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Hypertensive postmenopausal women are more likely to develop adverse cardiac remodeling and respond less effectively to drug treatment than men. High-intensity interval exercise (HIIE) is a nonpharmacological strategy for the treatment of hypertension; however, the effectiveness in women remains uncertain. This study was designed to evaluate 1) the effects of HIIE training upon morphological and functional markers of cardiovascular health in female SHR and 2) to determine whether the hormonal shift induced by ovariectomy could influence cardiovascular responses to HIIE. Thirty-six SHR were randomly assigned to four groups: ovariectomized sedentary, ovariectomized trained, sham-operated sedentary, and sham-operated trained. The trained rats performed HIIE 5 days/wk for 8 wk. Blood pressure and echocardiographic measurements were performed before and after training in animals. Cardiac response to β-adrenergic stimulation and the expression of calcium regulatory proteins and estrogen receptors in heart samples were assessed. Endothelium-dependent vasorelaxation in response to acetylcholine was evaluated in aortic rings as well as the expression of nitric oxide synthase isoforms (eNOS and P-eNOS) by Western blotting. In both groups of trained SHR, HIIE induced eccentric cardiac remodeling with greater inotropic and chronotropic effects, as well as an increase in SERCA and β1AR expression. However, although the trained rats showed improved endothelial function and expression of eNOS and P-eNOS in the aorta, there was no demonstrated effect on blood pressure. In addition, the responses to HIIE training were not affected by ovariectomy. This work highlights the importance of assessing the cardiovascular efficacy and safety of different exercise modalities in women. NEW & NOTEWORTHY: This study reports the effects of high-intensity interval exercise (HIIE) training on cardiac and endothelial function in female hypertensive rats. Despite a lack of effect on blood pressure (BP), HIIE training induces eccentric cardiac remodeling with greater functionals effects. Furthermore, training has beneficial effects on endothelial function. However, ovarian hormones do not seem to modulate cardiac and aortic adaptations to this training modality. All this underlines the need to consider training modalities on the cardiovascular system in women. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this work is to evaluate the impact on the rat microbiota of long‐term feeding with phenolic compounds (PC) rich grape pomace extracts. Thirty, 2‐mo‐old rats, were divided into 5 groups. Four groups were treated with different concentrations of PC (2.5, 5, 10, and 20 mg/kg/d diluted in 0.1% DMSO), and 1 group received 0.1% Dimethyl Sulfoxide (DMSO) alone (control group). The daily treatment lasted 14 mo. Major phenolic compounds constituents were characterized by the high‐performance liquid chromatography and free radical scavenging capacity was measured by means of the DPPH assay. Fecal samples from young rats (2‐mo old), and rats daily fed with PC or DMSO were collected at 6 and 14 mo posttreatment. The gut microbiota composition was analyzed by quantitative polymerase chain reaction. Bifidobacterium was significantly higher in the groups PC 2.5 and PC 5 than in control and young rats. Lactobacillus decreased with time in all treated and untreated groups. Bacteroides, Clostridium leptum subgroup (Clostridium cluster IV), and Enterococcus were not significantly changed by PC at any concentration when compared to control; nevertheless, after 14 mo of treatment all concentrations of PC abolished the increase of Clostridium sensu stricto (cluster I) (Clostridium Cluster I) observed in the control group when compared to young rats. PC do modulate selectively rat gut microbiome to a healthier phenotype in long‐term feeding rats, and could counteract the adverse outcomes of aging on gut bacterial population. Practical Application: This research shows that phenolic‐rich grape pomace extracts exhibiting a high antioxidant activity, selectively modulate rat gut microbiota to a healthier phenotype within age in a long‐term feeding rats. [ABSTRACT FROM AUTHOR]

