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Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S‐metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P

OBJECTIVE: To describe the successful management of 2 dogs with septic shock and persistent tachycardia using norepinephrine and esmolol, a short‐acting beta receptor antagonist. SERIES SUMMARY: Two cases are reviewed. In the first case, septic shock with ventricular tachycardia was diagnosed in a 4‐year‐old neutered female Great Dane that underwent jejunoileal resection and anastomosis for a partial mesenteric torsion. The patient's tachyarrhythmias failed to respond to lidocaine, and an esmolol infusion was used for heart rate control. The condition of the dog improved and she was discharged after 4 days of hospitalization. The second case was a 7‐year‐old neutered female Cavalier King Charles Spaniel with septic peritonitis. Following surgery for intestinal resection and anastomosis, supraventricular tachycardia developed that was not responsive to volume resuscitation and was treated with an esmolol infusion. The condition of the dog improved and she was discharged after 6 days of hospitalization. Both patients were doing well at the time of long‐term follow‐up. NEW OR UNIQUE INFORMATION PROVIDED: This case series highlights a novel method of managing dogs in septic shock with persistent tachycardia based on recently published data in the human literature. The use of esmolol may be considered in certain veterinary patients with septic shock to improve persistent tachycardia not related to hypovolemia.

Recently, several studies have reported their experience in using oral atenolol in patients with infantile haemangioma (IH), especially as an alternative to propranolol, but the efficacy and safety of oral atenolol has not been evaluated. We searched PubMed (Medline), Central, Embase, Web of Science and EBSCOhost (until May 2018) for the eligible studies reporting more than 10 IH patients who were treated with oral atenolol with detailed original data, including outcomes, regimens and adverse events (AEs). The data was standardised and analysed by using R software with meta-package. A total of 9 of 141 identified articles, including 341 infantile haemangioma patients treated with oral atenolol therapy, were included. The pooled response rate of atenolol was 0.90 (95% CI: 0.85-0.93), and the rebound rate was 0.11 (95% CI: 0.08-0.16). Among the 341 patients, 44 patients were switched to atenolol therapy from propranolol due to adverse events. The response rate of subsequent atenolol treatment was 90.9% (40/44). Regarding AEs, 141 patients reported 177 episodes of AEs, and the pooled rate was 0.26 (95% CI: 0.12-0.47). Gastrointestinal symptoms (e.g. constipation, diarrhoea and vomiting) were the most frequent AEs (22.6%). Widely known propranolol-related AEs, including hypoglycaemia, bronchospasm, bradycardia and hypotension, were not recorded. Overall, atenolol appears to be an effective and safe therapy for the treatment of IH and may be a promising alternative to propranolol.

This paper discusses multi-spectroscopic and molecular docking analysis of the interaction between atenolol (ATN) and deoxyribose nucleic acid (DNA) using alizarin (ALZ) as a spectroscopic probe. ATN is a β1 -receptor antagonist belonging to the β-blocker class of molecules. Experimental findings that were based on different spectroscopic analysis, melting studies, viscometric analysis, 1 H nuclear magnetic resonance and circular dichroism studies revealed the presence of a grove-binding mode. The effect of ionic strength was also studied, and observations suggested that electrostatic interaction also played a minor role during interaction. Molecular docking analysis suggested that the dominant force for the grove-binding phenomenon was hydrogen bonding between the 24-H residue of ATN and O of the 10-G residue, and the 40-H residue of ATN and N of the 17-A base residue. Competitive binding study of the ALZ-DNA complex with ATN showed that, despite an increase in the amount of ATN in the ALZ-DNA complex, the overall absorbance remained unchanged. The decrease in fluorescence in the ALZ-DNA system may be due to new non-fluorescent ATN-DNA-ALZ complex formation.

Purpose Increasing cohorts of patients present with diabetic cardiomyopathy, and with no targeted options, treatment often rely on generic pharmaceuticals such as β‐blockers. β‐blocker efficacy is heterogenous, with second generation β‐blocker metoprolol selectively inhibiting β1‐AR, while third generation β‐blocker carvedilol has α1‐AR inhibition, antioxidant, and anti‐apoptotic actions alongside nonselective β‐AR inhibition. These additional properties have led to the hypothesis that carvedilol may improve cardiac contractility in the diabetic heart to a greater extent than metoprolol. The present study aimed to compare the efficacy of metoprolol and carvedilol on myocardial function in animal models and cardiac tissue from patients with type 2 diabetes and preserved ejection fraction. Methods Echocardiographic examination of cardiac function and assessment of myocardial function in isolated trabeculae was carried out in patients with and without diabetes undergoing coronary artery bypass grafting (CABG) who were prescribed metoprolol or carvedilol. Equivalent measures were undertaken in Zucker Diabetic Fatty (ZDF) rats following 4 weeks treatment with metoprolol or carvedilol. Results Patients receiving carvedilol compared to metoprolol had no difference in cardiac function, and no difference was apparent in myocardial function between β‐blockers. Both β‐blockers similarly improved myocardial function in diabetic ZDF rats treated for 4 weeks, without significantly affecting in vivo cardiac function. Conclusions Metoprolol and carvedilol were found to have no effect on cardiac function in type 2 diabetes with preserved ejection fraction, and were similarly effective in preventing myocardial dysfunction in ZDF rats., In this manuscript, we present data comparing the effects of carvedilol and metoprolol on in vivo and in vitro cardiac function in both diabetic and non‐diabetic human patients, as well as in a rat model of type 2 diabetes (Zucker Diabetic Fatty rats). Our data demonstrate that both carvedilol and metoprolol are able to improve the contractility of cardiac muscle from diabetic humans and rats, as well as preserving cardiac function in both models. Importantly, we saw no extra improvement in individuals or animals that received carvedilol over those who received metoprolol, suggesting that any improvement in health outcomes provided by carvedilol (as seen in the COMET study) are not derived from differences in the contractile function of the cardiac muscle.

AIM Matrix metalloproteinases (MMPs) are zinc-containing proteinases that are involved in the degradation of extracellular matrix (ECM) and a number of cell surface proteins in order to maintain tissue homeostasis. They are involved in pathogenesis of several ischemic organ injuries. In the present study, we aimed to determine the expression and level of MMP-2 and MMP-9 in renal ischemia-reperfusion injury (IRI) model and the potential beneficial effect of nebivolol, a β1-adrenergic receptor blocker, on both MMP-2 and -9 level and expression and tubular injury caused by IRI. METHODS 20 Wistar albino rats were divided into three groups: sham-operated , ischemia-reperfusion, and nebivolol-pretreated . IRI model was induced by bilateral clamping of renal arteries for 45 minutes followed by 24 h of reperfusion. The analysis of serum creatinine levels, quantity and expression of MMP-2 and MMP-9 were performed after 24 h of IRI. The effects of nebivolol on level and expression of MMP-2 and MMP-9 levels were investigated by gelatin zymography and immunohistochemistry, respectively. The pathological examinations were performed to score tubular damage by light microscopy. RESULTS Creatinine levels increased significantly in the ischemia-reperfusion group compared to sham-operated group. Rats in the nebivolol-pretreated group showed significant decrease in expression and quantity of MMP-2 and MMP-9 during IRI. The pathological examinations demonstrated significantly low level of tubular injury score in nebivolol-pretreated group. CONCLUSION Nebivolol attenuated IRI by decreasing the expression and level of MMP-2 and MMP-9.

Background Heart rate has been associated with prognosis in patients with heart failure with reduced ejection fraction (HFREF) and sinus rhythm; whether this also holds true in patients with atrial fibrillation (AF) is unknown. Hypothesis To evaluate cardiac rhythm and baseline heart rate and the influence of outcome in patients with HFREF enrolled in the Cardiac Insufficiency Bisoprolol Study II. Methods In total, 2539 patients were stratified according to their baseline heart rhythm (AF or sinus rhythm) and into quartiles of heart rate (≤70 bpm, 71–78 bpm, 79–90 bpm, and >90 bpm). The primary outcome was all-cause mortality. Mean follow-up was 1.3 years. Results Mean age was 61 years, mean left ventricular ejection fraction was 28%, and 80% were male. A total of 521 (21%) patients had AF at baseline. The risk associated with all-cause mortality for each 5 bpm increase in heart rate in patients with sinus rhythm (hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.01-1.11, P = 0.012) was significantly different from those with AF (HR: 1.00, 95% CI: 0.94-1.07, P = 0.90, P for interaction = 0.041). The risk associated with higher heart rate in sinus rhythm was primarily attributable to excess risk in the highest quartile (HR: 1.64, 95% CI: 1.18–2.30, P = 0.003). Allocation to bisoprolol did not modify the interaction between heart rate, rhythm and outcome. Conclusions In HFREF patients with AF, a higher heart rate is not associated with increased event rates in contrast to HFREF patients with sinus rhythm.

