourteen participants (age 31 ± 6) completed three bouts of 30-min high-intensity cycling after ingesting the preferential β1-adrenergic receptor (AR) antagonist bisoprolol, the non-preferential β1 + β2 antagonist nadolol or placebo. Venous blood was collected before, during, and after exercise, and serum EPO levels were determined by ELISA. No detectable EPO response was observed during or after high intensity running, however, in the moderate-intensity trial EPO was significantly elevated at both during-exercise timepoints (+ 6.8% ± 2.3% at 15min and + 8.7% ± 2.2% at 60min). No significant change in EPO was observed post-cycling or between the trials involving βAR blockade. Neither training mode (running or cycling), nor beta-blockade significantly influenced the EPO response to 30min of high-intensity exercise, however, 90min of moderate-intensity running elevated EPO during exercise, returning to baseline immediately post-exercise. Identifying the optimal mode, duration and intensity required to evoke an EPO response to exercise may help tailor exercise prescriptions designed to maximize EPO response for both performance and clinical applications.

Management of a Patient with Pheochromocytoma Posted for Right Adrenalectomy

Introduction: Patients posted for adrenalectomy with pheochromocytoma pose major challenge to anaesthesiologist as there may be excess catecholamine release during its removal that leads to severe hypertension and arrythmias intra operatively. Case presentation: Here we discuss anaesthetic management of 27 year old female with right supra renal mass posted for right adrenalectomy. She came with complaints of abdominal pain and weight gain for which hormonal evaluation and CECT abdomen done and was diagnosed with pheochromocytoma of right adrenal gland. As patient was obese and venous accesibility was difficult central venous catheterisation was done prior to surgery. Case was done under combined epidural with general anaesthesia. Conclusion: In patients with pheochromocytoma posted for adrenalectomy, pre operative hormonal evaluation, intra operative and post operative hemodynamic stability are important. Intra operative and post operative tachycardia, hypertension prevented by smooth induction, minimise the intubation and extubation response and use of other adrenergic blockade drugs during and after surgery. Effective post operative pain management is necessary.

Molecular Determinants of D and L-Sotalol Stereoselective Proarrhythmia Procilivties

Cardiac arrhythmias can be caused by drug induced blockade of cardiac potassium channel KV11.1 encoded by the human Ether-à-go-go-Related Gene (hERG), being a major obstacle for the development of new pharmaceuticals. Inhibition of this protein activity leads to an increased cardiac action potential duration manifesting as a prolonged QT interval on the surface ECG, which can cause potentially lethal arrhythmias. However, not all hERG channel blocking and QT prolonging drugs are arrhythmogenic leading to possible attrition of safe and effective pharmaceuticals. Previously we developed a multi-scale in silico pipeline to predict arrhythmogenicity of two hERG blocking drugs, dofetilide and moxifloxacin, from their chemical structures using a combination of atomistic structural and functional kinetic modeling approaches (Yang et al. Circ. Res. 2020, 126: 947). Here we applied such computational pipeline backed by an enantiomeric separation and electrophysiology recordings to predict the pro-arrhythmia risks of two enantiomers of sotalol, an anti-arrhythmic drug with known stereoselective beta-blocking properties. We determined similar hERG channel binding affinities of d and l-sotalol from both patch-clamp recordings and umbrella sampling all-atom molecular dynamics (MD) simulations. MD derived hERG channel - drug on and off rates were used as functional model parameters. In cardiac tissue simulations our model predicted substantially higher emergent arrhythmogenicity of d-sotalol compared to the l-stereoisomer due to a more potent beta adrenergic receptor blockade by the latter and also provided good agreement with clinical QT interval prolongation for the racemic mixture. Our study helped to elucidate molecular mechanisms of stereoselective arrhythmogenicity for dl-sotalol allowing to predict cardiac safe and dangerous drug formulations. This work has been made possible by NIH NHLBI and Common Fund as well as American Heart Association funding, usage of XSEDE, PSC Anton 2, TACC Frontera, and Oracle for Research computational resources.

α-Adrenergic receptor blockade attenuates pressor response during mental stress in young black adults.

