Sympathetic stimulation increased maximum slope of restitution and electrical alternans but decreased ERP and VF threshold whilst vagus nerve stimulation had opposite effects. The interaction between action potential duration and beat-to-beat interval may play an important role in the autonomic modulation of VF initiation.

AimsFibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia.Methods and ResultsFGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased.ConclusionIn an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia.

We have previously shown that direct vagus nerve stimulation (VNS) reduces the slope of action potential duration (APD) restitution while simultaneously protecting the heart against induction of ventricular fibrillation (VF) in the absence of any sympathetic activity or tone. In the current study we have examined the role of nitric oxide (NO) in the effect of VNS. Monophasic action potentials were recorded from a left ventricular epicardial site on innervated, isolated rabbit hearts (n = 7). Standard restitution, effective refractory period (ERP) and VF threshold (VFT) were measured at baseline and during VNS in the presence of the NO synthase inhibitor N G -nitro-L-arginine (L-NA, 200 μM) and during reversing NO blockade with L-arginine (L-Arg, 1 mM). Data represent the mean ± S.E.M. The restitution curve was shifted upwards and became less steep with VNS when compared to baseline. L-NA blocked the effect of VNS whereas L-Arg restored the effect of VNS. The maximum slope of restitution was reduced from 1.17 ± 0.14 to 0.60 ± 0.09 (50 ± 5%, P < 0.0001) during control, from 0.98 ± 0.14 to 0.93 ± 0.12 (2 ± 10%, P = NS) in the presence of L-NA and from 1.16 ± 0.17 to 0.50 ± 0.10 (41 ± 9%, P = 0.003) with L-Arg plus L-NA. ERP was increased by VNS in control from 119 ± 6 ms to 130 ± 6 ms (10 ± 5%, P = 0.045) and this increase was not affected by L-NA (120 ± 4 to 133 ± 4 ms, 11 ± 3%, P = 0.0019) or L-Arg with L-NA (114 ± 4 to 123 ± 4 ms, 8 ± 2%, P = 0.006). VFT was increased from 3.0 ± 0.3 to 5.8 ± 0.5 mA (98 ± 12%, P = 0.0017) in control, 3.4 ± 0.4 to 3.8 ± 0.5 mA (13 ± 12%, P = 0.6) during perfusion with L-NA and 2.5 ± 0.4 to 6.0 ± 0.7 mA (175 ± 50%, P = 0.0017) during perfusion with L-Arg plus L-NA. Direct VNS increased VFT and flattened the slope of APD restitution curve in this isolated rabbit heart preparation with intact autonomic nerves. These effects were blocked using L-NA and reversed by replenishing the substrate for NO production with L-Arg. This is the first study to demonstrate that NO plays an important role in the anti-fibrillatory effect of VNS on the rabbit ventricle, possibly via effects on APD restitution.

T supplementation was well tolerated and improved body composition but had no effect on functional performance. T supplementation improved upper body strength only in nonexercisers compared with placebo.

Background and PurposeThe glucagon-like peptide 1 (GLP-1) receptor performs an important role in glycaemic control, stimulating the release of insulin. It is an attractive target for treating type 2 diabetes. Recently, several reports of adverse side effects following prolonged use of GLP-1 receptor therapies have emerged: most likely due to an incomplete understanding of signalling complexities.Experimental ApproachWe describe the expression of the GLP-1 receptor in a panel of modified yeast strains that couple receptor activation to cell growth via single Gα/yeast chimeras. This assay enables the study of individual ligand–receptor G protein coupling preferences and the quantification of the effect of GLP-1 receptor ligands on G protein selectivity.Key ResultsThe GLP-1 receptor functionally coupled to the chimeras representing the human Gαs, Gαi and Gαq subunits. Calculation of the dissociation constant for a receptor antagonist, exendin-3 revealed no significant difference between the two systems. We obtained previously unobserved differences in G protein signalling bias for clinically relevant therapeutic agents, liraglutide and exenatide; the latter displaying significant bias for the Gαi pathway. We extended the use of the system to investigate small-molecule allosteric compounds and the closely related glucagon receptor.Conclusions and ImplicationsThese results provide a better understanding of the molecular events involved in GLP-1 receptor pleiotropic signalling and establish the yeast platform as a robust tool to screen for more selective, efficacious compounds acting at this important class of receptors in the future.

Short-chain fatty acids play crucial roles in a range of physiological functions. However, the effects of short-chain fatty acids on brown adipose tissue have not been fully investigated. We examined the role of acetate, a short-chain fatty acid formed by fermentation in the gut, in the regulation of brown adipocyte metabolism. Our results show that acetate up-regulates adipocyte protein 2, peroxisomal proliferator-activated receptor-γ coactivator-1α, and uncoupling protein-1 expression and affects the morphological changes of brown adipocytes during adipogenesis. Moreover, an increase in mitochondrial biogenesis was observed after acetate treatment. Acetate also elicited the activation of ERK and cAMP response element-binding protein, and these responses were sensitive to G(i/o)-type G protein inactivator, Gβγ-subunit inhibitor, phospholipase C inhibitor, and MAPK kinase inhibitor, indicating a role for the G(i/o)βγ/phospholipase C/protein kinase C/MAPK kinase signaling pathway in these responses. These effects of acetate were mimicked by treatment with 4-chloro-α-(1-methylethyl)-N-2-thiazolylbenzeneacetamide, a synthetic G protein-coupled receptor 43 (GPR43) agonist and were impaired in GPR43 knockdown cells. Taken together, our results indicate that acetate may have important physiological roles in brown adipocytes through the activation of GPR43.

Abnormal autonomic activity has been shown to be a strong prognostic indicator of mortality in patients with heart failure (Nolan et al. 1998) and those who have had a previous myocardial infarct (La Rovere et al. 1998). Depressed heart rate variability and baroreceptor sensitivity are surrogate markers of impaired vagal tone associated with mortality in these conditions in which most of the deaths are sudden and due to ventricular arrhythmias, especially ventricular fibrillation (VF). We have recently shown that electrical stimulation of the vagus nerve in the neck ) has a strong anti-arrhythmic effect in the rabbit ventricle against VF. These effects are blocked in the presence of a nitric oxide (NO) synthase inhibitor providing indirect evidence that NO is involved in this effect. The implication of NO in mediating vagal activity in the ventricle is novel although

Rectangular concrete-filled double steel tubular (CFDST) columns with inner circular steel tube possess higher structural performance than conventional concrete-filled steel tubular (CFST) columns. However, the local buckling of the outer steel tube of thin-walled rectangular CFDST columns has not been accounted for in the existing fiber element models and design codes that may overestimate the column ultimate axial strengths. This paper describes a computationally efficient fiber-based modeling technique developed for determining the behavior of concentrically-loaded rectangular CFDST short columns including the local buckling effects of the external steel tube and the confinement offered by the internal circular steel tube. The effective width concept is used to simulate the post-local buckling of the outer steel tube. Comparative studies are undertaken to verify the fiber-based model with the relevant test results. The computational model is then employed to investigate the axial load-strain responses of rectangular CFDST short columns with various key design variables. A design equation is developed for computing the ultimate axial loads of short rectangular CFDST columns and compared with design methods given in several international design codes. It is shown that the fiber-based modeling technique and the proposed design model predict well the structural performance of short CFDST columns.