Β-adrenergic Receptor Blockers Research Articles

Mechanisms of Vasorelaxation Induced by Hexahydrocurcuminin Isolated Rat Thoracic Aorta.

This study was designed to examine the vasorelaxant effects of hexahydrocurcumin (HHC), one of the major natural metabolites of curcumin from Curcuma longa, on rat isolated aortic rings, and the underlying mechanisms. Isometric tension of the aortic rings was recorded using organ bath system. HHC (1 nM to 1 mM) relaxed the endothelium-intact aortic rings pre-contracted with PE and KCl in a concentration-dependent manner. Removal of the endothelium did not alter the effect of HHC-induced relaxation. In Ca(2+)-free Krebs solution, HHC significantly inhibited the CaCl2-induced contraction in high K(+) depolarized rings and suppressed the transient contraction induced by PE and caffeine in a concentration-dependent manner. HHC was also observed to relax phobal-12-myristate-13-acetate (PMA), an activator of protein kinase C (PKC), precontracted aortic rings in a concentration-dependent manner with EC50 values equivalent to 93.36 ± 1.03 μM. In addition, pre-incubation with propranolol (a β-adrenergic receptor blocker) significantly attenuated the HHC-induced vasorelaxation. These results suggest that the vasorelaxant effect of HHC is mediated by the endothelium-independent pathway, probably because of the inhibition of extracellular Ca(2+) influx through voltage-operated Ca(2+) channels and receptor-operated Ca(2+) channels, the inhibition of Ca(2+) mobilization from intracellular stores, as well as inhibition of PKC-mediated Ca(2+)-independent contraction. Moreover, HHC produces vasorelaxant effects probably by stimulating the β-adrenergic receptor.

Addition of ivabradine to betablockers in patients with atrial fibrillation: Effects on heart rate and exercise tolerance

Atrial fibrillation (AF) is one of the most common arrhythmias and is often responsible for impaired exercise tolerance and quality of life. Traditionally, in patients with persistent and/or permanent AF, heart rate (HR) control is obtained by using drugs that prolong atrioventricular (AV) node refractoriness such as β-adrenergic receptor blockers (βBs), nondihydropyridine calcium channel blockers, and digitalis glycosides. However a significant proportion of subjects with AF has poor HR control. According to current evidences βBs, the most effective drugs in achieving HR control, fail to obtain their goal in about 30% of cases [1]. Ivabradine, according to the traditional view, is a HR reducing agent that selectively inhibits the If current in the sinus node, without affecting heart contractility, relaxation and peripheral vascular resistance [2]. Recent studies conducted mainly in animal models support the hypothesis that ivabradine could have clinically valuable effects on AF by slowing the AV node conduction [3–5]. The goal of the present study was to test whether the addition of ivabradine to patients with persistent/permanent AF already taking βBs could be capable of improving HR control and clinical conditions of these patients. We evaluated 6 patients, mean age 66.4, (SD = 7), males/females: 4/2, with persistent or permanent AF already treated with βBs. Patients were considered suitable for this study if they fulfilled the following inclusion criteria: 1) they were taking the highest tolerated dose of a βB and no further increase were possible; 2) patients had HR N 110 bpy ata restingECG[6]; and3)they had dyspnea arisingfor mild efforts. Exclusion criteria were unstable clinical conditions (hospital admission in the last three months) or a previous diagnosis of pre-excitation. The study protocol was conform to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by San Raffaele Ethics Committee. After the enrollment and before starting ivabradine administration, all subjects underwent a 24/h ambulatory ECG monitoring (AEM) and asixminutewalkingtest(6MWT)withevaluationofthesubjectiveperceptionofdyspneathroughtheBorg'sscalescore.AEMand6MWTwere repeated after one, two and three months. The starting dose of

Simultaneous quantification of atenolol and chlorthalidone in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry.