Black individuals exhibit increased blood pressure (BP) responses to sympathetic stimulation that are associated with an increased risk of hypertension (HTN). We tested the hypothesis that α1‐adrenergic blockade inhibits the increased BP response during and after 45‐min stress in young normotensive Black adults, which may be mediated, in part, by dampened vasoconstriction and decreased renal sodium retention. Utilizing a double‐masked randomized, crossover study design, 51 normotensive Black adults (31 ± 8 yr) were treated with either a placebo or 1 mg/day of prazosin for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before (Rest), during (Stress) and after (Recovery) 45 min of mental stress induced via a competitive video game task. During the Stress period, diastolic BP and total peripheral resistance (TPR) were significantly lower with prazosin compared to placebo (p < .05 for both). Similarly, we observed lower systolic BP, diastolic BP, and TPR during the Recovery period with prazosin versus placebo (p < .05 for both). There was no effect of prazosin on stress‐associated UNaV. The change in systolic BP from Rest to Recovery was positively associated with the change in TPR with both treatments (p < .05 for both). In summary, prazosin treatment dampened BP reactivity to 45‐min mental stress and lowered post‐stress BP over the recovery period, which was linked to reduce TPR in young normotensive Black adults. These results suggest that α1‐adrenergic receptor activity may contribute to BP responses and delayed BP recovery to prolonged mental stress through increased vasoconstriction in Black adults.

Percutaneous Bilateral Adrenal Radiofrequency Ablation in Severe Adrenocorticotropic Hormone-dependent Cushing Syndrome.

Objectives:The objectives of the study were to evaluate adrenal radiofrequency ablation (RFA) as a method of treatment in patients with severe adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome, among whom bilateral adrenalectomy is not a suitable option.Material and Methods:Five patients with ACTH-dependent Cushing syndrome underwent RFA of both adrenal glands. Four of them presented with Cushing disease unsuccessfully treated with pituitary surgery and medical therapy, while one patient had ACTH-dependent Cushing syndrome due to pancreatic endocrine tumor with liver metastases. All patients were disqualified from adrenalectomy due to morbid obesity or lack of consent.Results:A technical success was obtained in all cases, with only one re-intervention necessitated by a cooling effect of the inferior vena cava. Despite pre-procedural adrenergic blockade, severe hypertension was noted during the procedure in three cases, this being treated immediately using direct-acting vasodilators. No complications occurred otherwise. In all cases, significant improvement of clinical symptoms was observed, as well as marked decreases in levels of serum cortisol, free urine cortisol, and dehydroepiandrosterone sulfate.Conclusion:Bilateral RFA under CT-guidance is technically feasible and clinical improvement can be achieved using the method. In patients disqualified from adrenal surgery, RFA might be considered as an alternative method of ACTH-dependent Cushing syndrome treatment.

Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure.

Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 μg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.

An update on the efficacy and safety of iloperidone as a schizophrenia therapy

ABSTRACT Introduction Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor. Areas covered This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication. Expert opinion Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.

The effects of moderate alterations in adrenergic activity on acute appetite regulation in obese women: A randomised crossover trial.

Background:Previous evidence has demonstrated that serum leptin is correlated with appetite in combination with, but not without, modest exercise.Aim:The present experiments investigated the effects of exogenous adrenaline and α/β adrenoceptor blockade in combination with moderate exercise on serum leptin concentrations, appetite/satiety sensations and subsequent food intake in obese women.Methods:A total of 10 obese women ((mean ± SEM), age: 50 (1.9) years, body mass index 36 (4.1) kg/m2, waist 104.8 (4.1) cm) participated in two separate, double-blind randomised experimental trials. Experiment 1: moderate exercise after α/β adrenergic blocker (labetalol, 100 mg orally) versus moderate exercise plus placebo; experiment 2: adrenaline infusion for 20 minutes versus saline infusion. Appetite/satiety and biochemistry were measured at baseline, pre- and immediately post-intervention, then 1 hour post-intervention (i.e., before dinner). Food intake was assessed via ad libitum buffet-style dinner.Results:No differences were found in appetite/satiety, subsequent food intake or serum leptin in any of the studies (experiment 1 or experiment 2). In experiment 1, blood glucose was higher (p < 0.01) and plasma free fatty acids lower (p = 0.04) versus placebo. In experiment 2, plasma free fatty acids (p < 0.05) increased after adrenaline versus saline infusion.Conclusions:Neither inhibition of exercise-induced adrenergic activity by combined α/β adrenergic blockade nor moderate increases in adrenergic activity induced by intravenous adrenaline infusion affected acute appetite regulation.