Cardiac fibroblasts are commonly known as supporting cells of the cardiac network and exert many essential functions that are fundamental for normal cardiac growth as well as for cardiac remodeling process during pathological conditions. This review focuses on the roles of cardiac fibroblasts in the formation and regulation of the extracellular matrix components, and in maintaining structural, biochemical and mechanical properties of the heart. Additionally, though considered as non-excitable cells, we review the functional expression in cardiac fibroblasts of a wide variety of transmembrane ion channels which activity may contribute to key regulation of cardiac physiological processes. All together, cardiac fibroblasts which actively participate to fundamental regulation of cardiac physiology and physiopathology processes may represent pertinent targets for pharmacological approaches of cardiac diseases and lead to new tracks of therapeutic strategies. J. Cell. Physiol. 232: 725-730, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Brugada syndrome (BrS) is an inherited autosomal dominant cardiac channelopathy. Several mutations on the cardiac sodium channel Nav1.5 which are responsible for BrS lead to misfolded proteins that do not traffic properly to the plasma membrane. In order to mimic patient heterozygosity, a trafficking defective mutant, R1432G was co-expressed with Wild Type (WT) Nav1.5 channels in HEK293T cells. This mutant significantly decreased the membrane Na current density when it was co-transfected with the WT channel. This dominant negative effect did not result in altered biophysical properties of Nav1.5 channels. Luminometric experiments revealed that the expression of mutant proteins induced a significant reduction in membrane expression of WT channels. Interestingly, we have found that the auxiliary Na channel b1-subunit was essential for this dominant negative effect. Indeed, the absence of the b1-subunit prevented the decrease in WT sodium current density and surface proteins associated with the dominant negative effect. Co-immunoprecipitation experiments demonstrated a physical interaction between Na channel a-subunits. This interaction occurred only when the β1-subunit was present. Our findings reveal a new role for b1-subunits in cardiac voltage-gated sodium channels by promoting α-α subunit interaction which can lead to a dominant negative effect when one of the a-subunits shows a trafficking defective mutation. [ABSTRACT FROM AUTHOR]

Key point Fibroblasts play a major role in heart physiology. In pathological conditions, they can lead to cardiac fibrosis when they differentiate into myofibroblasts., This differentiated status is associated with changes in expression profile leading to neo-expression of proteins such as ionic channels., The present study investigates electrophysiological changes associated with fibroblast differentiation focusing on voltage-gated sodium channels in human atrial fibroblasts and myofibroblasts., We show that human atrial fibroblast differentiation in myofibroblasts is associated with de novo expression of voltage gated sodium current. Multiple arguments support that this current is predominantly supported by the Nav1.5 α-subunit which may generate a persistent sodium entry into myofibroblasts., Our data revealed that Nav1.5 α-subunit expression is not restricted to cardiac myocytes within the atrium. Since fibrosis is one of the fundamental mechanisms implicated in atrial fibrillation, it is of great interest to investigate how this channel could influence myofibroblasts function., Abstract Fibroblasts play a major role in heart physiology. They are at the origin of the extracellular matrix renewal and production of various paracrine and autocrine factors. In pathological conditions, fibroblasts proliferate, migrate and differentiate into myofibroblasts leading to cardiac fibrosis. This differentiated status is associated with changes in expression profile leading to neo-expression of proteins such as ionic channels. The present study investigates further electrophysiological changes associated with fibroblast differentiation focusing on the activity of voltage-gated sodium channels in human atrial fibroblasts and myofibroblasts. Using the patch clamp technique we show that human atrial myofibroblasts display a fast inward voltage gated sodium current with a density of 13.28 ± 2.88 pA pF−1 whereas no current was detectable in non-differentiated fibroblasts. Quantitative RT-PCR reveals a large amount of transcripts encoding the Nav1.5 α-subunit with a fourfold increased expression level in myofibroblasts when compared to fibroblasts. Accordingly, half of the current was blocked by 1 μ m of tetrodotoxin and immunocytochemistry experiments reveal the presence of Nav1.5 proteins. Overall, this current exhibits similar biophysical characteristics to sodium currents found in cardiac myocytes except for the window current that is enlarged for potentials between −100 and −20 mV. Since fibrosis is one of the fundamental mechanisms implicated in atrial fibrillation, it is of great interest to investigate how this current could influence myofibroblast properties. Moreover, since several Nav1.5 mutations are related to cardiac pathologies, this study offers a new avenue on the fibroblasts involvement of these mutations. [ABSTRACT FROM AUTHOR]

Objective: The Shal (or Kv4) gene family has been proposed to be responsible for primary subunits of the transient outward potassium current (Ito). More precisely, Kv4.2 and Kv4.3 have been suggested to be the most likely molecular correlates for Ito in rat cells. The purpose of the present study was to compare the properties of the rat Kv4.3 gene product when expressed in a human cell line (HEK293 cells) with that of Ito recorded from rat ventricular cells. Methods: The cDNA encoding the rat Kv4.3 potassium channel was cloned into the pHook2 mammalian expression vector and expressed into HEK293. Patch clamp experiments using the whole cell configuration were used to characterise the electrophysiological parameters of the current induced by Kv4.3 in comparison with the rat ventricular myocyte Ito current. Results: The transfection of HEK293 cells with rat Kv4.3 resulted in the expression of a time- and voltage-dependent outward potassium current. The current activated for potentials positive to −40 mV and the steady-state inactivation curve had a midpoint of −47.4±0.3 mV and a slope of 5.9±0.2 mV. Rat ventricular Ito current was activated at potentials positive to −20 mV and inactivated with a half-inactivation potential and a Boltzmann factor of −29.1±0.7 mV and 4.5±0.5 mV, respectively. The time course of recovery from inactivation of rat Kv4.3 expressed in HEK293 cells and of Ito recorded from native rat ventricular cells were exponentials with time constants of 213.2±4.1 msec and 23.±1.5 msec, respectively. Pharmacologically, Ito of rat myocytes showed a greater sensitivity to 4-aminopyridine than Kv4.3 since half-maximal effects were obtained with 1.54±0.13 mM and 0.14±0.02 mM on Kv4.3 and Ito, respectively. In both Kv4.3 and Ito, 4-aminopyridine appears to bind to the closed state of the channel. Finally, although a higher level of expression was observed in the atria compared to the ventricle, the distribution of the Kv4.3 gene across the ventricles appeared to be homogenous. Conclusion: The results of the present study show that Kv4.3 channel may play a major role in the molecular structure of the rat cardiac Ito current. Furthermore, because the distribution of Kv4.3 across the ventricle is homogenous, the blockade of this channel by specific drugs may not alter the normal heterogeneity of Ito current. [ABSTRACT FROM PUBLISHER]