INTRODUCTION Chronic mitral regurgitation (MR) is characterized by adverse ventricular remodeling and progressive LV dysfunction leading to heart failure (HF). Beta-blockers (BB) improve LV remodeling and prognosis in patients with HF. As chronic severe MR results in neuroendocrine activation similar to HF, it is likely that BB may also exert favorable effects in these patients. No study has assessed the role of oral BB therapy in chronic rheumatic MR. AIMS A total of 100 patients of chronic rheumatic MR (mean age 30±13.48 years, NYHA 2.2±0.5) were randomized to BB (Metoprolol, 37±13.5 mg, n=48) vs no BB (n=52) in addition to standard therapy. RESULTS Baseline BNP and echocardiographic parameters were comparable in the two groups. At 3 months, BB therapy resulted in significantly lower NYHA class (1.97 vs 2.35), BNP (141 vs 207 pg/mL), LV end-systolic (35.89 vs 51.30) and LV end-diastolic volumes (101 vs 128 mL/m(2) ), LV end-systolic stress (81.1 vs 93.3 dyn/cm(2) ), LV mass (122 vs 154 gm/m(2) ), and LV work (737.02 vs 952.82 mm Hg L/min, all P significant). Therapy with BB resulted in a -15.6%, -10.4%,-12.1%, and -7.3% reduction in LV end-systolic and end-diastolic dimensions and LVESVi and LVEDVi, respectively. Following BB therapy, BNP levels, end-systolic stress, indexed LV mass, and LV work also reduced significantly by 27.3%, 15.6%, 8.7%, and 28%, respectively. The control group had no significant change. The MR grade reduced from severe to moderate in 11% of those on BB (controls: no change). At 6 months, the BB group had further improvement in all echocardiographic parameters ranging from +9.1 to -18.2%. CONCLUSION In this first study of BB in rheumatic MR, targeting the sympatho-adrenergic axis exerted favorable effects on NYHA class, LV volumes, LV end-systolic stress, and LV work. Further studies are required to elucidate the role of BB in rheumatic MR.

SummaryBackground Left ventricular outflow tract obstruction (LVOTO) may complicate an episode of Takotsubo cardiomyopathy (TTC), potentially leading to cardiogenic shock. Beta-blockers are considered the most suitable treatment for such complication. Aim of the study The objective of this study was to evaluate the hemodynamic effects, safety, and feasibility of a selective beta-blocker (β1) with a short half-life, esmolol, in subjects with a TTC episode. Methods Ninety-six consecutive patients with TTC were enrolled in a multicenter registry. The hemodynamic and echocardiographic effects of esmolol (0.15–0.3 mg/kg/min) were analyzed in nine consecutive patients with LVOTO. Clinical course of patients, hemodynamics, days of hospitalization, LV function, and adverse events at follow-up were recorded. Results Left ventricular outflow tract obstruction was present in 10 (10.4%) of 96 patients. Patients with LVOTO were older and had higher values of troponin-I at admission. LV ejection fraction at admission (36.1 ± 8.4%) significantly improved at discharge (51.4 ± 6.9%, P = 0.001). Among patients treated with esmolol infusion, LVOT pressure gradient before treatment was 47.6 ± 16.6 mmHg and after 18.2 ± 2.3 mmHg (P = 0.0091). Systolic blood pressure decreased from 123.8 ± 29.1 to 112.6 ± 12.7 mmHg (P = 0.1537). Mean hospital stay was 9 ± 2 days. No adverse events were observed during hospitalization and at follow-up. Conclusions Esmolol infusion was temporally associated with reduction in intraventricular gradient and systemic blood pressure in patients with TTC and LVOTO. Further controlled studies are warranted to confirm these preliminary findings.

INTRODUCTION The objective of this study was to establish the benefit of bisoprolol up-titration toward recommended dosage targets, versus lower-dose maintenance, in heart failure (HF) patients with systolic dysfunction. METHODS Korean HF patients received bisoprolol 1.25 mg/day, incrementally up-titrated toward 10 mg/day in the absence of contraindications. After 26 weeks' treatment, patients were grouped as low-dose (

OBJECTIVES To clarify the involvement of bladder α1-adrenoceptors (α1-ARs) in afferent pathways by investigating the effects of silodosin and BMY7378, selective α1A- or α1D-AR antagonists, respectively, on single-unit afferent nerve fibre activity (SAA) of the primary bladder afferent nerves and their relationship with bladder microcontractions in rats. MATERIALS AND METHODS A total of 63 female Sprague-Dawley rats were anaesthetized with urethane. The SAA of Aδ and C fibres generated from the left L6 dorsal roots was determined using electrical stimulation of the left pelvic nerve and bladder distension. After measuring baseline SAA during constant filling cystometry, the procedure was repeated with i.v. (0.3-30 μg/kg) or intravesical (10 μm) administration of each antagonist. In separate rats, the bladder was filled with saline until the intravesical pressure reached 30 cmH2 O, and was kept under isovolumetric conditions, then the recording was performed with i.v.-administered vehicle and silodosin (0.3 μg/kg). RESULTS A total of Aδ fibres and 33 C fibres were isolated from 63 rats. The SAA of Aδ fibres, but not C fibres, were dose-dependently decreased after both i.v. and intravesical administrations of each of the antagonists. In the experiments under bladder isovolumetric conditions, silodosin administration significantly decreased the SAA of Aδ fibres, but not C fibres, compared with vehicle administration. There were no significant effects on either the mean basal bladder pressure or microcontractions. CONCLUSION The present study suggests that both α1A- or α1D-ARs in the rat bladder are involved in the activation of the bladder mechanosensory Aδ fibres during bladder filling, and that this activation may not be related to bladder microcontractions.

Adrenergic β-antagonists, commonly known as β-blockers, are prescribed for many indications including hypertension, heart failure, arrhythmias, and migraines. Metoprolol is a moderately lipophilic β-blocker that in overdose causes direct myocardial depression leading to bradycardia, hypotension, and the potential for cardiovascular collapse. We describe the case of a 59-year-old man who intentionally ingested ~7.5 g of metoprolol tartrate. Initial treatment of bradycardia and hypotension included glucagon, atropine, dopamine, and norepinephrine. Despite these treatment modalities, the patient developed cardiac arrest. Intravenous lipid emulsion (ILE) and hyperinsulinemia/euglycemia (HIE) therapies were initiated during advanced cardiac life support and were immediately followed by return of spontaneous circulation. Further treatment included gastric lavage, activated charcoal, continued vasopressor therapy, and a repeat bolus of ILE. The patient was weaned off vasoactive infusions and was extubated within 24 hours. HIE therapy was continued for 36 hours after metoprolol ingestion. A urine β-blocker panel using mass spectrometry revealed a metoprolol concentration of 120 ng/ml and the absence of other β-blocking agents. To date, no clear treatment guidelines are available for β-blocker overdose, and the response to toxic concentrations is highly variable. In this case of a life-threatening single-agent metoprolol overdose, the patient was successfully treated with HIE and ILE therapy. Due to the increasing frequency with which ILE and HIE are being used for the treatment of β-blocker overdose, clinicians should be aware of their dosing strategies and indications.

Background Rikkunshito (RKT) is a gastroprotective herbal medicine. In this study, we investigated the role of RKT in the relaxation of the gastric body (fundus and corpus) and antrum. Methods We used Suncus murinus, a unique small model animal with similar gastrointestinal motility to humans and dogs. RKT was added at 0.1, 1.0, and 5.0 mg/mL to induce relaxation in vitro; the outcome measure was the intensity of relaxation. The number of spontaneous antral contractions in the absence or the presence of RKT was also counted. Key Results Rikkunshito induced the relaxation of the gastric body and antrum and decreased the number of spontaneous antral contractions in a dose-dependent manner. The responses to RKT (1.0 mg/mL) were not affected by pretreatment with atropine, N-nitro-l-arginine methyl ester, ritanserin, or ondansetron. On the other hand, timolol almost completely reversed the relaxation induced by RKT (1.0 mg/mL) on the gastric body and antrum and the occurrence of the spontaneous antral contractions. Both butoxamine, a β2-adrenoreceptor antagonist, and L 748337, a β3-adrenoreceptor antagonist, but not CGP 20712, a β1-adrenoreceptor antagonist, significantly reversed the RKT-induced (1.0 mg/mL) gastric relaxation. Conclusions & Inferences These results indicate that RKT stimulates and modulates gastric relaxation through β2- and β3-adrenergic, but not β1-adrenergic, pathways in S. murinus.