A simple, sensitive and reproducible ultra-performance liquid chromatography-tandem mass spectrometry method has been developed for the simultaneous determination of atenolol, a β-adrenergic receptor-blocker and chlorthalidone, a monosulfonamyl diuretic in human plasma, using atenolol-d7 and chlorthalidone-d4 as the internal standards (ISs). Following solid-phase extraction on Phenomenex Strata-X cartridges using 100 μL human plasma sample, the analytes and ISs were separated on an Acquity UPLC BEH C18 (50 mm × 2.1 mm, 1.7 µm) column using a mobile phase consisting of 0.1% formic acid-acetonitrile (25:75, v/v). A tandem mass spectrometer equipped with electrospray ionization was used as a detector in the positive ionization mode for both analytes. The linear concentration range was established as 0.50-500 ng/mL for atenolol and 0.25-150 ng/mL for chlorthalidone. Extraction recoveries were within 95-103% and ion suppression/enhancement, expressed as IS-normalized matrix factors, ranged from 0.95 to 1.06 for both the analytes. Intra-batch and inter-batch precision (CV) and accuracy values were 2.37-5.91 and 96.1-103.2%, respectively. Stability of analytes in plasma was evaluated under different conditions, such as bench-top, freeze-thaw, dry and wet extract and long-term. The developed method was superior to the existing methods for the simultaneous determination of atenolol and chlorthalidone in human plasma with respect to the sensitivity, chromatographic analysis time and plasma volume for processing. Further, it was successfully applied to support a bioequivalence study of 50 mg atenolol + 12.5 mg chlorthalidone in 28 healthy Indian subjects.

Antihypertensive therapy causes erectile dysfunction

Erectile dysfunction is a common sexual disorder affecting 40% of men in the United States. However, the pathophysiologic mechanism involved in the causation of erectile dysfunction is multifactorial and not well delineated. Several recent studies disclose that erectile dysfunction is the result of multiple interrelated comorbid conditions that include hypertension, coronary artery disease (CAD), heart failure, and diabetes mellitus among them. In addition to comorbid conditions, certain cardiovascular and antihypertensive drugs are also involved in the development of erectile dysfunction, with the most prominent being the thiazide type diuretics, the aldosterone receptor blockers, and the β-adrenergic receptor blockers. Also, knowledge by the patient of the drug and its action on erectile dysfunction may increase the incidence of erectile dysfunction (Hawthorn effect). Before treatment is initiated, patients should be screened for the presence of erectile dysfunction, because this condition is associated with hypertension, CAD, heart failure, diabetes mellitus, and their treatment and an appropriate treatment regimen should be selected. If that fails, the addition of phosphodiesterase 5 inhibitors to the treatment regimen is recommended. The only exception is a patient with CAD treated with organic nitrates, in which the coadministration of phosphodiesterase 5 inhibitors is strictly prohibited. Knowledge of the various comorbid conditions and their treatment associated with the development of erectile dysfunction will help the caring physician to treat his patients appropriately and safely. All these aspects will be discussed in this review.

Functional identification of organic cation transporter 1 as an atenolol transporter sensitive to flavonoids

Atenolol, a β1-adrenergic receptor blocker, is administered orally and its intestinal absorption has recently been indicated to be mediated by carrier protein and reduced markedly by ingestion of some fruit juices, such as apple and orange juices. This could be postulated to be a problem arising from the interaction of some components of fruit juices with atenolol at a transporter involved in its intestinal uptake, but the responsible transporter and its interacting components have not been identified yet. In an attempt to examine that possibility, we could successfully find that human organic cation transporter 1 (OCT1/SLC22A1), which is suggested to be expressed at the brush border membrane of enterocytes, is highly capable of transporting atenolol. In this attempt, OCT1 was stably expressed in Madin-Darby canine kidney II cells and the specific uptake of atenolol by the transporter was found to be saturable, conforming to the Michaelis-Menten kinetics with the maximum transport rate (Vmax) of 4.00 nmol/min/mg protein and the Michaelis constant (Km) of 3.08mM. Furthermore, the OCT1-specific uptake was found to be inhibited by various flavonoids, including those contained in fruit juices that have been suggested to interfere with intestinal atenolol absorption. Particularly, phloretin and quercetin, which are major components of apple juice, were potent in inhibiting OCT1-mediated atenolol transport with the inhibition constants of 38.0 and 48.0µM, respectively. It is also notable that the inhibition by these flavonoids was of the noncompetitive type. These results indicate that OCT1 is an atenolol transporter that may be involved in intestinal atenolol uptake and sensitive to fruit juices, although its physiological and clinical relevance remains to be further examined.

Transcriptional Responses in Adult Zebrafish (Danio rerio) Exposed to Propranolol and Metoprolol.

