Beta-adrenoceptor Blockade Research Articles

Nebivolol/valsartan: Fixed-dose combination for treatment of hypertension.

Clinical trials demonstrated that a fixed-dose combination (FDC) of the beta-blocker nebivolol (5 mg) and the angiotensin II antagonist valsartan (80 mg) produced a significant reduction of both diastolic and systolic blood pressure in patients with hypertension. Both nebivolol and valsartan contributed to this effect, partial additivity of 86.6% and 82.2% being observed for diastolic and systolic blood pressure, respectively. These values are very similar to the additivity ratios of other recently approved FDCs for hypertension. Use of the FDC nebivolol 5 mg/valsartan 80 mg formulation was associated with a low incidence of treatment-related adverse effects and of serious adverse effects. There was no evidence of adverse effects due to beta2-adrenoceptor blockade. The FDC (Byvalson) was approved and launched in 2016 in the U.S. for the treatment of hypertension.

Whole blood viscosity following cardioselective beta-adrenoceptor blockade in hypertension

Whole blood viscosity following cardioselective beta-adrenoceptor blockade in hypertension

The Beta-1-Receptor Blocker Nebivolol Elicits Dilation of Cerebral Arteries by Reducing Smooth Muscle [Ca2+]i.

RationaleNebivolol is known to have beta-1 blocker activity, but it was also suggested that it elicits relaxation of the peripheral arteries in part via release of nitric oxide (NO). However, the effect of nebivolol on the vasomotor tone of cerebral arteries is still unclear.ObjectiveTo assess the effects of nebivolol on the diameter of isolated rat basilar arteries (BA) in control, in the presence of inhibitors of vasomotor signaling pathways of know action and hemolysed blood.Methods and ResultsVasomotor responses were measured by videomicroscopy and the intracellular Ca2+ by the Fura-2 AM ratiometric method. Under control conditions, nebivolol elicited a substantial dilation of the BA (from 216±22 to 394±20 μm; p<0.05) in a concentration-dependent manner (10−7 to 10−4 M). The dilatation was significantly reduced by endothelium denudation or by L-NAME (inhibitor of NO synthase) or by SQ22536 (adenylyl cyclase blocker). Dilatation of BA was also affected by beta-2 receptor blockade with butoxamine, but not by the guanylate cyclase blocker ODQ. Interestingly, beta-1 blockade by atenolol inhibited nebivolol-induced dilation. Also, the BKCa channel blocker iberiotoxin and KCa channel inhibitor TEA significantly reduced nebivolol-induced dilation. Nebivolol significantly reduced smooth muscle Ca2+ level, which correlated with the increases in diameters and moreover it reversed the hemolysed blood-induced constriction of BA.ConclusionsNebivolol seems to have an important dilator effect in cerebral arteries, which is mediated via several vasomotor mechanisms, converging on the reduction of smooth muscle Ca2+ levels. As such, nebivolol may be effective to improve cerebral circulation in various diseased conditions, such as hemorrhage.

Morphological and functional changes in kidneys caused by propranolol: effects of melatonin.

Background. Beta-blockers, including propranolol, are widely used in clinical practice as effective heart medicines. By the spectrum of action, some of them are selectively blocking beta-blockers, which are located in the heart muscle, and called cardioselective (nebivolol, metoprolol, atenolol). Others (propranolol, oksyprenolol, pindolol), simultaneously affect β1- and β2-adrenergic receptors, referred to as non-selective. Objective. The aim of our study was to examine the value of blockade of beta-adrenergic receptors in the regulation of chronorhythms of excretory and ion-regulative renal functions. Determine the possible role of exogenous melatonin in mechanisms of correction of circadian renal function disorders and morphologic abnormalities of kidneys. M ethods. Experiments conducted on 35 male rats. One group of rats was daily administered by intragastric propranolol at a dose of 2,5 mg/kg body weight at 19.00 for 7 days. Another group of rats received intraperitoneal exogenous melatonin (Sigma, USA) (0,5 mg/kg body weight) at standard daylight against previous administration of propranolol. Results . Our studies showed that exogenous melatonin is able to influence the basic parameters of renal function caused by propranolol. Obviously, these effects are realized by stimulating specific melatonin receptors located on the basolateral membrane of the initial divisions of proximal tubules, and to a lesser extent – in the glomeruli. Thus, administration of melatonin on the background of propranolol action increases the urine output, increases the speed of ultrafiltration in glomeruli at 42 %, reduces the effects of azotemia, increases the excretion of sodium, increases proximal and distal transport of this cation. Conclusion . The influence of melatonin in condition of propranolol action was characterized by pleiotropic effect.