The hyperglycemia associated with the most commonly prescribed antihypertensive drug classes is of growing concern to the medical community. It is well documented that β-blockers and thiazide diuretics cause adverse metabolic effects, and large-scale studies and meta-analyses provide compelling data indicating that β-blockers and thiazide diuretics increase the risk of diabetes.1–5 The ability to discern which participants are at greatest risk for hyperglycemia associated with β-blockers and thiazide diuretics or the development of diabetes would be valuable to clinicians4,6–9. Previous studies found that African ancestry, higher body mass index, left ventricular hypertrophy, higher follow-up systolic blood pressure, elevated baseline glucose, uric acid, female sex, and age are associated with the development of diabetes after long-term β-blocker and/or thiazide diuretic therapy. 3, 4, 10, 11 One study found that African ancestry, lower baseline glucose, and urinary sodium excretion were significant predictors for change in glucose after hydrochlorothiazide (HCTZ) monotherapy.12 To date, no studies have evaluated predictors for glucose change associated with β-blockers. Given that hyperglycemia and diabetes associated with the use of thiazide diuretics and β-blockers may offset the clinical benefit of these two drug classes,10, 13–15 it is important to identify the clinical characteristics that increase risk. If such factors could be identified, they might be useful to guide selection of antihypertensive therapy. Therefore, the goal of the current study was to determine the clinical characteristics associated with change in glucose and impaired fasting glucose (IFG) following treatment with atenolol or HCTZ.

Aims There is limited information about the effects of beta-blockers in heart failure (HF) stratified by blood pressure, especially in the elderly and those with preserved EF. We evaluate the effects of nebivolol on outcomes in elderly patients with HF stratified by baseline systolic blood pressure (SBP) and EF. Methods and results The SENIORS trial evaluated the effects of nebivolol and enrolled 2128 patients ≥70 years of age with HF. Patients were divided into three baseline pre-treatment SBP categories ( 130 mmHg). In addition, we evaluated the influence of SBP (≤130 and >130 mmHg) on patients with LVEF

In this prospective, open-label, randomized, controlled clinical trial the effects of low-dose carvedilol, nebivolol, and metoprolol on central arterial pressure and augmentation index (AIx) and its heart rate–corrected value (AIx@75) were assessed. The authors randomized 75 hypertensive patients (18–70 years) to carvedilol 12.5/25 mg, metoprolol 50/100 mg, or nebivolol 2.5/5 mg daily and followed them up for 3 months. Central arterial pressure and AIx were measured with applanation tonometry at baseline and at the end of follow-up. Analyses were restricted to 60 completers. Central systolic pressure decreased equally in all 3 treatment arms. AIx remained unchanged, while AIx@75 decreased significantly by 5.4%2.5% in the nebivolol group. According to general linear models, individual change in heart rate was a strong predictor of change in AIx in the carvedilol group (r 2 =0.23, P=.03) although no similar association was found in the nebivolol group (r 2 =0.09). The impact of b-blockers with vasodilator effects on pressure augmentation seems to be different with nebivolol having the largest potential of decreasing AIx@75. While AIx changes associated with carvedilol treatment are strongly driven by heart rate changes, those associated with nebivolol treatment seem to be the result of other mechanisms. J Clin Hypertens (Greenwich). 2013;15:910‐917. a2013 Wiley Periodicals, Inc. In the past decade, increasing attention has been drawn to the unfavorable effects of b-blockers on central hemodynamics. It is assumed that bradycardia elicited by b-blockers results in slower development of the forward-traveling wave and allows the reflected wave— the energy of which is increased due to peripheral vasoconstriction—to arrive during systole. The ensuing interference of the forward-traveling and reflected waves augments systolic pressure in the large arteries, thereby diminishing the potential of central blood pressure (BP) reduction. 1 Indeed, many studies have found that at the same level of peripheral pressure reduction, b-blockers have a smaller effect on central BP compared with other types of antihypertensive agents. 2–4 According to the Conduit Artery Function Evaluation (CAFE) study, a smaller decrease in central BP may be a plausible mechanism for the reduced effectiveness of b-blockers in the prevention of cardiovascular events. 5 b-Blockers, however, cannot be considered a homogenous group. Unfavorable hemodynamic effects and clinical outcomes were demonstrated for atenolol, a drug selected for the treatment of hypertension with decreasing frequency. 6 Newer b-blockers, such as carvedilol and nebivolol, may elicit smaller wave reflection

The beneficial effects of nebivolol on arterial stiffness and endothelial dysfunction are well documented in untreated hypertensive patients and differ from nonvasodilatory β‐blockers. This study tests the hypothesis that the addition of nebivolol in predominantly African American patients with type 2 diabetes already receiving maximally tolerated doses of renin‐angiotensin system (RAS) blockers will further improve large artery compliance. Patients with type 2 diabetes and hypertension on maximal RAS blockade (n=70) were randomized to nebivolol or metoprolol succinate daily. Doses were titrated until systolic blood pressure (SBP) was

SUMMARY Objective: This study aimed to compare the acute effects of nicardipine and esmolol on hemodynamic and endothelial shear stress (ESS) in patients with unstable angina (UA) and moderate coronary stenosis (MCS). Background: Nicardipine and esmolol exhibit cardioprotection via different mechanisms. However, their acute effects on hemodynamic and ESS are still unknown. Methods: One-hundred sixteen patients with UA and MSC were randomly divided into nicardipine (n = 59) and esmolol (n = 57) groups. Drugs were injected as a bolus followed by continuous infusion to achieve the steady states defined as the mean blood pressure (MBP) reduced by ≥10% or a heart-rate change by ≥15 bpm, lasting for at least 10 min. The aortic pressure (AP), EKG, blood velocity, right atrial pressure, distal coronary pressure (DCP), systolic time (ST), isovolumetric diastolic time (IVDT), speed filling time (SFT), and ESS were simultaneously calculated at baseline and steady states. Results: Both drugs significantly reduced blood pressure and rate-pressure load. Infusion of nicardipine was associated with negative remodeling of the distal segment (P = 0.005). Esmolol, rather than nicardipine, increased minimal lumen diameter (P = 0.040), prolonged SFT (0.34 ± 0.03 s vs. 0.41 ± 0.03 s, P < 0.001), reduced DCP (P < 0.001) and increased blood velocity (33.65 ± 1.07 cm/s vs. 43.36 ± 1.25 cm/s, P < 0.001) at SFT stages, with increased blood-flow (P < 0.001). Both drugs increased downstream ESS. Esmolol significantly reversed abnormally increased ESS (P < 0.001) and increased upstream ESS compared with nicardipine (P < 0.001). Conclusion: Beyond a similar reduction of AP, patients with UA and MCS could benefit more from the reduction of heart rate induced by esmolol (ChiCTR-TRC-10000964).

Study Objective. To compare the effects of paroxetine on the pharmacokinetics and pharmacodynamics of the immediate-release (IR) and extended-release (ER) formulations of metoprolol. Design. Prospective, randomized, open-label, 3-way crossover study. Setting. General clinical research center. Subjects. Fifteen healthy volunteers with at least one active cytochrome P450 (CYP) CYP2D6 allele (CYP2D6*1 or CYP2D6*2). Intervention. In each of three phases conducted in random sequence, subjects received one of three metoprolol formulations administered on day 1: a single dose of metoprolol ER 100 mg, a single dose of metoprolol ER 200 mg, or two 100-mg doses of metoprolol IR administered 12 hours apart. Oral paroxetine 20 mg/day was then given alone on days 2–7 and coadministered with the same metoprolol formulation on day 8. Subjects received each of the other two formulations during the next two phases, with a 14-day washout period between each phase. Measurements and Main Results. After receiving metoprolol on days 1 (before paroxetine) and 8 (after paroxetine), S- and R-metoprolol pharmacokinetic parameters and exercise heart rate and blood pressure responses were measured. The mean area under the plasma concentration-time curve values of both S- and R-metoprolol for each formulation were increased approximately 3- and 4-fold, respectively, by paroxetine. Paroxetine significantly increased the S- and R-metoprolol maximum concentration (Cmax) of each formulation and increased the elimination half-life of both isomers approximately 2-fold. When metoprolol IR was given with paroxetine, the S-metoprolol Cmax was significantly greater than that of either the 100-mg or 200-mg ER products. The maximum effect of metoprolol IR on heart rate was significantly greater than that of metoprolol ER 200 mg, independent of whether the agents were administered alone or with paroxetine. Both the heart rate and systolic blood pressure area under the effect-time curve values were significantly decreased by paroxetine. Conclusion. Paroxetine significantly inhibits the metabolism of both metoprolol IR and ER, resulting in an increase in the magnitude and duration of β-blockade. The potential risk of adverse effects from excessive β-blockade may be greater with metoprolol IR than with metoprolol ER because of the significantly higher peak S-metoprolol plasma concentrations achieved with the IR formulation. Thus, if paroxetine treatment is indicated in patients receiving metoprolol, use of the ER formulation may reduce the risk of adverse effects.