Objective: The effects of BRL-32872, azimilide and a selective blocker of the delayed rectifier potassium current, E-4031, were measured at two different basic cycle lengths (BCL), 300 and 1000 ms. Calcium channel antagonists of sarcolemmal (verapamil and nitrendipine) and sarcoplasmic reticulum (ryanodine) membranes were used to investigate whether the inhibition of the calcium current or the calcium release from the sarcoplasmic reticulum could alter the reverse-rate dependence of E-4031 on action potential duration (APD). Methods: Guinea pig isolated papillary muscles were superfused with a Tyrode solution maintained at 37°C and stimulated at a BCL of 300 or 1000 ms. The standard microelectrode technique was used to record action potential parameters and to study the effects of azimilide, BRL-32872 and E-4031. E-4031 was superfused at increasing concentrations (0.01, 0.03, 0.1 and 0.3 μM) in the absence or in the presence of verapamil (0.3 μM), nitrendipine (0.03 μM) or ryanodine (0.1 μM). Results: BRL-32872 and azimilide induced a self-limited concentration-dependent increase in APD. The effect of BRL-32872 was not dependent on the stimulation frequency whereas the effect of azimilide was significantly reduced at the shorter BCL. E-4031 induced a concentration-dependent increase in APD at both stimulation BCL. The increase in APD was significantly more pronounced in fibres stimulated at a BCL of 1000 ms than in fibres stimulated at a BCL of 300 ms, characterising the reverse-frequency dependent effect of class III antiarrhythmic agents. The reverse-frequency dependence in action potential prolongation induced by E-4031 was significantly reduced in the presence of a low concentration of verapamil (0.3 μM), nitrendipine (0.03 μM), or ryanodine (0.1 μM). Conclusion: The results show that BRL-32872, in contrast to azimilide, does not induce the reverse-rate dependency of action potential prolongation typically produced by class III antiarrhythmic agents such as E-4031. Our results also show that reverse-rate dependency induced by E-4031 can be reduced by the simultaneous administration of a low concentration of a calcium channel antagonist or an inhibitor of the release of calcium from the sarcoplasmic reticulum. It is thus suggested that compounds with a suitable balance of potassium and calcium antagonistic activities may have less adverse effects than purely selective potassium channel blockers. [ABSTRACT FROM PUBLISHER]

Background: Human cardiac stem cells expressing the W8B2 marker (W8B2+ CSCs) were recently identified and proposed as a new model of multipotent CSCs capable of differentiating into smooth muscle cells, endothelial cells and immature myocytes. Nevertheless, no characterization of ion channel or calcium activity during the differentiation of these stem cells has been reported. Methods: The objectives of this study were thus to analyze (using the TaqMan Low-Density Array technique) the gene profile of W8B2+ CSCs pertaining to the regulation of ion channels, transporters and other players involved in the calcium homeostasis of these cells. We also analyzed spontaneous calcium activity (via the GCaMP calcium probe) during the in vitro differentiation of W8B2+ CSCs into cardiac myocytes. Results: Our results show an entirely different electrophysiological genomic profile between W8B2+ CSCs before and after differentiation. Some specific nodal genes, such as Tbx3, HCN, ICaT, L, KV, and NCX, are overexpressed after this differentiation. In addition, we reveal spontaneous calcium activity or a calcium clock whose kinetics change during the differentiation process. A pharmacological study carried out on differentiated W8B2+ CSCs showed that the NCX exchanger and IP3 stores play a fundamental role in the generation of these calcium oscillations. Conclusions: Taken together, the present results provide important information on ion channel expression and intrinsic calcium dynamics during the differentiation process of stem cells expressing the W8B2 marker. [ABSTRACT FROM AUTHOR]