β-adrenergic receptor blockers (β-blockers) are widely detected in the aquatic environment; however, the effects of these pharmaceuticals on aquatic organisms remain uncertain. In this study, adult zebrafish were exposed to two different β-blockers, propranolol and metoprolol, for 96h. After exposure, the transcriptional responses of genes encoding the β-adrenergic receptor (i.e., adrb1, adrb2a, adrb2b, adrb3a and adrb3b), genes involved in detoxification and the stress response (i.e., hsp70, tap, mt1 and mt2), and genes related to the antioxidant system (i.e., cu/zn-sod, mn-sod, cat and gpx) were examined in the brain, liver and gonad. Our results show that both propranolol and metoprolol exposure changes the mRNA level of β-adrenergic receptors, indicating clear pharmacological target engagement of the β-blockers. The transcription of genes related to antioxidant responses and detoxification process were induced, suggesting that β-blocker exposure can activate the detoxification process and result in oxidative stress in fish. Moreover, the transcriptional responses displayed substantial tissue- and gender-specific effects. Considering the environmental concentrations of propranolol and metoprolol, these results suggest that these pharmaceuticals are unlikely to pose a risk to fish. However, the impacts in prolonged exposure, along with other possible side effects due to β-adrenergic receptor blockade, should be further assessed.

Metoprolol Prevents Cardiac Oxidative Stress Associated with Myocardial Ischemia/Reperfusion Injury

Metoprolol, a selective β1 adrenergic receptor blocker is cardioprotective in a setting of ischemia /reperfusion injury. However, it remains controversial whether the cardioprotection is mediated by reducing oxidative stress. We tested the hypothesis that metoprolol prevents early cardiac oxidative stress during myocardial ischemia/reperfusion injury. Male Sprague‐Dawley rats were pretreated with metoprolol (1 mg/kg, i.v.) 10 min prior to a 30 min myocardial ischemia followed by 24 h reperfusion. Cardiac troponin I and T, and fatty acid binding protein 3 were measured at baseline (pre‐ischemia), 1, 2, 4, and 24 h after reperfusion using an MSD assay kit. To determine whether oxidative stress is involved in early myocardial ischemia/reperfusion injury, cardiac myosin binding protein C (MyBPC) carbonylation was determined by western blotting at 1 h after reperfusion. Infarct size was determined by TTC and Evans blue staining at 24 h after reperfusion. Ischemia/reperfusion injury significantly elevated plasma levels of cardiac injury markers for up to 24 h, reaching the peak at 1 h after reperfusion, increased MyBPC carbonylation 3.9‐fold, and caused a 56±6.2% infarct of the area at risk (n=6). Metoprolol attenuated peak and temporal plasma levels of cardiac injury markers, reduced MyBPC carbonylation by 52% (p<0.01), and reduced infarct size to 33±6.9% of the area at risk (n=6, P<0.01). Cardiac injury markers were positively correlated with infarct size, suggesting that metoprolol prevents cardiac oxidative stress associated with myocardial ischemia/reperfusion injury.

Arrhythmogenic remodeling of β2 versus β1 adrenergic signaling in the human failing heart.

Arrhythmia is the major cause of death in patients with heart failure, for which β-adrenergic receptor blockers are a mainstay therapy. But the role of β-adrenergic signaling in electrophysiology and arrhythmias has never been studied in human ventricles. We used optical imaging of action potentials and [Ca(2+)]i transients to compare the β1- and β2-adrenergic responses in left ventricular wedge preparations of human donor and failing hearts. β1-Stimulation significantly increased conduction velocity, shortened action potential duration, and [Ca(2+)]i transients duration (CaD) in donor but not in failing hearts, because of desensitization of β1-adrenergic receptor in heart failure. In contrast, β2-stimulation increased conduction velocity in both donor and failing hearts but shortened action potential duration only in failing hearts. β2-Stimulation also affected transmural heterogeneity in action potential duration but not in [Ca(2+)]i transients duration. Both β1- and β2-stimulation augmented the vulnerability and frequency of ectopic activity and enhanced substrates for ventricular tachycardia in failing, but not in donor, hearts. Both β1- and β2-stimulation enhanced Purkinje fiber automaticity, whereas only β2-stimulation promoted Ca-mediated premature ventricular contractions in heart failure. During end-stage heart failure, β2-stimulation creates arrhythmogenic substrates via conduction velocity regulation and transmurally heterogeneous repolarization. β2-Stimulation is, therefore, more arrhythmogenic than β1-stimulation. In particular, β2-stimulation increases the transmural difference between [Ca(2+)]i transients duration and action potential duration, which facilitates the formation of delayed afterdepolarizations.

