Novel oestrogen receptor beta-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

Hormonal changes due to menopause can cause various health problems including weight gain and depressive symptoms. Multiple lines of evidence indicate that oestrogen receptors (ERs) play a major role in postmenopausal obesity and depression. However, little is known regarding the ER subtype-specific effects on obesity and depressive symptoms. To delineate potential effects of ER beta activation in postmenopausal women, we investigated the effects of a novel oestrogen receptor beta-selective ligand (C-1) in ovariectomized mice. Uterine weight, depressive behaviour, and weight gain were examined in sham-operated control mice and ovariectomized mice administered placebo, C-1, or 17 beta-oestradiol (E2). Administration of C-1 or E2 reduced body weight gain and depressive-like behaviour in ovariectomized mice, as assessed by the forced swim test. In addition, administration of E2 to ovariectomized mice increased uterine weight, but administration of C-1 did not result in a significant increase in uterine weight. These results suggest that the selective activation of ERa in ovariectomized mice may have protective effects against obesity and depressive-like behaviour without causing an increase in uterine weight. The present findings raise the possibility of the application of ER beta-ligands such as C-1 as a novel treatment for obesity and depression in postmenopausal women.ArticleSCIENTIFIC REPORTS. 7:4663 (2017)journal articl

Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome Multicenter study in Japan

AbstractObjectivesWe sought to compare the arrhythmic risk and sensitivity to sympathetic stimulation of mutations located in transmembrane regions and C-terminal regions of the KCNQ1channel in the LQT1 form of congenital long QT syndrome (LQTS).BackgroundThe LQT1 syndrome is frequently manifested with variable expressivity and incomplete penetrance and is much more sensitive to sympathetic stimulation than the other forms.MethodsSixty-six LQT1 patients (27 families) with a total of 19 transmembrane mutations and 29 patients (10 families) with 8 C-terminal mutations were enrolled from five Japanese institutes.ResultsPatients with transmembrane mutations were more frequently affected based on electrocardiographic (ECG) diagnostic criteria (82% vs. 24%, p < 0.0001) and had more frequent LQTS-related cardiac events (all cardiac events: 55% vs. 21%, p = 0.002; syncope: 55% vs. 21%, p = 0.002; aborted cardiac arrest or unexpected sudden cardiac death: 15% vs. 0%, p = 0.03) than those with C-terminal mutations. Patients with transmembrane mutations had a greater risk of first cardiac events occurring at an earlier age, with a hazard ratio of 3.4 (p = 0.006) and with an 8% increase in risk per 10-ms increase in corrected Q-Tend. The baseline ECG parameters, including Q-Tend, Q-Tpeak, and Tpeak-end intervals, were significantly greater in patients with transmembrane mutations than in those with C-terminal mutations (p < 0.005). Moreover, the corrected Q-Tend and Tpeak-end were more prominently increased with exercise in patients with transmembrane mutations (p < 0.005).ConclusionsIn this multicenter Japanese population, LQT1 patients with transmembrane mutations are at higher risk of congenital LQTS-related cardiac events and have greater sensitivity to sympathetic stimulation, as compared with patients with C-terminal mutations

Triggers of ventricular tachyarrhythmias and therapeutic effects of nicorandil in canine models of LQT2 and LQT3 syndromes

AbstractObjectivesWe sought to identify the triggers of ventricular tachyarrhythmia (VTA) in experimental models of long QT type 2 (LQT2) and long QT type 3 (LQT3) syndromes.BackgroundMost adverse cardiac events occurring in the long QT type 1 syndrome are related to sympathetic nerve activity. In contrast, various factors may trigger VTA in patients with LQT2 and LQT3.MethodsThe mode of onset of VTA and therapeutic effects of the potassium-adenosine triphosphate channel opener nicorandil were compared in canine models of LQT2 and LQT3, using three induction protocols: 1) bradycardia produced by atrioventricular block (BRADY); 2) programmed ventricular stimulation; and 3) electrical stimulation of the left stellate ganglion (left stellate stimulation [LSS]). Transmural unipolar electrograms were recorded, and the activation-recovery interval (ARI) was measured.ResultsVentricular tachyarrhythmias developed during BRADY in all six experiments in the LQT3 model, but in none of the six experiments in LQT2. Programmed ventricular stimulation induced VTA in two experiments of the LQT2 model, but in none of the LQT3 experiments. Stimulation of the left stellate ganglion induced VTA in three experiments in LQT2 and in two experiments in LQT3. Nicorandil caused greater shortening of ARI and greater attenuation of transmural ARI dispersion in the LQT2 model than in the LQT3 model. After treatment with nicorandil, a single VTA was induced in the LQT2 model by LSS, whereas in the LQT3 model, VTA remained inducible by BRADY in four experiments and LSS in one experiment.ConclusionsAn abrupt increase in sympathetic activity appeared arrhythmogenic in both models. Nicorandil attenuated the heterogeneity of ventricular repolarization and suppressed the induction of VTA in the LQT2 model, but had a limited therapeutic effect in the LQT3 model