Development of an immunobiosensor assay for the beta-adrenergic compound zilpaterol

A surface plasmon resonance biosensor method was developed to measure zilpaterol residues in sheep urine. A CM-5 sensor chip previously reacted with ethylenediamine to produce an aminoethyl group was coupled with 4-carboxybutyl zilpaterol activated using EDC/NHS. Five polyclonal and four monoclonal antibodies were screened for their suitability to detect low levels of zilpaterol using the biosensor technology. Total binding was greater for polyclonal than monoclonal antibodies, but a less diluted antibody solution was required for polyclonal antibodies. A fixed antibody concentration and various concentrations of zilpaterol were injected to obtain a standard curve for each antibody to allow for B-0 and IC50 determination. The stability of the assay was assessed by the consistency of B0 in repeated experiments extending at least six hours. A measure of non-specific binding allowed the assessment of the specificity of the antibody-immobilized ligand interaction. The effect of varying concentrations of urine on B-0 and IC50 was evaluated to assess the degree of

New Perspectives on beta-Adrenergic Mediation of Innate and Learned Fear Responses to Predator Odor

In the present study, we investigated the role of noradrenergic transmission in unconditioned and conditioned responses to predatory threats. First, we examined the effects of systemically injected beta-blockers on unconditioned and contextual conditioned response to cat odor. The centrally acting beta-blocker (propranolol) was able to impair unconditioned responses, as well as the acquisition of the contextual fear to cat odor; however, the peripherally acting (nadolol) was not effective. Next, we examined the neural substrate underlying the noradrenergic modulation of the defensive response to cat odor and focused on the dorsal premammillary nucleus (PMd), because it represents the hypothalamic site most responsive to predatory threats and, at the same time, presents a dense plexus of noradrenergic fibers. We were able to see that propranolol significantly reduced PMd-Fos expression in response to cat odor and that beta-adrenoceptor blockade in the PMd, before cat odor exposure, reduced defensive responses to the cat odor and to the cat odor-related environment. We have also shown that beta-adrenoceptor blockade in the PMd, before the exposure to cat odor-related context, impaired the contextual conditioned responses. Overall, the present results provide convincing evidence suggesting that central noradrenergic mediation is critical for the expression of unconditioned and contextual conditioned antipredatory responses. We have further shown that the PMd appears to be an important locus to mediate these beta-adrenoceptor effects.

Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents and angiotensin receptor blockers for patients with left ventricular systolic dysfunction

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of nurse-led titration of ACEIs, beta-adrenergic blocking agents and ARBs in patients with left ventricular systolic dysfunction in terms of safety and patient outcomes.

Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents, and angiotensin receptor blockers for people with heart failure with reduced ejection fraction

BACKGROUND: Heart failure is associated with high mortality and hospital readmissions. Beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) can improve survival and reduce hospital readmissions and are recommended as first-line therapy in the treatment of heart failure. Evidence has also shown that there is a dose-dependent relationship of these medications with patient outcomes. Despite this evidence, primary care physicians are reluctant to up-titrate these medications. New strategies aimed at facilitating this up-titration are warranted. Nurse-led titration (NLT) is one such strategy. OBJECTIVES: To assess the effects of NLT of beta-adrenergic blocking agents, ACEIs, and ARBs in patients with heart failure with reduced ejection fraction (HFrEF) in terms of safety and patient outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library (CENTRAL Issue 11 of 12, 19/12/2014), MEDLINE OVID (1946 to November week 3 2014), and EMBASE Classic and EMBASE OVID (1947 to 2014 week 50). We also searched reference lists of relevant primary studies, systematic reviews, clinical trial registries, and unpublished theses sources. We used no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing NLT of beta-adrenergic blocking agents, ACEIs, and/or ARBs comparing the optimisation of these medications by a nurse to optimisation by another health professional in patients with HFrEF. DATA COLLECTION AND ANALYSIS: Two review authors (AD & JC) independently assessed studies for eligibility and risk of bias. We contacted primary authors if we required additional information. We examined quality of evidence using the GRADE rating tool for RCTs. We analysed extracted data by risk ratio (RR) with 95% confidence interval (CI) for dichotomous data to measure effect sizes of intervention group compared with usual-care group. Meta-analyses used the fixed-effect Mantel-Haenszel method. We assessed heterogeneity between studies by Chi(2) and I(2). MAIN RESULTS: We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. AUTHORS' CONCLUSIONS: Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.

