Beta-adrenergic Receptor Blockade Effects on Cardio-pulmonary Exercise Testing

Background: Beta-blockers are increasingly prescribed while the effects of beta-adrenergic receptor blockade on cardio-pulmonary exercise test (CPET) derived parameters remain under-studied. Methods: 21 young healthy adults repeated 3 CPET at an interval of 7 days at the same time of the day. The tests were performed 3 hours after a random, double blind, cross-over single dose intake of placebo, 2.5 mg bisoprolol or 5 mg bisoprolol. Gaz exchange, heart rate and blood pressure were measured at rest and during cyclo-ergometric CPET.Results: Maximal workload and VO2max were unaffected by the treatment, with maximal respiratory exchange ratio > 1.15 in all tests. A beta-blocker dose-dependent effect reduced resting and maximal blood pressure and heart rate and the chronotropic response to exercise, evaluated by the heart rate/VO2 slope (placebo: 2,9 ± 0,4 beat/ml/kg; 2,5 mg bisoprolol: 2,4 ± 0,5 beat/ml/kg; 5 mg bisoprolol: 2,3 ± 0,4 beat/ml/kg, p<0.001). Ventilation efficiency measured by the VE/VCO2 slope and the ventilatory equivalent for CO2 at the ventilatory threshold were not affected by beta1-receptor blockade. Post-exercise chronotropic recovery measured after 1 min was enhanced under beta1-blocker (placebo: 26 ± 7 bpm; 2,5 mg bisoprolol: 32 ± 6 bpm; 5 mg bisoprolol: 33 ± 6 bpm, p<0.01).Conclusion: The present results suggest that a single dose of bisoprolol does not affect metabolism, respiratory response and exercise capacity. However, beta-adrenergic blockade dose-dependently reduced exercise hemodynamic response by lowering the pressure and chronotropic responses.

Beta-Adrenergic Blockade in Critical Illness

Catecholamine upregulation is a core pathophysiological feature in critical illness. Sustained catecholamine β-adrenergic induction produces adverse effects relevant to critical illness management. β-blockers (βB) have proposed roles in various critically ill disease states, including sepsis, trauma, burns, and cardiac arrest. Mounting evidence suggests βB improve hemodynamic and metabolic parameters culminating in decreased burn healing time, reduced mortality in traumatic brain injury, and improved neurologic outcomes following cardiac arrest. In sepsis, βB appear hemodynamically benign after acute resuscitation and may augment cardiac function. The emergence of ultra-rapid βB provides new territory for βB, and early data suggest significant improvements in mitigating atrial fibrillation in persistently tachycardic septic patients. This review summarizes the evidence regarding the pharmacotherapeutic role of βB on relevant pathophysiology and clinical outcomes in various types of critical illness.

A case report of an open aortic valve replacement followed by open adrenalectomy in a patient with symptomatic pheochromocytoma and critical aortic stenosis

Background Pheochromocytoma is a rare medical condition caused by catecholamine-secreting tumor cells. Operative resection can be associated with significant hemodynamic fluctuations due to the nature of the tumor, as well as associated post-resection vasoplegia. To allow for cardiovascular recovery before surgery, patients require pre-operative alpha-adrenergic blockade, which would be limited in the setting of co-existent severe aortic stenosis. In this report, we describe a patient with severe aortic stenosis and symptomatic pheochromocytoma. Case presentation A 51-year-old man with severe aortic stenosis (valve area 0.8 cm2) was found to have a highly active 4 × 4 cm left adrenal pheochromocytoma. Alpha-adrenergic blockade for his pheochromocytoma was limited by syncope in the setting of his aortic stenosis. Open aortic valve replacement (AVR) was performed, followed by adrenalectomy the next day. The perioperative course for each surgical procedure was hemodynamically volatile, exacerbated by severe alcohol withdrawal. During the adrenalectomy, cardiogenic and vasoplegic shock developed immediately after securing the vascular supply to his tumor. This shock was refractory to vasopressin and methylene blue, but responded well to angiotensin II and epinephrine. After both surgeries were completed, his course was further complicated by severe ICU psychosis, ileus, fungal bacteremia, pneumonia/hypoxic respiratory failure and atrial fibrillation. He ultimately recovered and was discharged from the hospital after 38 days. Conclusion To our knowledge, this is the first report of surgical AVR and pheochromocytoma resection in a patient with critical aortic stenosis. The appropriate order and timing of surgeries when both these conditions co-exist remains controversial.