Nasal IgA secretion in a murine model of acute stress. The possible role of catecholamines.

Stress stimuli affect the immune system of the mucosa, and in particular IgA secretion. It is well documented that intense psychological and physical stress can increase susceptibility to infection by diverse pathogens in the upper respiratory tract. Our workgroup reported that chronic stress caused by immobilization elicits a decrease in nasal IgA levels in mice. Here, we explore how acute stress (caused by 4h of immobilization) affects IgA secretion in the nasal mucosa, and the possible role of the sympathetic nervous system in this effect. Nine-week-old male CD1 mice were divided into four groups: control, chemical sympathectomy (with 6-OHDA) and treatment with nadolol (5mg/kg) or phentolamine (15mg/kg). All these groups were subdivided into stressed and unstressed animals. The parameters evaluated included plasma corticosterone and epinephrine (only in control groups), SIgA levels (by ELISA) and SIgA expression (by Western Blot) in nasal fluid, percentage of IgA+ plasma cells, and mRNA expression of heavy alpha chain, pIgR, TNFα and TGFβ in nasal mucosa. Acute stress reduced the percentage of IgA+ cells while increasing the levels of IgA, the two hormones, and the mRNA expression of heavy alpha chain, pIgR, TNFα and TGFβ, which resulted in greater synthesis and transport of IgA. The treatments with 6-OHDA and α- and β-adrenergic receptor blockers suggest that sympathetic innervation by both types of adrenergic receptors is important for the control of SIgA secretion in nasal mucosa during acute stress. The increase in this parameter depended on the cytokines involved in IgA synthesis and transport.

Antiplatelet activity of β-blockers: new light on existing data.

Antiplatelet activity of β-blockers: new light on existing data.

Engineering of an epoxide hydrolase for efficient bioresolution of bulky pharmaco substrates

Optically pure epoxides are essential chiral precursors for the production of (S)-propranolol, (S)-alprenolol, and other β-adrenergic receptor blocking drugs. Although the enzymatic production of these bulky epoxides has proven difficult, here we report a method to effectively improve the activity of BmEH, an epoxide hydrolase from Bacillus megaterium ECU1001 toward α-naphthyl glycidyl ether, the precursor of (S)-propranolol, by eliminating the steric hindrance near the potential product-release site. Using X-ray crystallography, mass spectrum, and molecular dynamics calculations, we have identified an active tunnel for substrate access and product release of this enzyme. The crystal structures revealed that there is an independent product-release site in BmEH that was not included in other reported epoxide hydrolase structures. By alanine scanning, two mutants, F128A and M145A, targeted to expand the potential product-release site displayed 42 and 25 times higher activities toward α-naphthyl glycidyl ether than the wild-type enzyme, respectively. These results show great promise for structure-based rational design in improving the catalytic efficiency of industrial enzymes for bulky substrates.

Treatment for pulmonary arterial hypertension-associated right ventricular dysfunction.

Pulmonary arterial hypertension (PAH) includes a heterogeneous group of diseases characterized by pulmonary vasoconstriction and remodeling of the lung circulation. Although PAH is a disease of the lungs, patients with PAH frequently die of right heart failure. Indeed, survival of patients with PAH depends on the adaptive response of the right ventricle (RV) to the changes in the lung circulation. PAH-specific drugs affect the function of the RV through afterload reduction and perhaps also through direct effects on the myocardium. Prostacyclins, type 5 phosphodiesterase inhibitors, and guanylyl cyclase stimulators may directly enhance myocardial contractility through increased cyclic adenosine and guanosine monophosphate availability. Although this may initially improve cardiac performance, the long-term effects on myocardial oxygen consumption and function are unclear. Cardiac effects of endothelin receptor antagonists may be opposite, as endothelin-1 is known to suppress cardiac contractility. Because PAH is increasingly considered as a disease with quasimalignant growth of cells in the pulmonary vascular wall, therapies are being developed that inhibit hypertrophy and angiogenesis, and promote apoptosis. The inherent danger of these therapies is a further compromise to the already ischemic, fibrotic, and dysfunctional RV. More recently, the right heart has been identified as a direct treatment target in PAH. The effects of well established therapies for left heart failure, such as β-adrenergic receptor blockers, inhibitors of the renin-angiotensin system, exercise training, and assist devices, are currently being investigated in PAH. Future treatment of patients with PAH will likely consist of a multifaceted approaches aiming to reduce the pressure in the lung circulation and improving right heart adaptation simultaneously.