Abstract # 1731 Perioperative COX-2 inhibition and beta-adrenoceptor blockade in breast cancer patients improve markers of immunity and reduce inflammation and primary tumor epithelial-to-mesenchymal transition (EMT)

Preclinical research has implicated excess perioperative release of catecholamines and prostaglandins in mediating the metastasis-promoting effects of stress and surgery. This study reports the first clinical test of combined blockade of these pathways using the beta-adrenergic blocker, propranolol, and the COX-2 inhibitor, etodolac. In a double-blind placebo-controlled clinical trial, 36 breast cancer patients were randomized to an 11-day oral drug treatment beginning five days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4), and excised tumors were collected. No adverse effects of drug treatment were reported. Among other findings, in the placebo group, (i) serum IL-6 and CRP levels increased before surgery (T2), and (ii) stimulated IL-12 and IFN γ levels were reduced by stress and surgery (T2&T3). Both effects were blocked and further reversed by the drug treatment. Transcriptome analyses of excised tumor tissue identified 368 genes showing >1.20-fold differential expression as a function of drug treatment. Bioinformatics analyses based on a priory hypotheses indicated decreased tumor expression of several pro-metastatic gene programs, including inflammatory and epithelial-to-mesenchymal transition (EMT). Flow cytometry showed that drug treatment also abolished a postoperative (T3) circulating influx of immature-proinflammatory monocytes (CD14++CD16-), and enhanced perioperative (T2&T3) expression levels of CD11a on NK cells. These findings suggest pro-immune, anti-inflammatory, and potential anti-metastatic effects of this novel and safe therapy.

Chronic stress increases experimental pancreatic cancer growth, reduces survival and can be antagonised by beta-adrenergic receptor blockade.

Chronic stress could promote tumour growth and reduce survival of pancreatic cancer patients via beta-adrenergic receptors of tumour cells. We have tested the impact of chronic acoustic and restraint stress on tumour development in an orthotopic syngeneic murine model of pancreatic cancer. Tumour-bearing C57BL/6 mice exposed to chronic stress had 45% (p=0.0138) higher circulating steroid and 111% (p=0.0052) higher adrenal tyrosine hydroxylase levels. Their immune response was significantly suppressed: The invitro LPS response of splenocytes was significantly reduced regarding Th1- and Th2-cytokines including IFN-gamma, IL-6, IL-10 and MCP-1 (0.0011<p<0.043). Also, tumours of stressed mice showed a tendency towards fewer total CD4 cells, more regulatory T cells (Treg), less T cell/tumour cell contacts and a reduction of CTLA-4 in CD4 cells (p>0.05). TGF-beta invitro was increased by 23.4% using catecholamines (p<0.012) and invivo employing chronic stress (p<0.001). After 5 weeks tumour volumes were 130% (p=0.0061) larger and median survival reduced by 13.5% (p=0.0058). Tumours expressed more VEGF (p=0.0334), had greater microvessel densities (p=0.047), and an increased MMP-9 expression (p=0.0456). Beta-catecholamines increased proliferation in tumour cells by 18% (p<0.0001) and migration by 78% (p=0.0348) whereas the beta-blocker propranolol reduced these effects by 25% (p<0.0001) and 53% (p=0.045), respectively. When stressed tumour-bearing animals were treated with propranolol tumour volumes were reduced by 69% (p=0.0088) and survival improved by 14% (p<0.0058). The potential treatment with beta-blockers of patients with pancreatic cancer or other malignancies should be further evaluated as an adjuvant anti-neoplastic agent in clinical trials.