Chronotropic response of beta-adrenergic-, muscarinic-, and calcitonin gene-related peptide-receptor agonists in right atria from neonatal capsaicin-treated rats

We evaluated the potency of isoproterenol, carbachol, pilocarpine and calcitonin gene-related peptide (CGRP) in the rat right atria at 30, 60 and 90 days after neonatal capsaicin treatment. Neonatal rats were pretreated on the second day of life with capsaicin (50 mg/kg). The capsaicin pretreatment caused a five-fold rightward shift at the pEC(50) level on the concentration-response curves to isoproterenol in 30-day-old rats. Propranolol (10 mg/kg, given 15 min prior to capsaicin treatment) prevented this subsensitivity. No changes in the potency of isoproterenol were observed at 60 and 90 days after capsaicin pretreatment. The potency and maximal responses of CGRP in the right atria in 30-day-old rats were significantly higher than in 60- and 90-day-old rats; however, no differences were found between control and capsaicin groups. The potency and maximal responses to carbachol and pilocarpine were not changed in all groups. The neonatal capsaicin treatment reduced by about 74% the CGRP content in the heart in all groups. In summary, capsaicin treatment in newborn rats produces a desensitization of chronotropic response mediated by beta-adrenoceptors in isolated right atria from 30-day-old rats possibly due to a massive release of catecholamines. (C) 2002 Elsevier B.V. Ireland Ltd. All rights reserved.

Effect of cholinergic and adrenergic stimulation of the subfornical organ on water intake

Cholinergic and adrenergic agonists and antagonists were injected directly into the subfornical organ (SFO), via implanted cannulae, and the volume of water ingested was recorded over a period of 1 hour after injection. Application of 2 nmol carbachol caused intense water intake in 100% of the animals (8.78±0.61 ml), with a very short intake latency. When the 2 nmol carbachol dose was preceded by increased doses of atropine, a progressive reduction in water intake was observed, with complete blockage of the thirst-inducing response to carbachol at the 20 nmol dose level with atropine. Followed by several doses of hexamethonium, the water intake caused by application of 2 nmol carbachol was reduced, although the response was not totally blocked. Injection of 80 nmol of nicotine had a significant thirst-inducing inducing effect in 50% of the animals studied (1.06±0.18 ml) and increase in water intake was further reduced by application of increased doses of hexamethonium. Raising the dose levels of noradrenaline into th SFO caused an increase in water intake although to a lesser degree than was observed after carbachol injection. When the 40 nmol dose of noradrenaline was preceded by increased doses of propranolol (5 to 40 nmol), there was a gradual reduction in water intake, with total blockage at the 40 nmol dose. Application of phentolamine in doses of 10 to 80 nmol caused no reduction in water intake after 40 nmol of noradrenaline. Application of isoproterenol at doses from 20 to 160 nmol into the SFO caused a dosedependent increase in water intake which was blocked by previous applications of propranolol. These results support the hypothesis that the water intake caused by chemical stimulation of the SFO is mainly due to muscarinic cholinergic receptors, although the influence of nicotinic receptors or participation of adrenergic mediation should not be ruled out. © 1984.

Effect of an acute β-adrenergic blockade on the blood glucose response during lactate minimum test

The aim of this study was to determine the relationship between blood lactate and glucose during an incremental test after exercise induced lactic acidosis, under normal and acute β-adrenergic blockade. Eight fit males (cyclists or triathletes) performed a protocol to determine the intensity corresponding to the individual equilibrium point between lactate entry and removal from the blood (incremental test after exercise induced lactic acidosis), determined from the blood lactate (Lacmin) and glucose (Glucmin) response. This protocol was performed twice in a double-blind randomized order by ingesting either propranolol (80 mg) or a placebo (dextrose), 120 min prior to the test. The blood lactate and glucose concentration obtained 7 minutes after anaerobic exercise (Wingate test) was significantly lower (p<0.01) with the acute β-adrenergic blockade (9.1±1.5 mM; 3.9±0.1 mM), respectively than in the placebo condition (12.4±1.8 mM; 5.0±0.1 mM). There was no difference (p>0.05) between the exercise intensity determined by Lacmin (212.1±17.4 W) and Glucmin (218.2±22.1 W) during exercise performed without acute β-adrenergic blockade. The exercise intensity at Lacmin was lowered (p<0.05) from 212.1±17.4 to 181.0±15.6 W and heart rate at Lacmin was reduced (p<0.01) from 161.2±8.4 to 129.3±6.2 beats min-1 as a result of the blockade. It was not possible to determine the exercise intensity corresponding to Glucmin with β-adrenergic blockade, since the blood glucose concentration presented a continuous decrease during the incremental test. We concluded that the similar pattern response of blood lactate and glucose during an incremental test after exercise induced lactic acidosis, is not present during β-adrenergic blockade suggesting that, at least in part, this behavior depends upon adrenergic stimulation.