The effects of selective beta-adrenergic blockade on bone marrow dysfunction following severe trauma and chronic stress

IntroductionPropranolol has been shown to improve erythroid progenitor cell growth and anemia following trauma and this study sought to investigate the mechanisms involved by evaluating the effects of selective beta blockade. MethodsMale Sprague-Dawley rats were subjected to lung contusion, hemorrhagic shock and chronic stress (LCHS/CS) ± daily selective beta-1, beta-2, or beta-3 blockade (B1B, B2B, B3B). Bone marrow cellularity and growth of erythroid progenitor colonies, hemoglobin, plasma granulocyte colony-stimulating factor (G-CSF), hematopoietic progenitor cell mobilization, and daily weight were assessed. ResultsSelective beta-2 and beta-3 blockade improved bone marrow cellularity, erythroid progenitor colony growth and hemoglobin levels, while decreasing plasma G-CSF, progenitor cell mobilization and weight loss following LCHS/CS. ConclusionsAttenuating the neuroendocrine stress response with the use of selective beta-2 and 3 adrenergic blockade may be an alternative to improve bone marrow erythroid function following trauma.

Targeting the β‐adrenergic receptor in the clinical management of congenital long QT syndrome

The long QT syndrome (LQTS) is largely treated pharmacologically with β-blockers, despite the role of sympathetic activity in LQTS being poorly understood. Using the trigger-substrate model of cardiac arrhythmias in this review, we amalgamate current experimental and clinical data from both animal and human studies to explain the mechanism of adrenergic stimulation and blockade on LQT arrhythmic risk and hence assess the efficacy of β-adrenoceptor blockade in the management of LQTS. In LQTS1 and LQTS2, sympathetic stimulation increases arrhythmic risk by enhancing early afterdepolarizations and transmural dispersion of repolarization. β-Blockers successfully reduce cardiac events by reducing these triggers and substrates; however, these effects are less marked in LQTS2 compared with LQTS1. In LQTS3, clinical and experimental investigations of the effects of sympathetic stimulation and β-blocker use have produced contradictory findings, resulting in significant clinical uncertainty. We offer explanations for these contradicting results relating to study sample size, the dose of the β-blocker administered associated with its off-target Na+ channel effects, as well as the type of β-blocker used. We conclude that the antiarrhythmic efficacy of β-blockers is a genotype-specific phenomenon, and hence the use of β-blockers in clinical practice should be genotype dependent.

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

Pivoting Research to COVID-19.

Pivoting Research to COVID-19.

α 1-Adrenergic Receptor Blockade by Prazosin Synergistically Stabilizes Rat Peritoneal Mast Cells.

Background Adrenaline quickly inhibits the release of histamine from mast cells. Besides β2-adrenergic receptors, several in vitro studies also indicate the involvement of α-adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties. Methods Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of α-adrenergic receptor agonists or antagonists. Results Adrenaline dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a β2-adrenergic receptor antagonist. Among α-adrenergic receptor agonists or antagonists, high-dose prazosin, a selective α1-adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells. Conclusions This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell stabilizer. The pharmacological blockade of α1-adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by β2-adrenergic receptors.

SAT-212 Management of VHL-Associated Pheochromocytoma in Pregnancy

Background: The appropriate treatment of pheochromocytoma during pregnancy is crucial because, while its incidence is rare (0.007%), it is associated with increased maternal and fetal mortality1. Clinical Case: A 32 year old Caucasian primigravida female presented with intrauterine pregnancy at 25 weeks for evaluation and management of a 9 mm left adrenal mass. The patient was previously diagnosed at age 10 with Von-Hippel Lindau (VHL) syndrome and genetic testing was positive for a VHL gene mutation (Type 2C VHL). At age 14, she underwent laparoscopic adrenalectomy to excise a right sided pheochromocytoma. At age 20, imaging revealed an enhancing left adrenal mass with imaging characteristics consistent with pheochromocytoma and with catecholaminergic labs that were normal or only mildy increased to 1.5 times upper normal range. Pre-partum the patient had been experiencing periodic episodes of headaches and palpitations. She reported experiencing baseline levels of palpitations and sweating with new onset of pre-syncope and hypotension during her pregnancy. Labs revealed normal serum levels of fractionated free metanephrines. Alpha adrenergic blockade, beta adrenergic blockade, and surgery were considered but deemed unnecessary as the patient was asymptomatic, imaging indicated the left adrenal mass was stable in size, and the patient wished to avoid lifelong adrenal replacement therapy. The patient’s blood pressure and heart rate were monitored closely throughout pregnancy and the use of alpha blockade or beta blockade was not needed. The patient had an uncomplicated induced delivery at 39 weeks. MRI with contrast of abdomen performed 10 months postpartum confirmed the presence of an enhancing 8 mm lesion on the inferior pole of the left adrenal gland with imaging characteristics again consistent with pheochromocytoma. Conclusion: This case demonstrates that a conservative approach of monitoring blood pressure and heart rate can be sufficient and appropriate for management of some patients with pheochromocytoma and VHL during pregnancy.Citation:1. ENDOCRINOLOGY IN PREGNANCY: Pheochromocytoma in pregnancy: case series and review of literature in: European Journal of Endocrinology Volume 177 Issue 2 (2017).