Association between Depression, Pressure Pain Sensitivity, Stress and Autonomous Nervous System Function in Stable Ischemic Heart Disease: Impact of Beta-Adrenergic Receptor Blockade

Background: Depression and ischemic heart disease (IHD) are associated with persistent stress and autonomic nervous system (ANS) dysfunction. The former can be measured by pressure pain sensitivity (PPS) of the sternum, and the latter by the PPS and systolic blood pressure (SBP) response to a tilt table test (TTT). Beta-blocker treatment reduces the efferent beta-adrenergic ANS function, and thus, the physiological stress response. Objective: To test the effect of beta-blockers on changes in depression score in patients with IHD, as well as the influence on persistent stress and ANS dysfunction. Methods: Three months of non-pharmacological intervention aiming at reducing PPS and depression score in patients with stable IHD. Beta-blocker users (N = 102) were compared with non-users (N = 75), with respect to signs of depression measured by the Major Depressive Inventory questionnaire (MDI), resting PPS, and PPS and SBP response to TTT. Results: MDI score decreased 30% in non-users (p = 0.005) compared to 4% (p > 0.1) among users (between-group p = 0.003; effect size = 0.4). Resting PPS decreased in both the groups. Among most vulnerable patients with MDI ≥ 15, reductions in MDI score and resting PPS score correlated in non-users, only (r = 0.69, p = 0.007). Reduction in resting PPS correlated with an increase in PPS and SBP response to TTT. Conclusions: Stress intervention in patients with IHD was anti-depressive in non-users, only. Similarly, the association between the reduction in depression, reduction in persistent stress, and restoration of ANS dysfunction was only seen in non-users, suggesting a central role of beta-adrenergic receptors in the association between these factors.

Abstract 15493: Renal Sympathetic Denervation Reduces Ventricular Arrhythmias Inducibility in Dogs With Healed Myocardial Infarction

Introduction: Previous studies have suggested that renal sympathetic denervation (RSD) could suppress acute myocardial ischemia-induced ventricular arrhythmias (VAs), but the long-term effects of RSD in a post-infarction canine model is not fully established. Methods: Thirty dogs underwent embolization of the left anterior descending artery. After a 14-days of recovery period, all the dogs were equally randomized to the RSD, medicine (MED; carvedilol 12.5mg PO BID), or control (CTRL; no therapy) group. Animals were monitored for 3 months after interventions. The serum norepinephrine (NE), echocardiographic indices, heart rate variability (HRV), and VAs inducibility were measured at the end of 90-day follow-up. Tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43) expressions in the peri-infarcted zone were also determined immunohistochemically. The protein levels of metrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitor of matalloproteinases (TIMP-1) were also determined. Results: When compared with CTRL group, RSD significantly (1) decreased heart rate, serum NE, sympathetic nerve indices of HRV, and the density of both TH- and GAP43-positive nerves in the peri-infarcted zone; (2) increased left ventricular ejection fraction and reduced left ventricular dilatation; (3) decreased the protein levels of MMP-2, MMP-9 and TIMP-1 in left ventricular tissues; (4) decreased the inducibility of ventricular tachyarrhythmias. Beta-receptor blockade by carvedilol showed comparable effects. Conclusions: RSD could reduce VAs inducibility in a canine model of healed myocardial infarction. Inhibition of autonomic and structural remodeling by RSD may be responsible for this salutary result.

Prospective evaluation of early propranolol after traumatic brain injury

BackgroundAlthough beta-adrenergic receptor blockade may improve outcomes after traumatic brain injury (TBI), its early use is not routine. We hypothesize that judicious early low-dose propranolol after TBI (EPAT) will improve outcomes without altering bradycardia or hypotensive events. MethodsWe conducted a prospective, observational study on all patients who presented with moderate-to-severe TBI from March 2010–August 2013. Ten initial patients did not receive propranolol (control). Subsequent patients received propranolol at 1-mg intravenous every 6 h starting within 12 h of intensive care unit (ICU) admission (EPAT) for a minimum of 48 h. Heart rate and blood pressure were recorded hourly for the first 72 h. Bradycardia and hypotensive events, mortality, and length of stay (LOS) were compared between cohorts to determine significant differences. ResultsThirty-eight patients were enrolled; 10 control and 28 EPAT. The two cohorts were similar when compared by gender, emergency department (ED) systolic blood pressure, ED heart rate, and mortality. ED Glasgow coma scale was lower (4.2 versus 10.7, P < 0.01) and injury severity score higher in control. EPAT patients received a mean of 10 ± 14 doses of propranolol. Hypotensive events were similar between cohorts, whereas bradycardia events were higher in control (5.8 versus 1.6, P = 0.05). ICU LOS (15.4 versus 30.4 d, P = 0.02) and hospital LOS (10 versus 19.1 d, P = 0.05) were lower in EPAT. Mortality rates were similar between groups (10% versus 10.7%, P = 0.9). The administration of propranolol led to no recorded complications. ConclusionsAlthough bradycardia and hypotensive events occur early after TBI, low-dose intravenous propranolol does not increase their number or severity. Early use of propranolol after TBI appears to be safe and may be associated with decreased ICU and hospital LOS.

Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve

BackgroundThe central nervous origins of functional parasympathetic innervation of cardiac ventricles remain controversial.ObjectiveThis study aimed to identify a population of vagal preganglionic neurons that contribute to the control of ventricular excitability. An animal model of synuclein pathology relevant to Parkinson’s disease was used to determine whether age-related loss of the activity of the identified group of neurons is associated with changes in ventricular electrophysiology.MethodsIn vivo cardiac electrophysiology was performed in anesthetized rats in conditions of selective inhibition of the dorsal vagal motor nucleus (DVMN) neurons by pharmacogenetic approach and in mice with global genetic deletion of all family members of the synuclein protein.ResultsIn rats anesthetized with urethane (in conditions of systemic beta-adrenoceptor blockade), muscarinic and neuronal nitric oxide synthase blockade confirmed the existence of a tonic parasympathetic control of cardiac excitability mediated by the actions of acetylcholine and nitric oxide. Acute DVMN silencing led to shortening of the ventricular effective refractory period (vERP), a lowering of the threshold for triggered ventricular tachycardia, and prolongation of the corrected QT (QTc) interval. Lower resting activity of the DVMN neurons in aging synuclein-deficient mice was found to be associated with vERP shortening and QTc interval prolongation.ConclusionActivity of the DVMN vagal preganglionic neurons is responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its vulnerability in neurodegenerative diseases.

27 Heart Rate Control in High Risk Heart Failure Patients

Introduction NICE estimates that 900,000 people in the UK have heart failure (HF). It is well established that beta adrenoceptor blockade improves prognosis in HF patients via a variety of proposed mechanisms, including reduction in heart rate. In recent years, there has been an increased focus on heart rate control. The SHIFT trial (Systolic Heart failure treatment with If inhibitor Ivabradine Trial), found a reduction in mortality and hospital admissions in selected patients due to a rate-related effect. These findings have been incorporated in the NICE guidelines; Chronic Heart Failure- Ivabradine. Aims This study looks into a high risk HF population who have had two or more hospital admissions within a year to Lancashire Teaching Hospitals (LTHTr). The study looked at whether heart rate is being adequately controlled prior to discharge and whether beta-blockers are being maximally uptitrated. Patients who did not have a heart rate within target range, were assessed for their suitability to Ivabradine, thus assessing this new medication’s role within a high risk HF group. Methods A retrospective review of 100 patient’s case notes was carried out. Their heart rate upon discharge 1 and discharge 2 were analysed, alongside their beta-blocker dose and whether this was maximally up-titrated. For those whose heart rate was not adequately controlled, their suitability for Ivabradine was assessed. Results 32 patients died on their second admission to hospital, or were discharged to a hospice. After the second admission, only 30% of patients were on maximally tolerated beta-blocker therapy. Between hospital admissions, 14% had their beta-blocker down-titrated, 36% had no up-titration of beta-blocker. From the hospital notes, it was difficult to ascertain the reasons for this. On the second discharge; the average heart rate was 77, with 71% of patients having a heart rate which was above the target range (75bpm). Out of these patients, 24 patients were suitable candidates for Ivabradine. Conclusion/implications The population audited had a demonstrated high mortality rate. The common themes of lack of beta-blocker titrated and communication between primary and secondary care were evident. Patient’s heart rates are not being properly controlled prior to discharge, despite two admissions, and two opportunities to do so. Whilst many patients do not fulfil the criteria for Ivabradine, a high proportion of audited patients would be candidates. This is an important new medication on the HF market, which should be considered in appropriate HF patients. LTHTr is trialling a ‘heart failure passport’, in order to facilitate communication between the GP and hospital setting, and provide a summary of the patient’s care. They are also using a heart failure ‘sticker’ in the medical notes, aimed at encouraging all health professionals to employ a holistic approach to these patients, and of course, consider heart rate.

