Beta-adrenoceptor Blockade Research Articles

Autonomic Nervous System: A Therapeutic Target for Cardiac End-Organ Damage in Hypertension.

More than 1.5 billion people worldwide have arterial hypertension. Hypertension increases the risks of death and cardiovascular disease, such as atrial fibrillation and heart failure. The autonomic nervous system plays an essential role in hypertension development and disease progression. While lifestyle factors, such as obesity and obstructive sleep apnea, predispose to hypertension by increasing sympathetic activity, hypertension itself maintains the autonomic nervous imbalance, providing the substrate for atrial fibrillation and heart failure. Therefore, autonomic nervous system modulation either by direct targeting or indirect treatment of comorbidities has the potential to treat both hypertension and related atrial and ventricular end-organ damage. We discuss interventions for the modulation of the autonomic nervous system for hypertension and related cardiac end-organ damage, including pharmacological adrenergic beta-receptor blockade, renal denervation, carotid baroreceptor stimulation, low-level vagal stimulation, and ablation of ganglionated plexuses. In summary, the literature suggests that targeting the autonomic nervous system potentially represents a therapeutic approach to prevent atrial and ventricular end-organ damage in patients with hypertension. However, clinical trials specifically designed to test the effect of autonomic modulation on hypertension-mediated cardiac end-organ damage are scarce.

Abstract We107: Reduction of Six-Month Heart Failure Readmission Rates in Patients Undergoing MitraClip with Beta Receptor Blockade

Introduction: MitraClip has been shown to reduce heart failure readmissions in patients with moderate to severe mitral valve regurgitation. Likewise, beta-blocker (BB) therapy has been shown to reduce morbidity and mortality in select heart failure patients. At the cellular level, chronic myocardial insult from ongoing heart failure and mitral regurgitation leads to persistent overstimulation of myocardial beta-receptors, ultimately reducing cardiac inotropic reserve and contributing to myocardial injury. Thus, we hypothesized that patients on beta-blocker therapy before the MitraClip procedure would have fewer heart failure-related readmissions. Hypothesis: We assessed the hypothesis that beta-blocker therapy before the MitraClip procedure would lead to fewer heart failure-related readmissions by conducting a retrospective cohort study. This would help us better understand the pathogenesis of re-admissions in this patient population as well as help us decide whether prophylactic initiation of BB therapy before the procedure would reduce the risk of heart failure readmissions. Methods: We reviewed the records of patients who underwent the MitraClip procedure at our institution from January 2017 to July 2022. Patients without listed home medications, as well as non-heart failure-related readmissions and deaths, were excluded. Patients were split into those on BB therapy and those with no BB therapy. Of the 401 charts screened, 324 met the inclusion criteria. Results: From those who met the inclusion criteria, 226 patients were on beta-blocker therapy, while 98 patients were not. Of those who had at least one heart failure-related readmission within 6 months of the MitraClip procedure, 18 patients were on beta-blocker therapy and 16 patients were not. Meaning a 7.96% readmission rate for patients on beta-blocker therapy, and a 16.32% readmission rate for those who were not (OR 2.05, 95% CI: 1.004 to 4.186, p<0.05), with the number needed to treat being 11.9. Conclusions: Our data shows that the use of beta-blocker therapy was associated with a statistically significant decrease in 6-month heart failure readmissions in those undergoing the MitraClip procedure. This suggests that at the cellular level, cardiac beta receptor dysfunction plays an integral part in future hospitalizations in this population. In conclusion, beta-blocker therapy should be considered in heart failure patients planning to undergo the MitraClip procedure to reduce heart failure-related readmissions.

Elucidation of the Molecular Signal Linking Psychological Trauma to T-lymphocyte Inflammation