Mineralocorticoid and AT1 receptors in the paraventricular nucleus contribute to sympathetic hyperactivity and cardiac dysfunction in rats post myocardial infarct.

Intracerebroventricular infusion of a mineralocorticoid receptor (MR) or angiotensinII type1 receptor (AT1R) blocker in rats attenuates sympathetic hyperactivity and progressive left ventricular (LV) dysfunction post myocardial infarction (MI). The present study examined whether knockdown of MRs or AT1Rs specifically in the paraventricular nucleus (PVN) contributes to these effects, and compared cardiac effects with those of systemic treatment with the β1-adrenergic receptor blocker metoprolol. The PVN of rats was infused with adeno-associated virus carrying small interfering RNA against either MR (AAV-MR-siRNA) or AT1R (AAV-AT1R-siRNA), or as control scrambled siRNA. At 4weeks post MI, AT1R but not MR expression was increased in the PVN, excitatory renal sympathetic nerve activity and pressor responses to air stress were enhanced, and arterial baroreflex function was impaired; LV end-diastolic pressure (LVEDP) was increased and LV peak systolic pressure (LVPSP), ejection fraction (EF) and dP/dtmax decreased. AAV-MR-siRNA and AAV-AT1R-siRNA both normalized AT1R expression in the PVN, similarly ameliorated sympathetic and pressor responses to air stress, largely prevented baroreflex desensitization, and improved LVEDP, EF and dP/dtmax as well as cardiac interstitial (but not perivascular) fibrosis. In a second set of rats, metoprolol at 70 or 250mgkg(-1)day(-1) in the drinking water for 4weeks post MI did not improve LV function except for a decrease in LVEDP at the lower dose. These results suggest that in rats MR-dependent upregulation of AT1Rs in the PVN contributes to sympathetic hyperactivity, and LV dysfunction and remodelling post MI. In rats, normalizing MR-AT1R signalling in the PVN is a more effective strategy to improve LV dysfunction post MI than systemic β1 blockade.

The Effect of β Receptor Blockade Through Propranolol on Corneal Neovascularization

To evaluate the inhibitory effects of propranolol, a nonselective and lipophilic β-adrenergic receptor blocker, on alkali-induced corneal neovascularization (NV). Corneal NV was induced in 24 eyes of 24 Wistar rats using NaOH. Following alkali burn, animals were randomized into 4 groups according to topical treatment. Group I received 0.9% NaCl, Group II received preservative-free dexamethasone sodium phosphate 1 mg/mL, Group III received propranolol hydrochloride 1 mg/mL, and Group IV received 0.5 mg/mL propranolol hydrochloride drops twice a day for 7 days. The inhibitory effects of the drugs were compared as the percent areas of cornea covered by NV. Anti-vascular endothelial growth factor (VEGF) and anti-active caspase-3 immunostainings were also performed in corneal sections. The median percent area of corneal NV was 59% (40.3-65.6) in Group I, 25.5% (20.9-43.4) in Group II, 68.9% (36.7-78.0) in Group III, and 50.4% (42.2-63.3) in Group IV. Group III and IV did not show any difference in comparison to Group I. Group II showed a statistically significant smaller area of corneal NV compared with Group I, III, and IV (P=0.004 for each comparison). Anti-VEGF immunostaining was significantly less in Group II compared with the other groups. Anti-active caspase-3 immunostaining was not different among the treatment groups. Topical propranolol 1 or 0.5 mg/mL does not have a significant inhibitory effect on alkali-induced corneal NV in rats.