Two related ER oxidation 1 (ERO1) proteins, ERO1α and ERO1β, dynamically regulate the redox environment in the mammalian endoplasmic reticulum (ER). Redox changes in cysteine residues on intralumenal loops of calcium release and reuptake channels have been implicated in altered calcium release and reuptake. These findings led us to hypothesize that altered ERO1 activity may affect cardiac functions that are dependent on intracellular calcium flux. We established mouse lines with loss of function insertion mutations in Ero1l and Ero1lb encoding ERO1α and ERO1β. The peak amplitude of calcium transients in homozygous Ero1α mutant adult cardiomyocytes was reduced to 42.0 ± 2.2% (n=10, P≤0.01) of values recorded in wild-type cardiomyocytes. Decreased ERO1 activity blunted cardiomyocyte inotropic response to adrenergic stimulation and sensitized mice to adrenergic blockade. Whereas all 12 wild-type mice survived challenge with 4 mg/kg esmolol, 6 of 8 compound Ero1l and Ero1lb mutant mice succumbed to this level of β adrenergic blockade (P≤0.01). In addition, mice lacking ERO1α were partially protected against progressive heart failure in a transaortic constriction model [at 10 wk postprocedure, fractional shortening was 0.31±0.02 in the mutant (n=20) vs. 0.23±0.03 in the wild type (n=18); P≤0.01]. These findings establish a role for ERO1 in calcium homeostasis and suggest that modifying the lumenal redox environment may affect the progression of heart failure.—Chin, K. T., Kang, G., Qu, J., Gardner, L. B., Coetzee, W. A., Zito, E., Fishman, G. I., Ron, R. The sarcoplasmic reticulum luminal thiol oxidase ERO1 regulates cardiomyocyte excitation-coupled calcium release and response to hemodynamic load.

Aims Heart failure (HF) is associated with a prothrombotic state, resulting in an increased risk for thrombo-embolic events. Studies suggest a reduced prothrombotic state when non-selective beta-blockers relative to selective beta-blockers are given. We studied the influence of non-selective beta-blockers compared with selective beta-blockers on the occurrence of arterial and venous thrombo-embolic events in patients with HF. Methods and results Data were obtained from the PHARMO Record Linkage System, a population-based registry of pharmacy records linked with hospital discharge records in The Netherlands. In the period of 1998–2007, 20 870 patients were hospitalized for HF. We used Cox regression analysis with time-varying beta-blocker covariate to assess the difference in the incidence of thrombo-embolic events [acute coronary syndrome (ACS), stroke, or pulmonary embolism] among patients. Median follow-up was 2.0 years (inter-quartile range: 0.7–4.1). Directly after discharge, 6558 patients were prescribed a selective beta-blocker and 2202 patients a non-selective beta-blocker. The hazard ratio (HR) for any thrombo-embolic event for non-selective beta-blockers compared with selective beta-blockers was 0.76 [95% confidence interval (CI): 0.64–0.89]. After adjustment, the difference remained (HR 0.84, 95% CI: 0.72–0.99). The effect was most prominent for ACS (HR 0.78, 95% CI: 0.65–0.93), and not clear for stroke (HR 1.00, 95% CI: 0.67–1.50) or pulmonary embolism (HR 1.33, 95% CI: 0.66–2.71). Conclusion In patients with HF, the use of non-selective beta-blockers was associated with a lower risk of thrombo-embolic events than selective beta-blockers. Whether this beneficial effect is caused by the additional beta2-receptor blockade remains to be elucidated. These findings need to be validated in a well-designed randomized study.

1. The aim of the present study was to investigate the prevalence of hypertension in patients with dilated cardiomyopathy (DCM) and to determine the tolerance and efficacy of a high dose of the β1-adrenoceptor antagonist metoprolol in the long-term treatment of DCM patients. 2. The prevalence of hypertension in DCM patients (n = 362) and age-matched controls (n = 401) was evaluated and compared. To investigate the effects of metoprolol, DCM patients were divided into hypertensive (DCM-H) or normotensive (DCM-N) subgroups. Metoprolol was administered at a starting dosage of 6.25 mg/day and increased gradually to 250 mg/day or the maximum tolerable dose. Blood pressure (BP), heart rate (HR), left ventricular (LV) end-diastolic dimension (LVEDD), left atrial end-diastolic dimension (LAEDD), LV ejection fraction (LVEF), LV posterior wall thickness (LVPWT) and ventricular septal thickness (VST) were determined at baseline and 6 and 12 months after metoprolol treatment. 3. The prevalence of hypertension was significantly higher in DCM patients than in age-matched controls (32.8 vs 20.1%, respectively; P < 0.01). Resting HR and a family history of hypertension were highest in the DCM-H group. There were no significant differences in age, gender and occupation between the DCM-H, DCM-N and age-matched control groups. 4. The tolerable dose for metoprolol was significantly higher in the DCM-H group than the DCM-N group (189.6 ± 14.8 vs 133.9 ± 12.0 mg/day, respectively; P < 0.05). Metoprolol significantly reduced BP and HR in the DCM-H group and improved LVEDD, LAEDD and LVEF in all DCM patients, with a greater effect seen in the DCM-H group. 5. In conclusion, DCM patients have a higher prevalence of hypertension than the general population. Patients in the DCM-H subgroup were characterized by a higher resting HR and a family history of hypertension and were more tolerant of and more responsive to metoprolol treatment. These data suggest that this subgroup of DCM patients could have higher sympathetic nerve activity and is suitable for treatment with a higher dose of metoprolol.

The beta 1- and beta 2-antagonist activity of betaxolol and timolol in the systemic circulation was studied ex-vivo after their ocular administration in thirty patients during cataract surgery. The patients received 40 microliters of 0.5% betaxolol or 0.25% timolol into the lower cul-de-sacs of both eyes. Blood samples were collected up to four h after instillation of the doses. Plasma concentrations of betaxolol and timolol were analyzed using a radioreceptor assay. The ex-vivo-beta 1-and beta 2-receptor occupancies corresponding drug plasma levels were calculated using radioligand binding techniques. The extent of beta 1-receptor occupancy of betaxolol in the systemic circulation was less than 20% and its beta 2-receptor occupancy was negligible. The extent of beta 1-receptor occupancy of timolol was about 65% and its beta 2-receptor occupancy about 80%. Because receptor occupancy is the basis of antagonist activity of beta-blocking agents, this study shows that the beta 1-antagonist activity of betaxolol in the systemic circulation is much less than that of timolol, and that its beta 2-antagonist activity is negligible. The study suggests that the reported side effects of betaxolol in patients with obstructive pulmonary diseases are not mediated via its beta 2-receptor blocking properties.

Nebivolol is a racemic combination of d-nebivolol (+SRRR nebivolol) and l-nebivolol (-RSSS nebivolol) that differs chemically from other beta-blockers, with an absolutely symmetrical configuration developing from a central nitrogen atom. D-nebivolol and l-nebivolol divaricate pharmacologically and therapeutically, with a noticeably different profile from that of conventional beta-blockers; for instance, the selective blocking of beta(1)-adrenoceptors is determined almost exclusively by d-nebivolol. Both enantiomers act synergistically with respect to blood pressure reduction: the effect of nebivolol on heart rate is exclusively exerted by d-nebivolol, with these hypotensive effects enhanced by the addition of the l-enantiomer, which in itself does not influence systolic and diastolic blood pressure. Furthermore, this pronounced and lasting blood pressure reduction is roughly equal to the effect of conventional beta-blockers in high doses. In certain vascular districts, nebivolol stimulates endothelial nitric oxide (NO) synthesis, thereby increasing the availability of NO in the endothelium, smooth muscle, and platelets and, consequently, producing a sustained vasodilation, with decreases in peripheral resistance and blood pressure. These effects are not shared by other beta-adrenoceptor blockers used as references and mainly rely on the l-enantiomer. L-nebivolol also increases NO availability under conditions of oxidative stress by the inhibition of endothelial NO synthase (eNOS) uncoupling, thereby reducing NO inactivation. Furthermore, neither nebivolol nor its enantiomers show any intrinsic sympathomimetic activity and undesirable beta-blocker effects, such as a decrease in cardiac output, which do not occur or are less pronounced with the combination of d-nebivolol and l-nebivolol. In conclusion, the independent pharmacologic and clinical effects of d-nebivolol and l-nebivolol act synergistically to produce a cardiovascular profile that differs noticeably from that of conventional beta-blockers.