Left ventricular depression and pulmonary edema in rats after short-term normobaric hypoxia: effects of adrenergic blockade and reduced fluid load

Acute normobaric hypoxia may induce pulmonary injury with edema (PE) and inflammation. Hypoxia is accompanied by sympathetic activation. As both acute hypoxia and high plasma catecholamine levels may elicit PE, we had originally expected that adrenergic blockade may attenuate the severity of hypoxic pulmonary injury. In particular, we investigated whether administration of drugs with reduced fluid load would be beneficial with respect to both cardiocirculatory and pulmonary functions in acute hypoxia. Rats were exposed to normobaric hypoxia (10% O2) over 1.5 or 6 h and received 0.9% NaCl or adrenergic blockers either as infusion (1 ml/h, increased fluid load) or injection (0.5 ml, reduced fluid load). Control animals were kept in normoxia and received infusions or injections of 0.9% NaCl. After 6 h of hypoxia, LV inotropic function was maintained with NaCl injection but decreased significantly with NaCl infusion. Adrenergic blockade induced a similar LV depression when fluid load was low, but did not further deteriorate LV depression after 6 h of infusion. Reduced fluid load also attenuated pulmonary injury after 6 h of hypoxia. This might be due to an effective fluid drainage into the pleural space. Adrenergic blockade could not prevent PE. In general, increased fluid load and impaired LV inotropic function promote the development of PE in acute hypoxia. The main physiologic conclusion from this study is that fluid reduction under hypoxic conditions has a protective effect on cardiopulmonary function. Consequently, appropriate fluid management has particular importance to subjects in hypoxic conditions.

Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth via Endoplasmic Reticulum Stress and Mitochondria Dysfunction

Adrenergic nerve fibers in the tumor microenvironment promote tumor growth and represent a potential target for cancer therapy. However, the effectiveness of targeting adrenergic nerve fibers for oral squamous cell carcinoma (OSCC) therapy needs to be evaluated by preclinical data. Herein, the 4NQO-induced and orthotopic xenograft OSCC mice models were established. We demonstrated that using 6OHDA chemical denervation as well as using nebivolol adrenergic blockade could halt the oral mucosa carcinogenesis. Our preclinical studies suggested that nebivolol, which is widely used to treat cardiovascular diseases, can be repositioned as a potential candidate to treat OSCC. Remarkably, we revealed the precise effect and mechanism of nebivolol on OSCC cells proliferation, cell cycle, and cell death. Administration of nebivolol could activate the endoplasmic reticulum (ER) stress signaling pathway through increasing the expression of inducible nitric oxide synthase, which subsequently triggers the integrated stress response and cell growth arrest. Simultaneously, ER stress also induced mitochondrial dysfunction in OSCC cells. We found that the accumulation of dysfunctional mitochondria with the impaired electron transport chain caused increasing reactive oxygen species production, which ultimately resulted in OSCC cell death. Altogether, our finding suggested a novel therapeutic opportunity for OSCC by targeting adrenergic nerve fibers, and repurposing nebivolol to treat OSCC can be represented as an effective strategy.

Effect of the beta-adrenergic blockade on intestinal lactate production and glycogen concentration in dogs infused with hexoses

Objectives To investigate effect of beta adrenergic blockade on intestinal lactate production and glycogen concentration in dogs infused with hexoses. Methods Experiments were carried out on 35 fasted male anaesthetized dogs weighing between 9 and 16 kg. The animals were divided into 7 (5 dogs per group) groups. Group I dogs served as control and infused with normal saline, groups II-IV were intravenously infused with glucose (1.1 mg/kg/min), fructose (1.1 mg/kg/min) and galactose (1.1 mg/kg/min) respectively while groups V-VII animals were pretreated with propranolol (0.5 mg/kg) and were infused with glucose, fructose or galactose respectively. A vein draining the proximal segment of the jejunum was cannulated along with right and left femoral arteries and veins. Glucose uptake was calculated as the product of jejunal blood flow and the difference between arterial and venous glucose levels (A-V glucose), part of the jejunum tissue was homogenized for estimation of glycogen concentration, and plasma lactate was assayed using lactate colorimetric kit. Results The result showed significant increase in venous lactate production in response to glucose (78.30 ± 4.57 mg/dl), fructose (60.72 ± 1.82 mg/dl) and galactose (71.70 ± 1.30 mg/dl) when compared with the control group (51.75 ± 1.32 mg/dl) at (p<0.05) with no significant difference in animals pretreated with propranolol. There was no significant difference in glycogen concentration (p>0.05) in animals infused with hexoses only compared with propanolol pretreated group. Conclusions Results suggests that one of the possible fates of the enormous amount of glucose taken up by the intestine is conversion to lactate and not glycogen and β-adrenergic receptor does not affect it.