Carvedilol Attenuates 6-Hydroxydopamine-Induced Cell Death in PC12 Cells: Involvement of Akt and Nrf2/ARE Pathways

Oxidative stress is closely related to the pathogenesis of neurodegenerative disorders such as Parkinson's disease. Carvedilol, a nonselective β-adrenergic receptor blocker with pleiotropic activity has been shown to exert neuroprotective effect due to its antioxidant property. However, the neuroprotective mechanism of carvedilol is still not fully uncovered. The phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway plays key role in cell survival and the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is the major cellular defense mechanism against oxidative stress. Here we investigated the effects of carvedilol on 6-hydroxydopamine (6-OHDA)-induced cell death as well as the Akt and Nrf2/ARE pathways in PC12 cells. We found that carvedilol significantly increased cell viability and decreased reactive oxygen species in PC12 cells exposed to 6-OHDA. Furthermore, carvedilol activated the Akt and Nrf2/ARE pathways in a concentration-dependent manner, and increased the protein levels of heme oxygenase-1(HO-1) and NAD(P)H quinone oxidoreductase-1(NQO-1), two downstream factors of the Nrf2/ARE pathway. In summary, our results indicate that carvedilol protects PC12 cells against 6-OHDA-induced neurotoxicity possibly through activating the Akt and Nrf2/ARE signaling pathways.

β1-Adrenergic Receptor Signaling Activates the Epithelial Calcium Channel, Transient Receptor Potential Vanilloid Type 5 (TRPV5), via the Protein Kinase A Pathway

Epinephrine and norepinephrine are present in the pro-urine. β-Adrenergic receptor (β-AR) blockers administered to counteract sympathetic overstimulation in patients with congestive heart failure have a negative inotropic effect, resulting in reduced cardiac contractility. Positive inotropes, β1-AR agonists, are used to improve cardiac functions. Active Ca(2+) reabsorption in the late distal convoluted and connecting tubules (DCT2/CNT) is initiated by Ca(2+) influx through the transient receptor potential vanilloid type 5 (TRPV5) Ca(2+) channel. Although it was reported that β-ARs are present in the DCT2/CNT region, their role in active Ca(2+) reabsorption remains elusive. Here we revealed that β1-AR, but not β2-AR, is localized with TRPV5 in DCT2/CNT. Subsequently, treatment of TRPV5-expressing mouse DCT2/CNT primary cell cultures with the β1-AR agonist dobutamine showed enhanced apical-to-basolateral transepithelial Ca(2+) transport. In human embryonic kidney (HEK293) cells, dobutamine was shown to stimulate cAMP production, signifying functional β1-AR expression. Fura-2 experiments demonstrated increased activity of TRPV5 in response to dobutamine, which could be prevented by the PKA inhibitor H89. Moreover, nonphosphorylable T709A-TRPV5 and phosphorylation-mimicking T709D-TRPV5 mutants were unresponsive to dobutamine. Surface biotinylation showed that dobutamine did not affect plasma membrane abundance of TRPV5. In conclusion, activation of β1-AR stimulates active Ca(2+) reabsorption in DCT2/CNT; an increase in TRPV5 activity via PKA phosphorylation of residue Thr-709 possibly plays an important role. These data explicate a calciotropic role in addition to the inotropic property of β1-AR.

Abstract 429: Central Glucagon-Like Peptide-1 Reduces Intestinal Chylomicron Production via Melanocortin-4-Receptor Signaling

Insulin resistance and the metabolic syndrome are associated with intestinal overproduction of chylomicrons, resulting in postprandial dyslipidemia and atherogenic remnants. It is increasingly clear that a reduction in chylomicrons is achieved by the action of glucagon-like peptide-1 (GLP-1) in the periphery. However, this peptide is also generated by central neurons and regulates activity in brain regions that affect sympathetic signaling. Indeed, through sympathetic pathways GLP-1 can modulate peripheral lipogenesis. Therefore, we examined the potential role of peripheral and central GLP-1 in regulating chylomicron production. Healthy hamsters received an oral fat load followed by an intraperitoneal (IP) or intracerebroventricular (ICV) injection of the GLP-1 receptor (GLP-1R) agonist exendin-4. Postprandial triglyceride (TG) and apolipoprotein B48 (apoB48) levels from plasma TG-rich lipoproteins (TRL) were found to be reduced over 6 h. The effects of central exendin-4 were mirrored by ICV MK-0626, an inhibitor of GLP-1 degradation, and reversed by the GLP-1R antagonist exendin9-39. Given a potential link between central GLP-1 and the melanocortin-4-receptor (MC4R) system, hamsters received an MC4R antagonist ICV alongside exendin-4 and this prevented a lowering in TRL-TG levels. To determine whether subsequent communication with the gut was through sympathetic pathways, α- and β-adrenergic receptor blockers were infused intravenously prior to ICV exendin-4 treatment and prevented exendin-4 from reducing TRL-TG. Finally, to examine the interplay between central and peripheral GLP-1R signaling, exendin-4 was given IP while exendin9-39 was given ICV and vice-versa. IP exendin-4 diminished TRL-TG levels during central antagonism, while IP exendin9-39 prevented the action of ICV exendin-4. This suggests that peripheral GLP-1Rs may be potentiated by central stimulation, but can also act independently. Overall, we demonstrate a GLP-1-sensitive brain-gut axis for regulating chylomicron production, involving the MC4R system and sympathetic pathways. Future studies will investigate whether central GLP-1 signals via pro-opiomelanocortin neurons and sympathetic neurotransmitters to affect enterocyte chylomicron output.