Beta(1)- and beta(2)-adrenoceptors (AR) play a pivotal role in regulation of the cardiovascular system. Both beta-AR subtypes are polymorphic. There are two major single nucleotide polymorphisms (SNPs) in the beta(1)-AR gene: the Ser49Gly and Arg389Gly beta(1)-AR polymorphisms. In vitro, in recombinant cell systems Gly49 beta(1)-AR is much more susceptible to agonist-promoted downregulation than Ser49 beta(1)-AR, while Arg389 beta(1)-AR is three to four times more responsive to agonist-evoked stimulation than Gly389 beta(1)-AR. There are three major SNPs in the beta(2)-AR gene: the Arg16Gly, Gln27Glu and Thr164Ile beta(2)-AR polymorphisms (occur in humans only in the heterozygous form). In recombinant cell systems Gly16 beta(2)-AR is much more susceptible to agonist-promoted downregulation while Glu27 beta(2)-AR is rather resistant to agonist-induced downregulation but only in combination with Arg16, that occurs naturally extremely rare. Thr164 beta(2)-AR is three to four times more responsive to agonist-evoked stimulation than Ile164 beta(2)-AR. This review summarizes results from various studies on the possible relationship of these polymorphisms to cardiovascular diseases. At present it appears to be clear that, for cardiovascular diseases such as hypertension, coronary artery disease and chronic heart failure, beta(1)- and beta(2)-AR polymorphisms do not play a role as disease-causing genes; however, they might affect drug responses. Thus, it might be possible, by assessing the beta(1)-AR genotype, to predict responsiveness to beta(1)-AR agonist and -blocker treatment: patients homozygous for the Arg389 beta(1)-AR polymorphism should be good responders while patients homozygous for the Gly389 beta(1)-AR polymorphism should be poor responders or non-responders. Furthermore, subjects heterozygous for the Thr164Ile beta(2)-AR polymorphism exhibit blunted responses to beta(2)-AR stimulation. Finally, the Arg16Gln27 beta(2)-AR haplotype appears to be - at least in human vascular and bronchial smooth muscles - rather susceptible to agonist-induced desensitization (in contrast to the recombinant cell system findings), and might have some predictive value for poor outcome of heart failure. However, future large prospective studies have to replicate these findings in order to substantiate their clinical relevance.

Beta-blockers are well-established therapeutic agents in the treatment of hypertension and cardiovascular disease. However, these agents are highly heterogeneous. Beta-blockers differ in their ancillary pharmacologic properties, which are clinically important. Nebivolol is a highly selective beta(1)-adrenergic receptor blocker that induces vasodilation through stimulation of the endothelial nitric oxide/L-arginine pathway. As a racemic mixture of d- and l-enantiomers, nebivolol is highly lipophilic and rapidly absorbed. Nebivolol undergoes extensive hepatic metabolism through the cytochrome P450 2D6 (CYP2D6) system. As a result of genetic polymorphisms, CYP2D6 has variable activity, manifested by extensive and poor metabolizers of nebivolol. Time to maximum concentration is 0.5 to 2 hours, and half-life is 11 hours in extensive metabolizers; these values are about 3 times longer in poor metabolizers. Urinary and fecal excretion of unchanged nebivolol is less than 0.5% of the dose. Nebivolol has a unique hemodynamic profile of reduced systemic vascular resistance and increased left ventricular function. These properties are attributed to its vasodilating action and contrast with the hemodynamic effects of conventional beta-blockers. Nebivolol is thus a novel beta-blocker with several important pharmacologic properties that distinguish it from traditional beta-blockers. These unique properties may confer clinical benefits beyond simple blood pressure lowering.

OBJECTIVE To investigate the effects of TAK-802, a potent acetylcholinesterase inhibitor, and tamsulosin, an α1-adrenoceptor antagonist, and their concomitant administration on the urodynamic characteristics in a guinea-pig model of functional bladder outlet obstruction. MATERIALS AND METHODS Cystometry was performed in urethane-anaesthetized guinea pigs, and various urodynamic variables, including the maximum flow rate (Qmax), voiding efficiency, maximum intravesical pressure (Pvesmax) and intravesical pressure at Qmax (PvesQmax), were measured before and after administration of the drugs in combination and alone. RESULTS Continuous intravenous infusion of phenylephrine, an α1-adrenoceptor agonist (1–6 µg/animal/min), dose-dependently decreased the Qmax and voiding efficiency, and increased the Pvesmax and PvesQmax, possibly by constricting urethral smooth muscle. In this functional urethral constriction model, both TAK-802 at 1 and 10 µg/kg and tamsulosin at 3 and 10 µg/kg (intravenously) caused increasing effects on the Qmax and voiding efficiency. The effects were more apparent with combined exposure. Although the Pvesmax was dose-dependently increased by TAK-802 alone, the effects were completely abolished by concomitant treatment with tamsulosin. CONCLUSION These results suggest that TAK-802 and tamsulosin have synergistic effects in increasing the Qmax and voiding efficiency, and TAK-802 does not inhibit the decreasing effect of tamsulosin on urethral resistance. That TAK-802 increased Pves when administered alone implies that monotherapy using an acetylcholinesterase inhibitor should be withheld in patients with voiding dysfunction caused by obvious bladder outlet obstruction with benign prostatic hyperplasia, to avoid disorders of the upper urinary tracts, and it should be used with an α1-adrenoceptor antagonist. Whether TAK-802 combined with an α1-adrenoceptor antagonist confers additional clinical benefit is not yet known.

The effect of protein kinase C (PKC) activation on beta1-adrenergic receptor (beta1-AR) regulation of the cardiac L-type Ca2+ current (ICa,L) was studied using the whole-cell patch clamp technique. Treatment of guinea pig ventricular myocytes with phorbol-12,13-dibutyrate (PDBu) caused a significant decrease in ICa,L sensitivity to stimulation by submaximal beta1-AR activation using isoproterenol (Iso). This decrease in sensitivity was also associated with the ability of higher concentrations of Iso to directly inhibit the stimulatory response. PDBu treatment produced similar effects on H2 histamine receptor-mediated ICa,L responses. In the presence of PDBu, higher concentrations of Iso inhibited the histamine stimulated ICa,L, and this effect was blocked by a selective beta1-AR antagonist. Higher concentrations of histamine also inhibited the Iso stimulated ICa,L, and this effect was blocked by a selective H2 receptor antagonist. The effects of PDBu were blocked by the PKC inhibitor bisindolylmaleimide I, and they were not mimicked by the inactive phorbol ester 4alpha-phorbol-12,13-didecanoate. The inhibitory effects of Iso and histamine were significantly reduced when Gi/o mediated responses were blocked with pertussis toxin. These results suggest that PKC promotes coupling of cardiac beta1-adrenergic and H2 histamine receptors to Gi/o mediated inhibitory responses.

Summary 1 Cytokines may parallel or regulate the beneficial effects of β-adrenoceptor antagonist treatment observed in chronic heart failure (CHF) patients. Therefore, this study was performed in order to investigate alterations of cytokine levels in β-blocker-treated patients suffering from CHF. 2 We investigated plasma cytokine levels in eight healthy controls and 12 CHF patients. The patients were treated with standard medication (CHFstd) or with standard medication and additional β1-blocker metoprolol (CHFmet). Interleukin-(IL)-1α, IL-1β, IL-1 receptor antagonist (IL-1ra), IL-2, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF), soluble TNF receptor type 1 (sTNF-R1), sTNF-R2, and sCD14 were measured by ELISA. 3 IL-1α and IL-1β were not detectable in any of the tested groups. IL-2, TNF, or sCD14 were not altered as compared with healthy control subjects. CHFstd patients expressed enhanced IL-1ra, IL-6, IL-8, IL-10, sTNF-R1 and sTNF-R2. In CHFmet patients IL-1ra, IL-6 and IL-8 remained at the same level. In contrast, sTNF-R1 levels were significantly reduced, although not to control, whereas the sTNF-R2 and IL-10 were reduced to control levels. 4 The cAMP levels of mononuclear cells – recalculated for the patients included in this study from previous work [Werner et al. (2001). Basic Res. Cardiol., 96, 290]– correlated inversely with the sTNF-R2 data (Pearson, r=−0.46; P=0.041; Spearman, r=−0.64, P=0.002). 5 The present data indicate an interaction of the neurohumoral and the cytokine system in CHF patients at the cAMP level. Thus, measurement and correlation of sTNF-R2 and cAMP may provide a tool useful during investigation of β-blocker therapy.

Atenolol, a β-adrenergic receptor antagonist, is a chiral compound used for the treatment of cardiovascular diseases and to treat hypertension, coronary heart disease, arrhythmias, sinus tachycardia and myocardial infarction, where it acts preferentially upon the β-adrenergic receptors in the heart. It is marketed as a racemate, but only the (S)-enantiomer of (RS)-atenolol is responsible for the β-adrenoceptor blocking activity. Different chromatographic methods have been applied for the separation and determination of enantiomers. In this article a review is presented on liquid chromatographic methods for enantioseparation of (RS)-atenolol by both direct and indirect approaches involving practical applications of several chiral stationary phases, chiral derivatization reagents and ligand exchange and impregnation methods. These include methods using both HPLC and TLC for separation, determination and bioassay of enantiomers of atenolol. In addition, some aspects of enantioseparation under achiral phases of liquid chromatography have been briefly mentioned as applicable to (RS)-atenolol. This review provides current available enantioseparation choices not only for (RS)-atenolol but also for other applicable racemic drugs.