SUN-913 A MEN-2a Syndrome Index Case Presenting with Adrenergic Crisis and Cardiogenic Shock Due to Bilateral Pheochromocytoma

Background: MEN-2A syndrome is commonly asymptomatic at diagnosis. Withal, pheochromocytoma presenting as cardiogenic shock is a recognized but exceptional occurrence. Case: A healthy 26-year-old female presented to the emergency department with precordial discomfort, headache and shortness of breath, starting that morning. She had a gum corrective surgery in the day before, was medicated with ibuprofen, pantoprazole and amoxicillin/clavulanic acid, and had previous history of migraine and smoking. Her blood pressure was high, and she had pulmonary edema and respiratory failure. ECG: sinus tachycardia, left axis deviation, and negative T wave in aVL. Analytically: leukocytosis, elevated myocardial necrosis markers (troponin I 1.29 ng/mL, normal < 0 ng/mL), and hyperlactacidemia. Transthoracic echocardiogram: severe left ventricular dysfunction, akinesia of the basal mid segments of all walls; image of thickening immediately above the aortic valvular plane. CT angiography: bilateral adrenal masses (9.2x9.2x10.8 cm on the right; 2.3x2.8x3.3 cm on the left), suggestive of pheochromocytoma. Cardiogenic shock led to patient transfer to our hospital for ECMO, in which she was maintained for 14 days. Pheochromocytoma was confirmed (normetanephrine 15689 µg/24h [normal < 390 µg/24h], metanephrine 15000 [normal < 320 µg/24h]) and adrenergic blockade initiated. Hospitalization complications and surgical risk delayed bilateral adrenalectomy to 1 month after admission. She initiated glucocorticoid and mineralocorticoid replacement, was transferred to the ward stable, and started a rehabilitation program before hospital discharge. Phosphocalcic metabolism was normal (PTH 38.7 pg/mL, normal 10–65 pg/mL). High calcitonin levels (87 pg/mL, normal <5 pg/mL) lead to the diagnosis of medullary thyroid carcinoma, followed by total thyroidectomy. MIBG showed “No foci of radiopharmaceutical overaptation related to norepinephrine transporter overexpression lesions.”, and genetic study revealed heterozygous variant c.1900T>C [p. (Cys634Arg)] in exon 11 of the RET gene, confirming suspicion of MEN-2A syndrome. As there was no family history of endocrine neoplasias, she was referred to genetic counselling for evaluation of family members. She maintains follow-up, currently treated with hydrocortisone 7.5 + 5 + 2.5 mg od, fludrocortisone 0.1 mg od, and levothyroxine 137 mcg, with improvement of functional capacity and general state (weight gain of 13 kg), recovery of left ventricular function, normal urinary metanephrines, and calcitonin < 2.0 pg/mL. Conclusions: To our knowledge, MEN-2A syndrome presenting with cardiogenic shock due to pheochromocytoma was not yet described. Knowledge of unusual presentations of rare syndromes is important to arise suspicion and improve differential diagnosis in life-threatening conditions as cardiogenic shock.

Adrenergic Blockade Promotes Maintenance of Dormancy in Prostate Cancer Through Upregulation of GAS6

Men diagnosed with localized prostate cancer can develop metastases many years after initial treatment, resulting in a poor prognosis. The purpose of this study was to investigate the mechanisms by which signaling through norepinephrine (NE) may incite relapse of quiescent prostate cancer. We used an unbiased bioinformatics pipeline to examine mechanisms for recurrence related to sympathetic signaling in the bone marrow. A transcription factor cell array identified ATF1, RAR, and E2F as key nodes in prostate cancer cells exiting quiescence through adrenergic signaling. Subsequent secretome analysis identified GAS6 as affecting activity of these three factors, leading to cell cycle reentry. GAS6 expression was downregulated in osteoblasts through activation of the cAMP pathway and was targeted in vitro and in vivo using pharmacological agents (propranolol and phentolamine). Propranolol increased expression of GAS6 by osteoblasts, and phentolamine significantly inhibited expression. Propranolol treatment was sufficient to both increase GAS6 expression in marrow osteoblasts as well as eliminate the effects of NE signaling on GAS6 expression. These results demonstrate a strong correlation between adrenergic signaling, GAS6 expression, and recurrence in prostate cancer, suggesting a novel therapeutic direction for patients at high risk of metastasis.