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that not only exhibits significant behavioral pathology, but also increases the likelihood of comorbid inflammatory conditions such as autoimmune and cardiovascular diseases. While PTSD patients experience heightened systemic inflammation, the exact link between psychological trauma and immune dysregulation remains to be elucidated. Our group has recapitulated the psychological trauma-induced inflammatory phenotype in a pre-clinical murine model of PTSD known as repeated social defeat stress (RSDS). Importantly, a key site of this inflammation appears to originate from T-lymphocytes in the spleen, and targeted splenic nerve denervation was able to completely prevent splenic T-lymphocyte inflammation after RSDS (p<0.0001). This critical observation suggests the T-lymphocyte response to psychological trauma is neural derived as opposed to circulating, therefore, we began systematic investigation into possible neural-derived signals that may lead to enhanced T-lymphocyte inflammation. To investigate whether the signal involves the T-cell receptor (TCR), we utilized OT-I and OT-II mice that possess non-mouse antigen-restricted TCRs. RSDS induced T-lymphocyte inflammation in these mice similar to wild-type, therefore, suggesting the signal is not antigenic in nature (p>0.05). Next, we examined the role of norepinephrine and adrenergic signaling using both pharmacological blockade and genetic knockouts of both alpha and beta adrenergic receptors, but this too was insuffcient to reverse the RSDS-induced T-lymphocyte inflammation (p>0.05). Following this, we examined the role of damage associated molecular patterns (DAMPs) by pharmacological blockade of the toll-like receptor 4 (TLR4), yet again, this intervention did not attenuate T-lymphocyte inflammation after RSDS (p>0.05). Last, our data suggests interleukin 6 (IL-6) is upregulated early after psychological trauma; therefore, we examined the role for cytokine-induced T-lymphocyte inflammation. Using anti-IL-6 antibodies during RSDS, T-lymphocyte inflammation appeared blunted compared to wild-type animals (p<0.05). Moreover, T-lymphocytes treated with only IL-6 expressed similar inflammation gene profiles as those from RSDS animals (p<0.05). Taken together, our data suggest IL-6 may be the T-lymphocyte inflammation-inducing signal, but additional studies are warranted to understand the exact source of IL-6 and mechanisms underlying IL-6’s ability to drive T-lymphocyte inflammation. R01HL158521. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Anxiolytic-like effects of Atenolol injected into the nucleus accumbens septi in rats after restrain stress in the elevated plus maze test

Objetives: Previously, we observed that the injection of glutamate antagonists injected within the Nucleus Accumbens Septi (NAS) produced an anxiolytic-like effect in the elevated plus maze (EPM) test in basal non-disturbed state rats. The effect of metoprolol, a specific Beta-1 Adrenoreceptor antagonist in the EPM, was studied previously in a resting condition in male rats bilaterally cannulated in the NAS. Methods: Rats were previously submitted to restrain stress and divided into four groups. They received bilaterally 1 μl injections of saline (n=13) or atenolol in different doses within the NAS: 0.75 (n=15), 1 (n=13) and 2 µg/1 µl (n=13), 15 min before testing. Rats were maintained under restrain between injection and test. Results: Time Spent in the Open Arm (TSOA) was modified by treatment (F = 4.239, p = 0.0096, df = 3) and increased by the medium dose group when it was compared with the saline group (p<0.05) and the lowest dose group (p<0.01). Open arms entries (OAE) were modified by treatment (F = 3.461, p = 0.0231, df = 3). This parameter was increased by the medium dose of atenolol (p<0.05) when compared to saline and the lowest dose. No significant differences were observed in other parameters studied. Conclusion: We conclude that atenolol beta-1 receptor blockade within the NAS after restraint leads to an anxiolytic-like effect related to an increase in the Time Spent in the Open Arm (TSOA), and behavioural disinhibition, evidenced in the increase in the Open Arm Entries (OAE), showing a specific behavioural pattern.