Background Stroke affects 15 million people per year worldwide. Despite recent developments in acute stroke treatment, prevention remains very important. Stroke has a high rate of recurrence; therefore secondary prevention is also important. Many clinical approaches to control risk factors have been proposed. One of these approaches is the prescription of beta-blockers that have effects beyond the reduction of blood pressure, which can reduce the recurrence of stroke. Objectives To evaluate the efficacy of beta-blockers for preventing stroke recurrence and for reducing death and major vascular events in people with a previous stroke or transient ischaemic attack (TIA), and to determine their safety, particularly with regard to the development of diabetes mellitus. Search methods We searched the Cochrane Stroke Group Trials Register (May 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR) (The Cochrane Library 2014, Issue 5), the Database of Abstracts of Reviews of Effects (DARE) (May 2014), MEDLINE (1966 to May 2014), EMBASE (1980 to May 2014), and Latin American and Caribbean Health Sciences Literature (LILACS) (1982 to May 2014). We also searched ongoing trials registers and reference lists. Selection criteria Randomised controlled trials (RCTs) that included participants with previous stroke or TIA due to arterial thrombosis or embolism. The intervention was any beta-blocker versus control, or beta-blocker plus other treatment versus other treatment. Data collection and analysis Two review authors independently screened the trials identified, appraised quality, and extracted data. Main results We included two RCTs involving 2193 participants in the review. Both studies randomised participants to either beta-blocker (atenolol 5 mg) or placebo and were of a high methodological quality. We noted no statistical differences among the groups in risks of fatal and non-fatal stroke (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.76 to 1.18). For other outcomes analysed (major vascular events, death from all causes, death from cardiovascular causes) , we observed no significant differences between the groups. There were minor blood pressure reductions in the intervention group. Neither of the included studies reported the occurrence of diabetes among their outcomes or assessed quality of life. Adverse events were significantly more frequent in participants taking atenolol than in those given placebo, and were the most common reason given for discontinuing treatment (RR 1.85, 95% CI 1.45 to 2.35). Authors' conclusions To date, no available evidence supports the routine use of beta-blockers for secondary prevention after stroke or TIA. More studies with larger samples are needed.

Background Post-traumatic stress disorder (PTSD) is a debilitating disorder which, after a sufficient delay, may be diagnosed amongst individuals who respond with intense fear, helplessness or horror to traumatic events. There is some evidence that the use of pharmacological interventions immediately after exposure to trauma may reduce the risk of developing of PTSD. Objectives To assess the effects of pharmacological interventions for the prevention of PTSD in adults following exposure to a traumatic event. Search methods We searched the Cochrane Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR-Studies and CCDANCTR-References) (to 14 February 2014). This register contains relevant reports of randomised controlled trials from the following bibliographic databases: CENTRAL (all years); EMBASE (1974 to date); MEDLINE (1950 to date) and PsycINFO (1967 to date). We identified unpublished trials by searching the National Institute of Health (NIH) Reporter, the metaRegister of Controlled Trials database (mRCT) and the WHO International Clinical Trials Registry Platform (to December 2013). We scanned the reference lists of articles for additional studies. We placed no constraints on language and setting. Selection criteria We restricted studies to randomised controlled trials (RCTs) of pharmacological interventions compared with placebo for the prevention of PTSD in adults. Data collection and analysis Two authors (TA and JI) independently assessed trials for eligibility and inclusion based on the review selection criteria. We independently extracted sample, methodological, outcome and 'Risk of bias' data, as well as the number of side effects, from each trial and entered these into a customised data extraction form. We contacted investigators for missing information. We calculated summary statistics for continuous and dichotomous variables (if provided). We did not undertake subgroup analyses due to the small number of included studies. Main results We included nine short-term RCTs (duration 12 weeks or less) in the analysis (345 participants; age range 18 to 76 years). Participants were exposed to a variety of traumas, ranging from assault, traffic accidents and work accidents to cardiac surgery and septic shock. Seven studies were conducted at single centres. The seven RCTs included four hydrocortisone studies, three propranolol studies (of which one study had a third arm investigating gabapentin), and single trials of escitalopram and temazepam. Outcome assessment measures included the Clinician-Administered PTSD Scale (CAPS), the 36-Item Short-Form Health Survey (SF-36) and the Center for Epidemiological Studies – Depression Scale (CES-D). In four trials with 165 participants there was moderate quality evidence for the efficacy of hydrocortisone in preventing the onset of PTSD (risk ratio (RR) 0.17; 95% confidence interval (CI) 0.05 to 0.56; P value = 0.004), indicating that between seven and 13 patients would need to be treated with this agent in order to prevent the onset of PTSD in one patient. There was low quality evidence for preventing the onset of PTSD in three trials with 118 participants treated with propranolol (RR 0.62; 95% CI 0.24 to 1.59; P value = 0.32). Drop-outs due to treatment-emergent side effects, where reported, were low for all of the agents tested. Three of the four RCTs of hydrocortisone reported that medication was more effective than placebo in reducing PTSD symptoms after a median of 4.5 months after the event. None of the single trials of escitalopram, temazepam and gabapentin demonstrated evidence that medication was superior to placebo in preventing the onset of PTSD. Seven of the included RCTs were at a high risk of bias. Differential drop-outs between groups undermined the results of three studies, while one study failed to describe how the allocation of medication was concealed. Other forms of bias that might have influenced study results included possible confounding through group differences in concurrent medication and termination of the study based on treatment response. Authors' conclusions There is moderate quality evidence for the efficacy of hydrocortisone for the prevention of PTSD development in adults. We found no evidence to support the efficacy of propranolol, escitalopram, temazepam and gabapentin in preventing PTSD onset. The findings, however, are based on a few small studies with multiple limitations. Further research is necessary in order to determine the efficacy of pharmacotherapy in preventing PTSD and to identify potential moderators of treatment effect.

Sawicki PT, Siebenhofer A (St Franziskus Hospital in Cologne, Germany; Karl-Franzens University in Graz, Austria). Betablocker treatment in diabetes mellitus (Review). J Intern Med 2001; 250: 11–17. Objectives. Betablockers have been convincingly shown to reduce total and cardiovascular morbidity and mortality of hypertensive diabetic patients. In diabetic patients, after myocardial infarction, these agents confer a twice as high protective effect when compared to non-diabetic patients. However, most paradoxically, betablocking agents are used less frequently in diabetes. Control of hypertension is insufficient in most of the diabetic patients, probably because a combination of antihypertensive agents including betablockers is frequently needed to sufficiently control blood pressure but is not used in these patients. The fear of betablocker-associated side effects in diabetes may be partly responsible for the frequent antihypertensive mono-therapy and the resulting poor quality of blood pressure control among diabetic patients. Design. We have performed an analysis of the literature to assess whether possible adverse metabolic effects, a higher risk of hypoglycaemia or less nephroprotective effects of s1-selective betablocking agents could justify the reticence in prescribing these antihypertensive agents to diabetic patients. Results. A thorough review of the literature does not indicate that s1-selective betablocking agents have important adverse effects on glucose metabolism, prolong hypoglycaemia or mask hypoglycaemic symptoms. In diabetic nephropathy, betablockers are as nephroprotective as angiotensin converting enzyme inhibitors. Conclusions. The unnecessary less frequent prescription of s1-selective betablockers in diabetes mellitus may contribute to the higher cardiovascular mortality among these patients.

Anthracyclines have contributed to a marked increase in survival in different types of cancer [1,2]. Unfortunately, they are associated with dose-dependent cardiotoxicity and heart failure (HF) [3–8]. Change to a weekly dosage schedule with slow infusions has been tested, a strategy that requires more frequent hospital visits and increased storage resources[7,9]. Liposomal anthracycline formulations with reduced drug exposure and lower plasma concentrations may still be cardiotoxic at higher cumulative doses [10]. Beta-blockers and angiotensin converting enzyme(ACE) inhibitors have been shown to reduce anthracycline-induced cardiotoxicity,but have not been tested in long-term prospective, randomized,controlled studies with well defined cardiotoxicity criteria and careful cardiac function monitoring [11–16]. We investigated doxorubicin-induced clinical or subclinical cardiotoxicity in lymphoma patients after concomitant prophylactic therapy with metoprolol or enalapril or no concomitant treatment. We examined whether cardiotoxicity was related to the treatment or any other variable. We found that HF was less frequent under concomitant treatment than no treatment, especially in the metoprolol group, but the differences were not significant. No association was found between the presence of cardiotoxicity and concomitant treatment or other variable apart of age that had a significant impact. The marginal benefit seen with metoprolol should be investigated further.