Effects of one month treatment with propranolol and metoprolol on the relaxant and contractile function of isolated trachea from rats exposed to cigarette smoke for four months

Background and objective: The effects of one-month treatment of β-adrenergic receptor (AR) blockers on the relaxant function of airway in chronic obstructive pulmonary disease (COPD) are unknown. A passive cigarette smoking rat model was used to investigate the effect of β-AR blockers.Methods: Thirty-six rats were randomly divided into six groups: control (C); propranolol (P); metoprolol (M); smoking (S); smoking + propranolol (SP); and smoking + metoprolol (SM). Histological analysis of the lungs was done and isolated tracheal segments were studied in vitro to assess the contractile and relaxant function of the smooth muscle. The level of norepinephrine (NE) was measured.Results: Airway inflammation was more severe in group S than group C (p < 0.001), and it was alleviated in group SP (p < 0.001) while had no change in group SM. After propranolol or metoprolol administration, the level of NE was significantly lower in both SP and SM groups (p < 0.01). The maximal contractile response to acetylcholine (Ach) in groups S and SM was increased compared to group C (p < 0.01). Propranolol significantly inhibited contractile response in group SP (p < 0.05), while metoprolol did not show the same effect. The curve of maximum relaxant rate to isoprenaline (Iso) shifted to the left in group SP (p < 0.01), while group SM showed no changes.Conclusion: One-month treatment with propranolol increased the relaxant effect mediated by the β2-AR and decreased the contractile response to Ach by reducing the level of NE.

β-Adrenergic blockade combined with subcutaneous B-type natriuretic peptide: a promising approach to reduce ventricular arrhythmia in heart failure?

AimsClinical studies failed to prove convincingly efficiency of intravenous infusion of neseritide during heart failure and evidence suggested a pro-adrenergic action of B-type natriuretic peptide (BNP). However, subcutaneous BNP therapy...

Dickkopf-3: a stubborn protector of cardiac hypertrophy

This editorial refers to ‘Dickkopf-3 attenuates pressure overload-induced cardiac remodelling’ by Y. Zhang et al. , pp. 35–45, this issue. In response to haemodynamic overload under pathological conditions such as hypertension, valvular heart disease, and myocardial infarction, the heart undergoes hypertrophic growth by increasing cell size and protein synthesis as well as changing the transcriptional programme in cardiac myocytes.1 Although cardiac hypertrophy is beneficial in the way that it reduces ventricular wall tension and maintains pump function, it promotes cardiac structural remodelling and dysfunction, and eventually leads to development of congestive heart failure, arrhythmia, and sudden death. At present, several drugs such as inhibitors of the renin–angiotensin–aldosterone system, β-adrenergic receptor blockers, and calcium channel blockers are clinically available for the management of hypertension, and these drugs have shown significant efficacy in preventing load-induced cardiac hypertrophy and remodelling. However, these pharmacological agents are currently of limited effectiveness, and further discovery and development of novel classes of cardioprotective drugs are in urgent need.2 For that purpose, it is important to elucidate the molecular mechanisms underlying the development of cardiac hypertrophy. In the article by Zhang et al. ,3 integrating genetic approaches in mice have shed light on Dickkopf-3 (DKK3) as a cardioprotective regulator of cardiac hypertrophy. DKK3 is a secreted glycoprotein of the Dickkopf family that typically antagonizes the Wnt/β-catenin signalling by interfering with Wnt co-receptors, low-density lipoprotein receptor-related protein and kremen.4 ‘Dickkopf’ is a German word for ‘big head’ or ‘stubborn’, and the protein …