SAT312 CT-guided Cryoablation Of Hereditary Pheochromocytoma

Abstract Disclosure: E. Griffing: None. B. Reading: None. F. De Luca: None. Background: Guidelines surrounding the management of hereditary pediatric pheochromocytomas (PHEO) are lacking. This is the first report of a pediatric patient with bilateral hereditary PHEO treated with right adrenalectomy and computed tomography (CT) percutaneous-guided cryoablation (CRA) of the left-sided lesion.Clinical case: A previously healthy 15 years-old male presented to a tertiary care hospital with a months-long history of episodic chest pain, flushing, shortness of breath, diaphoresis, and tremulousness. Paternal family history was significant for PHEO and brain stem hemangioblastoma in grandmother and PHEO in the great-grandfather. Targeted familial mutation analysis of the von Hippel-Lindau tumor suppressor gene was positive for pathogenic mutation c.500G>A (p.R167Q). Plasma free normetanephrine level was 4,625 pg/mL (nl: <145 pg/mL), while free metanephrines were normal. Magnetic-resonance imaging of the abdomen visualized a 4.4 x 3.4 x 5.3 cm right adrenal mass and a 1.4 x 1.4 x 1.4 cm left adrenal mass, consistent with bilateral PHEO. He underwent right adrenalectomy after initiation of alpha-receptor blockade and later addition of beta-receptor blockade due to heart rates in the 150’s. After discussion with parents, it was decided to observe the smaller left-sided adrenal lesion. Plasma free normetanephrines initially decreased to 338 pg/mL, but then increased to 507 pg/mL five months post-operatively. Six months after surgery, due to the persistence of hypertension with systolic blood pressure in the 140’s as well as tachycardia with heart rates in the 150’s, he underwent CT-guided CRA of the left-sided PHEO. A 12-minute freeze, 5-minute thaw, and 10-minute freeze, followed by an active thaw were performed. There was an increase in blood pressure during the initial thaw with systolic blood pressure in the 230s, accompanied by bradycardia to the 30s, treated with nitroprusside, phentolamine, and increased sedation. He required continuation of nitroprusside infusion for five hours post-procedure. He was discharged the following day with normal blood pressure and heart rate. He was able to completely wean off anti-hypertensive medications within one month and symptoms of chest pain and tachycardia resolved. In the four years since his procedure, he has not had a recurrence of PHEO nor development of adrenal insufficiency. Plasma free normetanephrines and metanephrines have remained within normal limits. Conclusion: Percutaneous ablation of hereditary PHEO has not been reported before in the pediatric population and may represent a novel treatment strategy that reduces the risk of adrenal insufficiency. Presentation: Saturday, June 17, 2023

COMPARATIVE EFFECT OF ATENOLOL AND NEBIVOLOL ON REVERSE REMODELING OF INTRAMURAL CORONARY ARTERIOLES IN THE SPONTANEOUSLY HYPERTENSIVE RAT MODEL

Objective: Arterial hypertension is an established major risk factor for ischemic heart disease. Functional and structural abnormalities at the level of the microcirculation may play a crucial role in coronary microvascular dysfunction. Indeed, coronary flow reserve is often reduced at angiography in hypertensive patients independently on the presence of left ventricular hypertrophy (Mancini M. et al. Microcirculation 2017). The aim of this study was to assess the effect of the beta-blocker Atenolol and the selective third-generation beta1-adrenergic antagonist Nebivolol on markers of remodeling and endothelial dysfunction in coronary microvascular. Nebivolol has been demonstrated to possess direct vasodilator and antioxidant properties which may improve endothelial dysfunction and reduce smooth muscle cell proliferation. Design and method: For this purpose, we used three groups of SHR rats: Hypertensive untreated group (SHR); SHR plus Atenolol 50 mg/kg/day by oral gavaging for 8 weeks (SHR + ATE); SHR plus Nebivolol 20 mg/kg/day by oral gavaging for 8 weeks (SHR + NEB). Protein expression levels of vasoactive factors, oxidative stress and remodeling markers in coronary microcirculation were determined by immunohistochemical analysis of Endothelin-1 (ET-1), inducible nitric oxide synthase (iNOS) and transforming growth factor-beta1 (TGF-beta1). Results: No differences were observed in structural parameters of mesenteric arteries among groups. SHR + NEB showed a significant reduction in ET-1, iNOS, and TGF-beta1 staining in coronary small arteries comparing to SHR and SHR + ATE. Conclusions: In comparison to atenolol, nebivolol may provide additional benefit beyond blood pressure reduction and beta-receptor blockade since show greater activity in the modulation of protein involved in vasodilation and oxidative stress protection.