1. Perforated patch recordings were used to determine how plating atrial cells on laminin alters beta-adrenergic receptor (beta-AR) regulation of L-type Ca2+ current (ICa,L). 2. Isoproterenol (isoprenaline; ISO; 0.01 microM), a non-selective beta-AR agonist, elicited a greater stimulation of ICa,L in cells plated on laminin (+79 +/- 16 %; n = 17) than on glass (+33 +/- 5 %; n = 23). Also, desensitization to ISO was greater in cells on laminin (-16 +/- 2 %) than on glass (-3 +/- 1 %). Atenolol (0.1 microM), a selective beta1-AR antagonist, inhibited the effects of ISO in cells on glass but not laminin. Conversely, 0.1 microM ICI 118,551, a selective beta2-AR antagonist, inhibited the effects of ISO in cells on laminin but not glass. With beta2-ARs blocked, ISO-induced stimulation of ICa,L was greater in cells on glass than laminin. 3. Zinterol (0.01-0.1 microM), a selective beta2-AR agonist, elicited a greater stimulation of ICa,L in cells on laminin than on glass. The effects of zinterol were blocked by ICI 118,551. 4. ISO-induced stimulation of ICa,L was greater in cells plated on an alphabeta1-integrin antibody than on glass. Also, addition of 20 microM cytochalasin D to cells on laminin prevented the enhanced effects of ISO typically elicited in cells on laminin alone. 5. We conclude that laminin binding to alphabeta1-integrins, in conjunction with the actin cytoskeleton, reduces beta1-AR and enhances beta2-AR signalling which regulates ICa,L. This novel mechanism may contribute to remodelling of beta-AR signalling in the failing heart.

The action of isoprenaline has been evaluated in an isolated, left atrial assay, from aged transgenic mice with cardiac-specific over-expression of the β2-adrenoceptor. In the assay, isoprenaline produced a negative inotropic concentration-response curve that was not altered by incubation with CGP-20712A (1 μM), a β1-adrenoceptor antagonist. However, after incubation with ICI-118,551 (300 nM), a selective β2-adrenoceptor antagonist, isoprenaline produced a positive inotropic concentration-effect curve that was located to the left of the negative inotropic curve. This suggests that the negative inotropic effect was mediated by a homogenous population of negatively-coupled β2-adrenoceptors. In the presence of CGP-20712A (300 nM), the positive curve was shifted to the right, suggesting that the positive inotropic effect was mediated, at least in part, by β1-adrenoceptors. These results differ substantially from those previously obtained in young transgenic mice. An outline of an explanatory model, based on a concept of over-expressed receptors ‘stealing’ G-proteins, is suggested. British Journal of Pharmacology (2000) 129, 1285–1288; doi:10.1038/sj.bjp.0703238

Hypothermia increases preglomerular vasoconstriction leading to decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Since plasma catecholamine concentrations are increased during hypothermia, the present study was performed to determine the role of the renal sympathetic nervous system in the cold-induced renal vasoconstriction. In Inactin anaesthetized rats, hypothermia at 28 degrees C decreased GFR by 50% but failed to alter efferent renal sympathetic nerve activity (ERSNA). Since hypothermia causes shivering which could have influenced the ERSNA recording, Inactin anaesthetized rats were treated with pethidine or rats were anaesthetized with pentobarbital sodium or Saffan to eliminate cold-induced shivering. In these non-shivering rats, hypothermia produced a reversible decrease in ERSNA in association with a fall in GFR that was of a similar magnitude as in shivering rats. Further studies in Inactin anaesthetized rats showed that the fall in GFR was unaltered by renal denervation, bilateral adrenalectomy or intrarenal administration of the alpha 1-adrenoceptor antagonist prazosin. We conclude that cold-induced renal vasoconstriction is not due to an increase in ERSNA or adrenaline/noradrenaline-mediated activation of renal alpha 1-adrenoceptors.

1. The purpose of this study was to examine effects of the beta(1)-adrenoreceptor antagonist esmolol (infused at 2 or 4 mg kg-1 body wt min-1) on heart rate, blood pressure, respiratory rate, localized body temperature changes, survival times, and lethal body temperatures that occur during the exposure of anaesthetized rats to 35 GHz microwaves. 2. Forty Sprague-Dawley rats, anaesthetized with ketamine, were exposed to 35 GHz microwaves at a level that resulted in heating and death. During irradiation, a continuous increase in heart rate and a biphasic response in blood pressure (initial increase followed by a decrease) were observed in all groups of animals. 3. Esmolol caused a significant dose-dependent decrease in blood pressure, relative to saline-treated animals, but only a small attenuation of the heat-induced rise in heart rate. In experiments in which esmolol was infused and microwave exposure was continued until death, drug-treated animals survived for significantly shorter periods and died at significantly lower body temperatures. The change in survival may have been related to the lower blood pressure due to esmolol treatment.

Sympathetic beta-adrenergic influences on cardiovascular responses to 50 degrees head-up tilt were evaluated with metoprolol (beta 1-blockade; 0.29 mg kg-1) and propranolol (beta 1 and beta 2-blockade; 0.28 mg kg-1) in eight males. A normotensive-tachycardic phase was followed by a hypotensive-bradycardic episode associated with presyncopal symptoms after 23 +/- 3 min (control, mean +/- SE). Head-up tilt made thoracic electrical impedance (3.0 +/- 1.0 omega), mean arterial pressure (MAP, 86 +/- 4-93 +/- 4 mmHg), heart rate (HR, 63 +/- 3-99 +/- 10 beats min-1) and total peripheral resistance (TPR, 15 +/- 1-28 +/- 4 mmHg min L-1) increase, while central venous oxygen saturation (74 +/- 2-58 +/- 4%), cardiac output (5.7 +/- 0.1-3.1 +/- 0.3 L min-1), stroke volume (95 +/- 6-41 +/- 5 mL) and pulse pressure (55 +/- 4-49 +/- 4 mmHg) decreased (P < 0.05). Central venous pressure decreased during head-up tilt (7 +/- 2-0 +/- 1 mmHg), but it remained stable during the sustained tilt. At the appearance of presyncopal symptoms MAP (49 +/- 3 mmHg), HR (66 +/- 4 beats min-1) and TPR (15 +/- 3 mmHg min L-1) decreased (P < 0.05). Neither metoprolol or propranolol changed tilt tolerance or cardiovascular variables, except for HR that remained at 57 +/- 2 (metoprolol) and 55 +/- 3 beats min-1 (propranolol), and MAP that remained at 87 +/- 5 mmHg during the first phase with metoprolol. In conclusion, sympathetic activation was crucial for the heart rate elevation during normotensive head-up tilt, but not for tilt tolerance or for the associated hypotension and bradycardia.

1. The study was undertaken to assess the role of beta-adrenoceptors in the induction of compensatory cardiac hypertrophy in an in vivo model. 2. In the rat, exposure to severe hypoxia (6% inspired oxygen for 8 h day) caused a 51% increase in right heart weight and a 75% increase in haematocrit. 3. The hypoxia-induced right ventricular hypertrophic response was reduced by 65% by oral treatment with a high dose of the non-selective beta-adrenoceptor antagonist, propranolol (80 mg kg-1 body weight); the drug treatment caused only a minor reduction (6%) in secondary polycythaemia. 4. With a less severe degree of hypoxia (7% inspired oxygen) there was only minimal secondary polycythaemia (+15%), and a lesser degree of compensatory right ventricular hypertrophy in untreated rats (+33%). 5. Treatment with the beta 1-adrenoceptor antagonist, atenolol, in a dose of 80 mg kg-1 body weight abolished right ventricular hypertrophy in response to 7% inspired oxygen, without affecting haematocrit and caused a small reduction in the ratio of heart weight to body weight in normoxic rats. 6. The results show that the effect of propranolol on hypoxic right ventricular hypertrophy is not secondary to any effect on secondary polycythaemia as has previously been suggested and that a marked reduction of compensatory cardiac hypertrophy can be obtained by a beta 1-selective adrenoceptor antagonist. Thus these findings support the view that noradrenaline released from cardiac sympathetic nerve terminals exerts a trophic effect on myocardial cells and demonstrates that in vivo, this trophic effect can be reduced by beta 1-adrenoceptor blockade.

1. The pharmacological actions of the beta-adrenoceptor antagonists, celiprolol, bisoprolol and propranolol were investigated in human lung tissue by radioligand binding experiments as well as in human isolated bronchi by functional experiments in organ baths. 2. Data from lung tissue were compared to those obtained from myocardial membranes. 3. Lung tissue was obtained from 10 patients having undergone lung resection for bronchial carcinoma and myocardial tissue from a patient who had received a heart transplantation. 4. In radioligand binding experiments, celiprolol exhibited a high affinity binding to beta 1-adrenoceptors in heart and a low affinity binding to beta 2-adrenoceptors in lung tissue. The selectivity obtained for the beta 1-adrenoceptor was calculated to a factor of eleven. 5. Compared to bisoprolol and propranolol, celiprolol elicited the lowest affinity for the beta-adrenoceptor, as judged from the K1-values. 6. In the absence and presence of the guanine nucleotide Gpp(NH)p celiprolol did not affect receptor binding. 7. In functional experiments on intact bronchi, celiprolol, bisoprolol and propranolol failed to produce relaxation (+/- forskolin) or a significant difference in efficacy in antagonizing the relaxant effects of isoprenaline. However, a rank order of potencies was revealed (propranolol:bisoprolol:celiprolol = 46:12:1). 8. Plasma concentrations for celiprolol and bisoprolol usually achieved in vivo were below the IC50 value obtained in vitro. In contrast, for propranolol, plasma concentrations were nearly identical with the IC50 value. 9. It is concluded that celiprolol is a selective beta 1-adrenoceptor antagonist on human heart and has no agonistic properties on intact human bronchi. Compounds such as celiprolol and bisoprolol may in comparison to propranolol, possess reasonable therapeutic advantages in the treatment of patients with obstructive lung disease due to their low affinity for beta 2-adrenoceptors.