Global Reach 2018 Heightened α-Adrenergic Signaling Impairs Endothelial Function During Chronic Exposure to Hypobaric Hypoxia.

Chronic exposure to hypoxia is associated with elevated sympathetic nervous activity and reduced vascular function in lowlanders, and Andean highlanders suffering from excessive erythrocytosis (EE); however, the mechanistic link between chronically elevated sympathetic nervous activity and hypoxia-induced vascular dysfunction has not been determined. To determine the impact of heightened sympathetic nervous activity on resistance artery endothelial-dependent dilation (EDD), and endothelial-independent dilation, in lowlanders and Andean highlanders with and without EE. We tested healthy lowlanders (n=9) at sea level (344 m) and following 14 to 21 days at high altitude (4300 m), and permanent Andean highlanders with (n=6) and without (n=9) EE at high altitude. Vascular function was assessed using intraarterial infusions (3 progressive doses) of acetylcholine (ACh; EDD) and sodium nitroprusside (endothelial-independent dilation) before and after local α+β adrenergic receptor blockade (phentolamine and propranolol). Intraarterial blood pressure, heart rate, and simultaneous brachial artery diameter and blood velocity were recorded at rest and during drug infusion. Changes in forearm vascular conductance were calculated. The main findings were (1) chronic hypoxia reduced EDD in lowlanders (changes in forearm vascular conductance from sea level: ACh1: -52.7±19.6%, ACh2: -25.4±38.7%, ACh3: -35.1±34.7%, all P≤0.02); and in Andeans with EE compared with non-EE (changes in forearm vascular conductance at ACh3: -36.4%, P=0.007). Adrenergic blockade fully restored EDD in lowlanders at high altitude, and normalized EDD between EE and non-EE Andeans. (2) Chronic hypoxia had no effect on endothelial-independent dilation in lowlanders, and no differences were detected between EE and non-EE Andeans; however, EID was increased in the non-EE Andeans after adrenergic blockade (P=0.012), but this effect was not observed in the EE Andeans. These data indicate that chronic hypoxia reduces EDD via heightened α-adrenergic signaling in lowlanders and in Andeans with EE. These vascular mechanisms have important implications for understanding the physiological consequences of acute and chronic high altitude adaptation.

Alpha adrenergic blockade does not change coronary circulation during handgrip exercise or isolated metaboreflex activation in humans