Laparoscopic adrenalectomy in a pediatric patient

A pheochromocytoma is a highly vascular neuroendocrine tumor of the medulla of the adrenal glands, originating from the chromaffin cells or extra-adrenal chromaffin tissue and secreting an excessive amount of catecholamines. Medical management of this tumor includes correction of hypertension and arrhythmias, and assessment of end organ damage. This can be achieved by alpha-receptor blockade and beta-receptor blockade, calcium channel blockers (CCBs), alpha-methyl-tyrosine, etc. Surgical excision of the tumor, either open laparotomy or laparoscopy, is the definitive management. A laparoscopic approach offers several advantages compared with an open laparotomy such as decreasing fluid shifts that may accompany an open procedure, potentially decreasing the surgical stress imposed on the patient, decreasing the need for postoperative analgesia, shortening postoperative convalescence including an intensive care unit stay, and decreasing the overall hospital stay. A 11-year-old male patient with left adrenal mass measuring 2.9 cm × 3.9 cm × 4.7 cm on alpha-blocker and beta-blocker for laparoscopic adrenalectomy was successfully managed perioperatively.

Impact of β-adrenoceptor blockade on systemic inflammation and coagulation disturbances in rats with acute traumatic coagulopathy.

BackgroundSympathetic hyperactivity occurs early in acute traumatic coagulopathy (ATC) and is closely related to its development. β-adrenoceptor antagonists are known to alleviate adverse sympathetic effects and improve outcome in various diseases. We investigated whether β-blockers have protective effects against inflammation and endothelial and hemostatic disorders in ATC.Material/MethodsATC was induced in male Sprague-Dawley rats by trauma and hemorrhagic shock. Rats were randomly assigned to the sham, ATCC (ATC control), and ATCB (ATC with beta-adrenoceptor blockade) groups. Rats were injected intraperitoneally with propranolol or vehicle at baseline. Heart rate variability (HRV) and markers of inflammation, coagulation, and endothelial activation were measured, and Western blotting analysis of nuclear factor (NF)-κB was done after shock. Separate ATCC and ATCB groups were observed to compare overall mortality.ResultsHRV showed enhanced sympathetic tone in the ATCC group, which was reversed by propranolol. Propranolol attenuated the induction of pro-inflammatory cytokines TNF-α and IL-6, as well as fibrinolysis markers plasmin antiplasmin complex and tissue-type plasminogen activator. The increased serum syndecan-1 and soluble thrombomodulin were inhibited by propranolol, and the NF-κB expression was also decreased by propranolol pretreatment. But propranolol did not alter overall mortality in rats with ATC after shock.ConclusionsBeta-adrenoceptor blockade can alleviate sympathetic hyperactivity and exert anti-inflammatory, anti-fibrinolysis, and endothelial protective effects, confirming its pivotal role in the pathogenesis of ATC. Its mechanism in ATC should be explored further.

Abstract 641: Renal Denervation does not Lower Blood Pressure in Spontaneously Hypertensive Rats Treated with a Beta-1 Adrenergic Receptor Antagonist.