1. The present study was undertaken to characterize the beta 3-adrenoceptor agonist activity of ICI-215001 and to determine whether it exhibits additional activities on beta 1- and beta 2-adrenoceptors in isolated spontaneously beating atrium, trachea and ileum of guinea-pig. 2. In guinea-pig atrium, isoprenaline, a non-selective beta-adrenoceptor agonist, caused concentration-dependent, positive chronotropic effects that were inhibited by atenolol, a selective beta 1-antagonist. ICI-215001 also competitively antagonized the increase in heart rate caused by isoprenaline. 3. ICI-215001 exhibited low intrinsic activity at increasing the beating rate of atrium and no activity on resting or induced tone of tracheal strips. 4. In strips of guinea-pig trachea, contracted submaximally with carbachol, isoprenaline, caused concentration-dependent relaxations. Both ICI-118551, a selective beta 2-adrenoceptor antagonist, and ICI-215001 competitively inhibited the relaxations caused by isoprenaline. 5. In isolated strips of guinea-pig ileum longitudinal smooth muscle contracted with histamine, isoprenaline and ICI-215001 caused relaxations which were inhibited by alprenolol, a beta-adrenoceptor antagonist with modest affinity for beta 3-adrenoceptors, but were resistant to ICI-118551 and atenolol. 6. These results indicate that ICI-215001 exhibits beta 3-adrenoceptor agonist activity as demonstrated by relaxations mediated via atypical beta-adrenoceptors in the longitudinal smooth muscle of guinea-pig ileum. Further, the studies demonstrate that ICI-215001 can act as an antagonist at beta 1- and beta 2-adrenoceptors in situations where its intrinsic agonist activity is low.

We investigated the effects of adrenergic, cholinergic and vasoactive intestinal polypeptide (VIP)-ergic agonists and antagonists on the amplitude of gastric phasic contractions in the anaesthetized rat using a volumetric model. The amplitude of the phasic contractions was reduced significantly by atropine, hexamethonium or bilateral cervical vagotomy indicating that cholinergic neural activity involving both muscarinic and nicotinic receptors and intact vagal nerve function are integral parts of the control of basal gastric phasic motility. In contrast, neither selective alpha 1-, alpha 2- or non-selective beta-blockers had any significant influence on the amplitude of the gastric contractions suggesting that adrenergic neurones are not tonically active in the maintenance of basal phasic motility in the stomach. The amplitude of the gastric phasic contractions was, however, significantly reduced by the alpha 1-agonist L-phenylephrine, the alpha 2-agonist clonidine and a close intraarterial injection of VIP (3 micrograms kg-1) but not be the selective beta 1-agonist, prenalterol, or the beta 2-agonist, salbutamol. These data suggest the presence of superimposed inhibitory control of phasic activity by VIP-ergic stimulation and by adrenergic neurones via alpha-receptor stimulation.

1. The pharmacological activity of (-)-discretamine, isolated from Fissistigma glaucescens, was determined in rat isolated thoracic aorta, cardiac tissues and ventricular myocytes and guinea-pig isolated trachea. 2. (-)-Discretamine was found to be an alpha 1-adrenoceptor blocking agent in rat thoracic aorta as revealed by its competitive antagonism of noradrenaline (pA2 = 7.20 +/- 0.10)- or phenylephrine (pA2 = 7.60 +/- 0.09)-induced vasoconstriction. It was as potent as phentolamine (pA2 = 7.51 +/- 0.10), but was more potent than yohimbine (pA2 = 6.18 +/- 0.06). Removal of endothelium significantly increased the antagonistic potency of (-)-discretamine on noradrenaline (pA2 = 7.52 +/- 0.09)- or phenylephrine (pA2 = 7.90 +/- 0.09)-induced vasoconstriction. 3. (-)-Discretamine was also an alpha 2-adrenoceptor blocking agent (pA2 = 6.30 +/- 0.15) and a 5-hydroxytryptamine antagonist (pA2 = 6.87 +/- 0.06), both in rat aorta denuded of endothelium. 4. (-)-Discretamine protected alpha-adrenoceptors from alkylation by the irreversible blocking agent, phenoxybenzamine. 5. [3H]-inositol monophosphate formation caused by noradrenaline (3 microM) in rat thoracic aorta was suppressed by (-)-discretamine (10 and 30 microM) and prazosin (3 microM). 6. A high concentration of (-)-discretamine (30 microM) did not affect the contraction induced by the thromboxane receptor agonist U-46619, prostaglandin F2 alpha (PGF2 alpha), angiotensin II, high K+ or endothelin in rat aorta denuded of endothelium. Neither cyclic AMP nor cyclic GMP content of rat thoracic aorta was changed by (-)-discretamine. 7. Contraction of guinea-pig trachea caused by histamine, leukotriene C4 or carbachol was not affected by (-)-discretamine (30 microM). (-)-Discretamine also did not block beta l- or beta2-adrenoceptor-mediated responses induced by isoprenaline in rat right atria and guinea-pig trachea.8. A voltage clamp study in rat ventricular single myocytes revealed that sodium inward current, slow inward Ca2+ current or transient (ItO) and steady state (I800) outward current was not affected by(-)-discretamine (30 microM).9. It is concluded that (-)-discretamine is a selective x-adrenoceptor and 5-HT receptor antagonist in vascular smooth muscle.

The compounds 1-isopropylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate ( 5 ) and 1- tert -butylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate ( 6 ) were synthesized from thymol ( 1 ), a naturally occurring agent in Thymus vulgaris L. Pharmacological evaluation of 5 and 6 were carried out using mouse ECG and isolated rat uterus models. Pretreatment of 5 (100 μg/kg, i.v.) and 6 (50 μg/kg, i.v.) antagonized isoprenaline (2 μg/kg, i.v.) induced tachycardia, similar to that of atenolol (CAS 29122-68-7, 20 μg/kg, i.v.) pretreatment in mouse ECG experiments as measured by R-R interval. Pretreatment of 5 and 6 blocked isoprenaline and adrenaline induced relaxation of isolated rat uterus (unprimed). Also the compounds 5 and 6 were subjected to in vitro β 1 - and β 2 -adrenergic receptor binding assay using turkey erythrocyte membrane (β 1 ) and lung homogenate of rats (β 2 ). Both 5 and 6 showed β-adrenergic receptor affinity comparable with that of propranolol (propranolol hydrochloride, CAS 318-98-9) with out selectivity to any one β-adrenergic receptor. These results suggest that both the compounds possess non-selective β-adrenergic blocking activity, with the tert -butyl derivative 6 being more active than the isopropyl derivative 5 .

The effect of metoprolol, a new beta1-adrenoceptor blocking agent, was compared to practolol in the treatment of hypertension in seventeen asthmatics during concurrent optimum bronchodilator therapy with a selective beta2-adrenoceptor-stimulant. The two beta-adrenoceptor antagonists were given at two dose levels, practolol (200 mg and 400 mg) daily, and metoprolol (100 mg and 200 mg) daily, in a twice-daily dosage schedule, at 12 h intervals, for 17 days. The comparison was made double-blind and a crossover design was used. The drugs were given in randomized order. The study started with a run-in placebo period and there was a washout period on placebo between the treatment periods. Spirometry, blood pressures and heart rates were recorded in a standardized manner. At the lower dose levels no influence on FEV1 was noted, and no difference was found between the two active drugs. At the higher dose level FEV1 was reduced by both beta-adrenoceptor-blocking drugs. Four out of twelve patients given the higher dose experienced exacerbation of their asthma. The heart rate fell with both drugs and at both dose levels. During the placebo period a marked increase of heart rate was noted. The blood pressure fell at both dose levels compared to placebo, no difference being recorded between the two drugs. Metoprolol and practolol are equally effective beta1-adrenoceptor blocking drugs. In this study it was found that metoprolol could be used in asthmatics who had indications for beta-adrenoceptor blockade, provided that the total daily dose did not exceed 100 mg. Optimal bronchodilator treatment with a bronchoselective beta-adrenoceptor agonist is an absolute prerequisite in order to avoid the risk of aggravation of asthma.