Beta blockers reduce uterine fibroid incidence in hypertensive women

ObjectiveIs prior beta blocker (BB) use associated with reduced odds of the clinical incidence of leiomyomas? What is known alreadyIn-vitro and in-vivo evidence has supported the role of beta receptor blockade in reducing leiomyoma cell proliferation and growth. However, no population-based study to date has investigated this potential association. Study design, size, durationA nested case-control study was conducted in a population of women aged 18–65 with arterial hypertension (n = 699,966). Cases (n = 18,918) with a leiomyoma diagnosis were matched to controls (n = 681,048) with no such diagnosis at a 1:36 ratio by age and region of origin within the United States. Participants/materials, setting, methodsThis population was assembled from the Truven Health MarketScan® Research Database, which includes health insurance claims from January 1st, 2012 to December 31st, 2017. Prior use of BB wasdetermined fromoutpatient drug claims and leiomyoma development was indicated by a first-time diagnosis code. We conducted a conditional logistic regression to determine the odds of uterine fibroid development in women with prior use of BB compared to women with no such history. We then conducted subset analyses, stratifying the women by age group and by type of BB. ResultsWomen on a BB experienced 15% reduced odds of developing clinically recognized leiomyoma compared to non-users (OR 0.85, 95% CI 0.76–0.94). This association was significant for the 30–39 age group (OR 0.61, 95% CI 0.40–0.93) but no other age group. Of the BBs, propranolol (OR 0.58, 95% CI 0.36–95) demonstrated a significant association with reduced leiomyoma incidence and metoprolol (OR 0.82, 95% CI 0.70–0.97) was associated with lower uterine fibroid incidence after adjustment for comorbidities. ConclusionsHypertensive women with prior BB use experienced reduced odds of developing clinically recognized leiomyoma compared to non-users. A key predisposing risk factor for uterine leiomyoma is elevated blood pressure. Thus, the results of this analysis may have clinical relevance to women with hypertension, as the use of this drug may introduce a dual benefit of managing hypertension as well as curbing an increased risk of leiomyomas.

Beta1-receptor blockade attenuates atherosclerosis progression following traumatic brain injury in apolipoprotein E deficient mice.

Traumatic brain injury (TBI) is associated with cardiovascular mortality in humans. Enhanced sympathetic activity following TBI may contribute to accelerated atherosclerosis. The effect of beta1-adrenergic receptor blockade on atherosclerosis progression induced by TBI was studied in apolipoprotein E deficient mice. Mice were treated with metoprolol or vehicle following TBI or sham operation. Mice treated with metoprolol experienced a reduced heart rate with no difference in blood pressure. Six weeks following TBI, mice were sacrificed for analysis of atherosclerosis. Total surface area and lesion thickness, analyzed at the level of the aortic valve, was found to be increased in mice receiving TBI with vehicle treatment but this effect was ameliorated in TBI mice receiving metoprolol. No effect of metoprolol on atherosclerosis was observed in mice receiving only sham operation. In conclusion, accelerated atherosclerosis following TBI is reduced with beta-adrenergic receptor antagonism. Beta blockers may be useful to reduce vascular risk associated with TBI.

Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine-1,5-Benzodiazepine Hybrids.

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5'-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5'-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.

Examination of the role of adrenergic receptor stimulation in the sensitization of neuroinflammatory-based depressive-like behavior in isolated Guinea pig pups

Early-life attachment disruption appears to sensitize neuroinflammatory signaling to increase later vulnerability for stress-related mental disorders, including depression. How stress initiates this process is unknown, but studies with adult rats and mice suggest sympathetic nervous system activation and/or cortisol elevations during the early stress are key. Guinea pig pups isolated from their mothers exhibit an initial active behavioral phase characterized by anxiety-like vocalizing. This is followed by inflammatory-dependent depressive-like behavior and fever that sensitize on repeated isolation. Using strategies that have been successful in adult studies, we assessed whether sympathetic nervous system activity and cortisol contributed to the sensitization process in guinea pig pups. In Experiment 1, the adrenergic agonist ephedrine (3 or 10 mg/kg), either alone or with cortisol (2.5 mg/kg), did not increase depressive-like behavior or fever during initial isolation the following day as might have been expected to if this stimulation was sufficient to account for the sensitization process. In Experiment 2, both depressive-like behavior and fever sensitized with repeated isolation, but beta-adrenergic receptor blockade with propranolol (10 or 20 mg/kg) did not affect either of these responses or their sensitization. The high dose of propranolol did, however, reduce vocalizing. These results suggest sympathetic nervous system activation is neither necessary nor sufficient to induce the presumptive neuroinflammatory signaling underlying sensitization of depressive-like behavioral or febrile responses in developing guinea pigs. Thus, processes mediating sensitization of neuroinflammatory-based depressive-like behavior following early-life attachment disruption in this model appear to differ from those previously found to underlie neuroinflammatory priming in adults.