Peripheral CB1 receptor blockade acts as a memory enhancer through an adrenergic-dependent mechanism

Peripheral inputs to the brain continuously shape its function and adjust non-emotional memory, but the mechanisms involved are not fully understood. Cannabinoid type-1 receptors (CB1Rs), widely distributed in the organism, are well recognized players in memory performance and their systemic modulation significantly influence memory function. By assessing non-emotional memory in mice, we found a relevant role of peripheral CB1R in memory persistence. Indeed, peripherally restricted CB1R antagonist AM6545 showed a mnemonic effect occluded in adrenalectomized mice, after peripheral adrenergic blockade, or when vagus nerve was chemogenetically inhibited. Genetic CB1R deletion in dopamine β-hydroxylase-expressing cells enhanced memory persistence, supporting a role of peripheral CB1Rs modulating the adrenergic tone. Notably, while brain connectivity was slightly affected by peripheral CB1R inhibition, locus coeruleus activity and extracellular norepinephrine in the hippocampus, were increased, and intra-hippocampal β-adrenergic blockade prevented AM6545 mnemonic effects. Together, we disclose a novel peripheral mechanism relevant for non-emotional memory persistence modulation.

β-Adrenergic blockade in patients with dementia and hip fracture is associated with decreased postoperative mortality

Purpose Dementia, present in 20% of hip fracture patients, is associated with an almost threefold increase in postoperative mortality risk. These patients have a substantially higher incidence of cardiovascular, respiratory, and cerebrovascular mortality after hip fracture surgery compared to patients without dementia. This study aimed to investigate the association between beta-blocker therapy and postoperative mortality in patients with dementia undergoing hip fracture surgery. Methods This nationwide study included all patients in Sweden with the diagnosis of dementia who underwent emergency surgery for a hip fracture between January 2008 and December 2017. Cases where the hip fracture was pathological or conservatively managed were not included. Poisson regression analysis with robust standard errors was performed while controlling for confounders to determine the relationship between beta-blocker therapy and all-cause, as well as cause-specific, postoperative mortality. Results A total of 26,549 patients met the study inclusion criteria, of whom 8258 (31%) had ongoing beta-blocker therapy at time of admission. After adjusting for clinically relevant variables, the incidence of postoperative mortality in patients receiving beta-blocker therapy was decreased by 50% at 30 days [adj. IRR (95% CI) 0.50 (0.45–0.54), p < 0.001] and 34% at 90 days [adj. IRR (95% CI) 0.66 (0.62–0.70), p < 0.001]. Cause-specific mortality analysis demonstrated a significant reduction in the incidence of postoperative cardiovascular, respiratory, and cerebrovascular death within 30 and 90 days postoperatively. Conclusion Beta-blocker therapy is associated with decreased postoperative mortality in hip fracture patients with dementia up to 90 days after surgery. This finding warrants further investigation.

Effects of mechanical ventilation with expiratory negative airway pressure on porcine pulmonary and systemic circulation: mechano-physiology and potential application

We studied the impact of mechanically regulated, expiratory negative airway pressure (ENAP) ventilation on pulmonary and systemic circulation including its mechanisms and potential applications. Microminipigs weighing about 10 kg were anesthetized (n = 5). First, hemodynamic variables were evaluated without and with ENAP to approximately −16 cmH2O. ENAP significantly increased heart rate and cardiac output, but decreased right atrial, pulmonary arterial and pulmonary capillary wedge pressures. Second, the evaluation was repeated following pharmacological adrenergic blockade, modestly blunting ENAP effects. Third, fluvoxamine (10 mg/kg) was intravenously administered to intentionally induce cardiovascular collapse in the presence of adrenergic blockade. ENAP was started when systolic pressure was < 40 mmHg in the animals assigned to ENAP treatment-group. Fluvoxamine induced cardiovascular collapse within 4 out of 5 animals. ENAP increased systolic pressure to > 50 mmHg (n = 2): both animals fully recovered without neurological deficit, whereas without ENAP both animals died of cardiac arrest (n = 2). ENAP may become an innovative treatment for drug-induced cardiovascular collapse.