We have used the SHR as an animal model to understand how renal denervation (RDN) lowers blood pressure. In order to determine how concomitant antihypertensive drug therapy could affect the blood pressure response to RDN, we performed RDN both before and after chronic (several days) treatment via the drinking water with the selective alpha-1 adrenergic antagonist prazosin and the selective beta-1 adrenergic antagonist atenolol. In the presence of prazosin treatment, RDN (n=7) significantly (p&lt;0.05) lowered mean arterial pressure (MAP) compared to sham operated (SO; n=6) SHR (Δ=–4.0±1.7mmHg in RDN-SHR vs +1.5±1.3 in SO-SHR). Subsequent addition of atenolol during prazosin treatment reduced MAP significantly in both groups, but MAP in SO-SHR fell to the same level as in RDN-SHR, i.e. the antihypertensive effect of RDN was lost. After discontinuation of all drug treatment, the change in MAP from pre-treatment baseline was –7.7±3.5mmHg in RDN-SHR and +3.0±4.0mmHg in SO-SHR, p=0.06). To test whether the BP response to RDN would be lost during blockade of beta-1 adrenergic receptors alone, we performed RDN in SHR (n=5) pre-treated with atenolol. Atenolol alone significantly reduced MAP (Δ=-20.7±2.5mmHg). Steady-state MAP was not further reduced by RDN (Δ=+2.1±0.9mmHg). When atenolol was withdrawn MAP rose but remained reduced from baseline (Δ= -9.5±0.9mmHg). This magnitude of BP reduction is comparable to what we have previously observed after RDN in untreated SHR. In summary, in SHR RDN does not lower BP in the presence of an effective antihypertensive dose of a beta-1 antagonist. This indicates that RDN is reducing BP in SHR by interrupting a mechanism also affected by beta-1 adrenergic receptor signaling. Although further investigation is necessary, the data suggest that possibility that patients on clinically effective antihypertensive doses of beta-blockers may not exhibit a good response to RDN.

Maternal Regulation of Infant Brain State

Patterns of neural activity are critical for sculpting the immature brain, and disrupting this activity is believed to underlie neurodevelopmental disorders [1-3]. Neural circuits undergo extensive activity-dependent postnatal structural and functional changes [4-6]. The different forms of neural plasticity [7-9] underlying these changes have been linked to specific patterns of spatiotemporal activity. Since maternal behavior is the mammalian infant's major source of sensory-driven environmental stimulation and the quality of this care can dramatically affect neurobehavioral development [10], we explored, for the first time, whether infant cortical activity is influenced directly by interactions with the mother within the natural nest environment. We recorded spontaneous neocortical local field potentials in freely behaving infant rats during natural interactions with their mother on postnatal days ∼12-19. We showed that maternal absence from the nest increased cortical desynchrony. Further isolating the pup by removing littermates induced further desynchronization. The mother's return to the nest reduced this desynchrony, and nipple attachment induced a further reduction but increased slow-wave activity. However, maternal simulation of pups (e.g., grooming and milkejection) consistently produced rapid, transient cortical desynchrony. The magnitude of these maternal effects decreased with age. Finally, systemic blockade of noradrenergic beta receptors led to reduced maternal regulation of infant cortical activity. Our results demonstrate that during early development, mother-infant interactions can immediately affect infant brain activity, in part via a noradrenergic mechanism, suggesting a powerful influence of the maternal behavior and presence on circuit development.

Electrophysiology of T-wave alternans: Mechanisms and pharmacologic influences

Extensive experimental evidence indicates a fundamental link between T-wave alternans (TWA) and arrhythmogenesis. Diverse physiologic and pathophysiologic influences alter TWA magnitude in parallel with their effects on vulnerability to ventricular tachyarrhythmias. Specifically, interventions that impede intracellular calcium handling, such as elevated heart rate, heightened adrenergic activity, myocardial ischemia, and heart failure, predispose to greater levels of TWA, reflecting heightened risk for arrhythmias. Conversely, vagus nerve stimulation, blockade of beta-adrenergic receptors and late sodium and L-type calcium channels, and sympathetic denervation decrease TWA magnitude, reflecting the potential of these interventions to reduce risk for ventricular tachycardia and fibrillation. TWA thus appears able to detect the influence of pathophysiologically relevant triggers as well as the efficacy of antiarrhythmic drugs without reducing the predictive capacity of the phenomenon.

EQUIPPED TO SURVIVE: COMPREHENSIVE RESPONSE TO THREAT ENABLES OPTIMAL BEHAVIOUR

Guillén Fernández is Professor for Cognitive Neuroscience and director of the Donders Center for Neuroscience at the Radboud University Nijmegen Medical Center. He obtained his medical degree, doctorate, and habilitation...