Synthesis new fluorinated 4-phenyl-1,4-dihydropyridine derivatives, as perspective antiarrhythmic and antihypertensive drugs

Derivatives of dihydropyridines are promising agents for research, as they have high biological activity. Their low toxicity and polytargeted properties make it possible to create new derivatives and identify new biological activity. As part of this work, we have obtained six new fluorinated derivatives of 4-phenyl-1,4-dihydropyridines. These compounds were synthesized by a modified Hantzsch reaction, the interaction of polyfluorinated sulfur-containing benzaldehydes with ethyl acetoacetate and ethyl 3-aminobut-2-enoate. Studies on the isolated atrium have shown that the possible mechanism of action of the dihydropyridine derivatives lies in the blockade of beta-adrenergic receptors. At the same time, it is not a blocker of potassium and calcium channels. The fluorinated 4-phenyl-1,4-dihydropyridine derivatives, with SCF2H (decrease pressure) and SO2CH3 (increase pressure) groups showed pronounced activity in the study of these derivatives on the blood pressure of rats.

Beta-Adrenergic Receptor Blockade Effects on Cardio-Pulmonary Exercise Testing in Healthy Young Adults: A Randomized, Placebo-Controlled Trial

BackgroundBeta-blockers are increasingly prescribed while the effects of beta-adrenergic receptor blockade on cardio-pulmonary exercise test (CPET)-derived parameters remain under-studied.MethodsTwenty-one young healthy adults repeated three CPET at the same time with an interval of 7 days between each test. The tests were performed 3 h after a random, double-blind, cross-over single-dose intake of placebo, 2.5 mg or 5.0 mg bisoprolol, a cardio-selective beta1-adrenoreceptor antagonist. Gas exchange, heart rate (HR) and blood pressure (BP) were measured at rest and during cyclo-ergometric incremental CPET.ResultsMaximal 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 BP and HR and the chronotropic response to exercise, evaluated by the HR/VO2 slope (placebo: 2.9 ± 0.4 beat/ml/kg; 2.5 mg bisoprolol: 2.4 ± 0.5 beat/ml/kg; 5.0 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; 5.0 mg bisoprolol: 33 ± 6 bpm, p < 0.01).ConclusionThe present results suggest that a single dose of bisoprolol does not affect metabolism, respiratory response and exercise capacity. However, beta-adrenergic blockade dose dependently reduces exercise hemodynamic response by lowering BP and the chronotropic response.

LBMON137 Don't Be Fooled By Normotension Pheo Could Be The Potential

Abstract Introduction Sustained or proximal hypertension is the most common sign of pheochromocytoma, but approximately 5-15% of pts present with normal blood pressure. We report a case of a patient incidentally found to have a catecholamines secreting adrenal tumor, but was normotensive on admission. Case 30-year-old morbidly obese woman incidentally found to have a 4.8 cm left adrenal gland mass while being worked up for sepsis secondary to atypical pneumonia. Initially, the patient presented with dyspnea, chest pain, palpitation, nausea, and vomiting. Her past medical history is significant for preeclampsia, 200 lb wt loss in 1 year, NSTMI a few months prior to admission discharged on dual antiplatelet and metoprolol which she couldn't tolerate due to hypotensive episodes. On arrival to the ED the patient was afebrile, normotensive SBP 90-110 DBP 57-70 mmHg, HR 86 BPM, RR 20, saturating 98% on room air. Her laboratory workup was significant for leukocytosis, elevated D-dimer, hyperkalemia 5.9 mmol/L, mildly elevated liver enzymes, and mildly elevated troponin. MRI abdomen 4.8×4.4×5. 0 cm complex enhancing mass with eccentric necrosis and/or fibrosis arising from the left adrenal gland. Ur Normetanephrine 5867 mcg/24h, Ur Metanephrine 3017 Mcg/24hr, urine dopamine and norepinephrine were within normal limits. Serum Metanephrine 2.64 nmol/L normetanephrine 13.50 nmol/L, aldosterone, renin, and cortisol levels were normal. Discussion Sustained or proximal hypertension is the most common sign of pheochromocytoma, but approximately 5-15% of pts present with normal blood pressure. Other signs and symptoms that may occur include orthostatic hypotension, visual blurring, papilledema, weight loss, polyuria, polydipsia, constipation, increased ESR, insulin resistance, hyperglycemia, leukocytosis, psychiatric disorders, and, rarely, secondary erythrocytosis due to overproduction of erythropoietin. The beta-adrenergic blocker should never be started first because a blockade of vasodilatory peripheral beta-adrenergic receptors with unopposed alpha-adrenergic receptor stimulation can lead to a further elevation in blood pressure. Our patient was normotensive throughout the hospitalization, and before admission was on metoprolol for NSTMI, however, she was unable to tolerate it due to hypotensive episodes. Conclusion Most patients with pheochromocytoma present with hypertension, however, few cases could present with normotension or even hypotension. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Beta-adrenergic receptor blockade in angiosarcoma: Which beta-blocker to choose?