Coronary circulation control entails several redundant mechanisms, and is primarily regulated by the myocardial metabolism. Therefore, exercise increases coronary blood flow. Animal studies consistently demonstrate an α‐adrenergic vasoconstriction response in coronary arteries during exercise and metaboreflex activation. Additionally, α‐adrenergic receptor (α‐AR) blockade disrupts the increase of coronary circulation coupled with the metabolic demand. However, whether this α‐adrenergic vasoconstrictory mechanism is present in coronary circulation control during exercise has never been tested in humans. Twenty healthy participants were tested [26±15 yr; 24±1 kg·m−2;1.8±0.1 m2; men (n=11); women (n=9); mean±SE]; Heart rate (HR) was continuously monitored, cardiac output (CO) were estimated from finger photoplethysmography arterial pressure waveform using the modelflow method, and cardiac index (CI) calculated by the ratio between CO and body surface area. Mean arterial pressure (MAP) was calculated by the integration of arterial blood pressure waveform over a cardiac cycle. Myocardial oxygen consumption (MVO2) was estimated applying the following formula: MVO2 = 7.2×10−4 (SBP×HR)+1.43; where SBP is systolic blood pressure. Coronary blood flow peak velocity (CBFVpeak) was measured on the left anterior coronary artery from the parasternal short‐axis view with duplex ultrasound. The protocol consisted in three minutes of rest, three minutes of handgrip exercise, followed by three minutes of post‐exercise occlusion (PEO) and three minutes of recovery; in a control (C) condition and after α1‐AR blockade with prazosin. HR increased during exercise and returned to resting values during the PEO in the control and after the α1‐AR blockade. But α‐AR blockade kept HR higher throughout the protocol. In control condition, MAP increased during exercise (Δ36±2 mmHg) and was elevated after PEO (Δ28±3 mmHg). The α1‐AR blockade blunted the pressure response to grip exercise (Δ27±3 mmHg) and to PEO (Δ16±4 mmHg). CI did not change during grip exercise or PEO, during the control condition or after the α1‐AR blockade. CBFVpeak increased during exercise (CΔ6±1 cm·s−1; Blockade Δ8±1 cm·s−1) and return to resting values with PEO (Δ1±0.8 cm·s−1; Δ0.8±1 cm·s−1), and the α1‐AR blockade did not change this condition. MVO2 increased during exercise (CΔ5.0±0.5; Blockade Δ 6.3±0.6) and return to resting values after PEO (C Δ2.1±0.3; Blockade Δ2.1±0.3), and the α1‐AR blockade did not change this condition. Linear regression shows a significant increase in coronary blood flow velocity with the increase of MVO2 from rest to exercise, in the control session (slope=1.18; R2=0.28; p&lt;0.01) and no effect of α1‐AR receptor blockade was observed (slope=1.10; R2=0.28; p&lt;0.01). Which shows that the α1‐AR receptor blockade did not disrupt the coupling between the coronary circulation and the metabolic demand in humans. Therefore, the neural control of coronary circulation via α1‐AR vasoconstriction seems to play a secondary role in humans, differently as observed in dogs and pigs.Support or Funding InformationCAPES; FAPERJ; CNPq; FINEP

The “ABC” of anaesthesia for resection of a catecholamine secreting vagal paraganglioma: Adrenergic Blockade Confirmed

The “ABC” of anaesthesia for resection of a catecholamine secreting vagal paraganglioma: Adrenergic Blockade Confirmed

Effects of sympatho-vagal interaction on ventricular electrophysiology and their modulation during beta-blockade

AimsThe effects of sympatho-vagal interaction on heart rate (HR) changes are characterized by vagal dominance resulting in accentuated antagonism. Complex autonomic modulation of ventricular electrophysiology may exert prognostic arrhythmic impact. We examined the effects of concurrent sympathetic (SNS) and vagus (VNS) nerve stimulation on ventricular fibrillation threshold (VFT) and standard restitution (RT) in an isolated rabbit heart preparation with intact dual autonomic innervation, with and without beta-blockade. Methods and resultsMonophasic action potentials were recorded from left ventricular epicardial surface of dual-innervated isolated heart preparations from New Zealand white rabbits (n = 18). HR, VFT and RT were measured during different stimulation protocols (Protocol 1: VNS-SNS; Protocol 2: SNS-VNS) involving low- and high-frequency stimulations. A sub-study of Protocol 2 was performed in the presence of metoprolol tartrate.In both protocols, HR changes were characterized by vagal-dominant bradycardic component, affirming accentuated antagonism. During concurrent high-frequency VNS (HV), SNS prevails in lowering VFT in a frequency-sensitive manner during low (LS) or high (HS)-frequency stimulations (HV-LS: −2.8 ± 0.8 mA; HV-HS: −4.0 ± 0.9 mA, p < .05 vs. HV), with accompanying steepening of relative RT slope gradients (HV-LS: 223.54 ± 37.41%; HV-HS: 295.20 ± 60.86%, p < .05 vs. HV). In protocol 2, low (LV) and high (HV) vagal stimulations during concurrent HS raised VFT (HS-LV: 1.0 ± 0.4 mA; HS-HV: 3.0 ± 0.6 mA, p < .05 vs HS) with associated flattening of RT slopes (HS-LV: 32.40 ± 4.97%;HS-HV: 38.07 ± 6.37%; p < .05 vs HS). Metoprolol abolished accentuated antagonism in HR changes, reduced VFT and flattened RT globally during SNS-VNS. ConclusionsAccentuated antagonism is absent in ventricular electrophysiological changes during sympatho-vagal interaction with sympathetic effect prevailing, suggesting a different mechanism at the ventricular level from heart rate effects. Metoprolol nullified accentuated antagonism with additional anti-fibrillatory effect beyond adrenergic blockade during sympatho-vagal stimulations.