Autonomic Substrates of the Response to Pups in Male Prairie Voles

Caregiving by nonparents (alloparenting) and fathers is a defining aspect of human social behavior, yet this phenomenon is rare among mammals. Male prairie voles (Microtus ochrogaster) spontaneously exhibit high levels of alloparental care, even in the absence of reproductive experience. In previous studies, exposure to a pup was selectively associated with increased activity in oxytocin and vasopressin neurons along with decreased plasma corticosterone. In the present study, physiological, pharmacological and neuroanatomical methods were used to explore the autonomic and behavioral consequences of exposing male prairie voles to a pup. Reproductively naïve, adult male prairie voles were implanted with radiotransmitters used for recording ECG, temperature and activity. Males responded with a sustained increase in heart-rate during pup exposure. This prolonged increase in heart rate was not explained by novelty, locomotion or thermoregulation. Although heart rate was elevated during pup exposure, respiratory sinus arrhythmia (RSA) did not differ between these males and males exposed to control stimuli indicating that vagal inhibition of the heart was maintained. Blockade of beta-adrenergic receptors with atenolol abolished the pup-induced heart rate increase, implicating sympathetic activity in the pup-induced increase in heart rate. Blockade of vagal input to the heart delayed the males’ approach to the pup. Increased activity in brainstem autonomic regulatory nuclei was also observed in males exposed to pups. Together, these findings suggest that exposure to a pup activates both vagal and sympathetic systems. This unique physiological state (i.e. increased sympathetic excitation of the heart, while maintaining some vagal cardiac tone) associated with male caregiving behavior may allow males to both nurture and protect infants.

Renal denervation suppresses ventricular arrhythmias during acute ventricular ischemia in pigs

Increased sympathetic activation during acute ventricular ischemia is involved in the occurrence of life-threatening arrhythmias. To test the effect of sympathetic inhibition by renal denervation (RDN) on ventricular ischemia/reperfusion arrhythmias. Anesthetized pigs, randomized to RDN or SHAM treatment, were subjected to 20 minutes of left anterior descending coronary artery (LAD) occlusion followed by reperfusion. Infarct size, hemodynamics, premature ventricular contractions, and spontaneous ventricular tachyarrhythmias were analyzed. Monophasic action potentials were recorded with an epicardial probe at the ischemic area. Ventricular ischemia resulted in an acute reduction of blood pressure (-29%) and peak left ventricular pressure rise (-40%), which were not significantly affected by RDN. However, elevation of left ventricular end-diastolic pressure (LVEDP) during LAD ligation was attenuated by RDN (ΔLVEDP: +1.8 ± 0.6 mm Hg vs +9.7 ± 1 mm Hg in the SHAM group; P = .046). Infarct size was not affected by RDN compared to SHAM. RDN significantly reduced spontaneous ventricular extrabeats (160 ± 15/10 min in the RDN group vs 422 ± 36/10 min in the SHAM group; P = .021) without affecting coupling intervals. In 5 of 6 SHAM-treated animals, ventricular fibrillation (VF) occurred during LAD occlusion. By contrast, only 1 of 7 RDN-treated animals experienced VF (P = .029). Beta-receptor blockade by atenolol showed comparable effects. Neither VF nor transient shortening of monophasic action potential duration during reperfusion was inhibited by RDN. RDN reduced the occurrence of ventricular arrhythmias/fibrillation and attenuated the rise in LVEDP during left ventricular ischemia without affecting infarct size, changes in ventricular contractility, blood pressure, and reperfusion arrhythmias. Therefore, RDN may protect from ventricular arrhythmias during ischemic events.

The role of Beta-adrenergic receptor blockers in Alzheimer's disease: potential genetic and cellular signaling mechanisms.

According to genetic studies, Alzheimer's disease (AD) is linked to beta-adrenergic receptor blockade through numerous factors, including human leukocyte antigen genes, the renin-angiotensin system, poly(adenosine diphosphate-ribose) polymerase 1, nerve growth factor, vascular endothelial growth factor, and the reduced form of nicotinamide adenine dinucleotide phosphate. Beta-adrenergic receptor blockade is also implicated in AD due to its effects on matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase-2, and nitric oxide synthase. Beta-adrenergic receptor blockade may also have a significant role in AD, although the role is controversial. Behavioral symptoms, sex, or genetic factors, including Beta 2-adrenergic receptor variants, apolipoprotein E, and cytochrome P450 CYP2D6, may contribute to beta-adrenergic receptor blockade modulation in AD. Thus, the characterization of beta-adrenergic receptor blockade in patients with AD is needed.