Beta-blockers are currently studied to improve therapeutic options for patients with angiosarcoma. However, most of these patients have no cardiovascular co-morbidity and it is therefore crucial to discuss the most optimal pharmacological properties of beta-blockers for this population. To maximize the possible effectiveness in angiosarcoma, the use of a non-selective beta-blocker is preferred based on in vitro data. To minimize the risk of cardiovascular adverse events a beta-blocker should ideally have intrinsic sympathomimetic activity or vasodilator effects, e.g. labetalol, pindolol or carvedilol. However, except for one case of carvedilol, only efficacy data of propranolol is available. In potential follow-up studies labetalol, pindolol or carvedilol can be considered to reduce the risk of cardiovascular adverse events.

Perioperative Beta-Blocker Supply and Survival in Women With Epithelial Ovarian Cancer and a History of Cardiovascular Conditions.

Surgery for epithelial ovarian cancer (EOC) may activate stress-inflammatory responses that stimulate tumor growth and increase metastatic growth. Animal and in vitro studies have shown that inhibition of the catecholamine-induced inflammatory response via beta-adrenergic receptor blockade has antitumor potential in EOC. However, observational studies have reported mixed results. We assessed whether beta-blocker (BB) use at the time of primary ovarian cancer surgery was associated with improved survival in a large population-based study. Using linked administrative data, a population-based cohort of 3,844 Australian women age 50 years or older with a history of cardiovascular conditions who underwent surgery for EOC was followed for survival outcomes. The average treatment effect of selective BB (SBB) and nonselective BB (NSBB) supply at the time of surgery on survival was estimated from a causal inference perspective using covariate-balanced inverse probability of treatment weights with flexible parametric survival models that allowed for time-varying survival effects. Around the time of surgery, 560 (14.5%) women were supplied a SBB and 67 (1.7%) were supplied a NSBB. At 2 years postsurgery, the survival proportion was 80% (95% CI, 68 to 88) for women dispensed NSBBs at surgery compared with 69% (95% CI, 67 to 70) for women not supplied NSBBs. The survival advantage appeared to extend to at least 8 years postsurgery. No association was observed for women dispensed a SBB around the time of surgery. Perioperative supply of NSBBs appeared to confer a survival advantage for women age over 50 years with a history of cardiovascular conditions. Long-term clinical trials are required to confirm these findings.

Blockade of beta-adrenergic receptors reduces cancer growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment

The development of immune checkpoint inhibitors (ICI) marks an important breakthrough of cancer therapies in the past years. However, only a limited fraction of patients benefit from such treatments, prompting the search for immune modulating agents that can improve the therapeutic efficacy. The nonselective beta blocker, propranolol, which for decades has been prescribed for the treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma model and MC38 colon cancer model and increases the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol treatment leads to an upregulation of PD-L1 on tumor associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the co-administration of propranolol significantly enhances the efficacy of anti-CTLA4 therapy. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially in other cancers.

Blockade of beta adrenergic receptors protects the blood brain barrier and reduces systemic pathology caused by HIV-1 Nef protein.

Combination antiretroviral therapy (cART) targets viral replication, but early viral protein production by astrocytes may still occur and contribute to the progression of HIV-1 associated neurocognitive disorders and secondary complications seen in patients receiving cART. In prior work with our model, astrocytic HIV-1 Nef expression exhibits neurotoxic effects leading to neurological damage, learning impairment, and immune upregulation that induces inflammation in the lungs and small intestine (SI). In this follow-up study, we focus on the sympathetic nervous system (SNS) as the important branch for peripheral inflammation resulting from astrocytic Nef expression. Male and female Sprague Dawley rats were infused with transfected astrocytes to produce Nef. The rats were divided in four groups: Nef, Nef + propranolol, propranolol and naïve. The beta-adrenergic blocker, propranolol, was administered for 3 consecutive days, starting one day prior to surgery. Two days after the surgery, the rats were sacrificed, and then blood, brain, small intestine (SI), and lung tissues were collected. Levels of IL-1β were higher in both male and female rats, and treatment with propranolol restored IL-1β to basal levels. We observed that Nef expression decreased staining of the tight junction protein claudin-5 in brain tissue while animals co-treated with propranolol restored claudin-5 expression. Lungs and SI of rats in the Nef group showed histological signs of damage including larger Peyer’s Patches, increased tissue thickness, and infiltration of immune cells; these findings were abrogated by propranolol co-treatment. Results suggest that interruption of the beta adrenergic signaling reduces the peripheral organ inflammation caused after Nef expression in astrocytes of the brain.

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.

Effect of Adrenergic Drugs on the Lipopolysaccharide-Induced Oxidative Stress and Liver Damage in the Rat

Aim: We aimed to investigate the effect of the adrenergic system on oxidative stress and liver damage during mild systemic inflammation in rats. Methods: For this purpose, Eschrechia coli lipopolysacchride (LPS; 300μg/kg) was intraperitoneally injected either alone or along with the α-2 adrenoceptor antagonist yohimbine, the non-selective β adrenoceptor antagonist propranolol, the and β-adrenoceptor agonist adrenaline and rats euthanized 4h later. The effects of these drugs in saline-treated rats were also studied. Serum alanine aminotransferase (ALT), aspartate aminotransferase, and alkaline phosphatase activities were measured. Liver tissue levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH) were determined and liver histology evaluated. Results: In saline-treated rats (i) yohimbine caused significantly increased ALT, AST and ALP in serum. In addition, yohimbine increased MDA, NO and decreased GSH in liver tissue and caused cytoplasmic vacuolations and cellular infiltration: (ii) adrenaline treatment increased serum ALT, AST, liver MDA, decreased liver GSH and caused minute vacuolar degeneration and foci of necrosis; (iii) in contrast, there were no biochemical or histologic alterations after propranolol treatment. In endotoxaemic rats; (i) serum aminotransferases and alkaline phosphatase were significantly increased by yohimbine together with increased liver MDA, NO and decreased GSH content; (ii) serum ALT decreased by propranolol and adrenaline while serum ALP increased by adrenaline; (iii) liver GSH increased by propranolol; (iv) LPS administration caused acute liver damage in the form of foci of necrosis, vacuolar degeneration and aggregates of inflammatory cellular infiltration. Compared with the LPS only group, treatment with yohimbine increased while propranolol or adrenaline produced less liver damage. Conclusions: Thus, blockade of α-2 adrenoceptors increased while β adrenoceptor antagonism decreased oxidative stress and liver damage following LPS administration in rats. Collectively, these results indicate a benefit from blockade of beta-adrenoceptors in protecting the liver during mild systemic inflammation in part by decreasing oxidative stress.

Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through release of neuropeptide Y

The sympathetic nervous system plays an important role in the occurrence of ventricular tachycardia (VT). Many patients, however, experience VT despite maximal doses of beta blocker therapy, possibly due to the effects of sympathetic cotransmitters such as neuropeptide Y (NPY). The purpose of this study was to determine, in a porcine model, whether propranolol at doses higher than clinically recommended could block ventricular electrophysiological effects of sympathoexcitation via stellate ganglia stimulation, and if any residual effects are mediated by NPY. Greater release of cardiac NPY was observed at higher sympathetic stimulation frequencies (10 and 20 vs. 4 Hz). Despite treatment with even higher doses of propranolol (1.0 mg/kg), electrophysiological effects of sympathetic stimulation remained, with residual shortening of activation recovery interval (ARI), a surrogate of action potential duration (APD). Adjuvant treatment with the NPY Y1 receptor antagonist BIBO 3304, however, reduced these electrophysiological effects while augmenting inotropy. These data demonstrate that high-dose beta blocker therapy is insufficient to block electrophysiological effects of sympathoexcitation, and a portion of these electrical effects in vivo are mediated by NPY. Y1 receptor blockade may represent a promising adjuvant therapy to beta-adrenergic receptor blockade.