A Multi-Centre, Double-Blind, Randomised, Placebo-Controlled Phase II Study to Assess the Effects on Atrial and Ventricular Refractoriness of an Intravenous Infusion of AZD2927 in Patients Undergoing an Invasive Electrophysiological Procedure

Medical Products Agency

开始日期2011-09-01

申办/合作机构

AstraZeneca PLC

NCT01264250 / Completed临床1期

A Phase I, Single-centre, Single-blind, Randomised, Placebo-controlled, Single-dose Study to Assess the Safety, Tolerability and Pharmacokinetics After Single Ascending Intravenous Doses of AZD2927 in Healthy Male Subjects

In this early phase study, healthy male volunteers will be randomly assigned to one dose of either AZD2927 or placebo. The objective will be to assess the Safety,Tolerability and Pharmacokinetics of AZD2927.

开始日期2011-01-01

申办/合作机构

AstraZeneca PLC

100 项与 Kir3.4 x Kir3.1 相关的临床结果

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100 项与 Kir3.4 x Kir3.1 相关的转化医学

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0 项与 Kir3.4 x Kir3.1 相关的专利（医药）

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项与 Kir3.4 x Kir3.1 相关的文献（医药）

2024-05-01·Journal of Biological Chemistry

Structural determinants of the direct inhibition of GIRK channels by Sigma-1 receptor antagonist

Article

作者: Kubo, Yoshihiro ; Tateyama, Michihiro ; Liu, Chang ; Chen, I-Shan

G-protein-gated inward rectifier K⁺ (GIRK) channels play a critical role in the regulation of the excitability of cardiomyocytes and neurons and include GIRK1, GIRK2, GIRK3 and GIRK4 subfamily members. BD1047 dihydrobromide (BD1047) is one of the representative antagonists of the multifunctional Sigma-1 receptor (S1R). In the analysis of the effect of BD1047 on the regulation of Gi-coupled receptors by S1R using GIRK channel as an effector, we observed that BD1047, as well as BD1063, directly inhibited GIRK currents even in the absence of S1R and in a voltage-independent manner. Thus, we aimed to clarify the effect of BD1047 on GIRK channels and identify the structural determinants. By electrophysiological recordings in Xenopus oocytes, we observed that BD1047 directly inhibited GIRK channel currents, producing a much stronger inhibition of GIRK4 compared to GIRK2. It also inhibited ACh-induced native GIRK current in isolated rat atrial myocytes. Chimeric and mutagenesis studies of GIRK2 and GIRK4 combined with molecular docking analysis demonstrated the importance of Leu77 and Leu84 within the cytoplasmic, proximal N-terminal region and Glu147 within the pore-forming region of GIRK4 for inhibition by BD1047. The activator of GIRK channels, ivermectin, competed with BD1047 at Leu77 on GIRK4. This study provides us with a novel inhibitor of GIRK channels and information for developing pharmacological treatments for GIRK4-associated diseases.

2024-01-01·Cell Calcium

TRPV2 inhibitor tranilast prevents atrial fibrillation in rat models of pulmonary hypertension

Article

作者: Liu, Xin ; Yang, Bo ; Zhou, Yunping ; Zhang, Cui ; Yu, Fangcong ; Chu, Yanan ; Wang, Xingxiang ; Song, Zhuonan ; Yu, Yi ; Liu, Zhangchi ; Shi, Jiaran ; Wang, Longbo ; Yang, Jinxiu ; Ye, Tianxin

Atrial fibrillation (AF) is common in pulmonary hypertension (PH), whereas the mechanisms and treatments remain to be explored. TRPV2 regulates the structure and function of the cardiovascular system; however, little attention has been given to its role in AF. This study was to determine whether TRPV2 was involved in PH-induced AF and the effects of TRPV2 inhibitor tranilast on AF in rat models of PH. Monocrotaline (MCT) and SU5416/hypoxia (SuHx)-induced PH models were performed to detect atrial electrophysiological parameters. Daily tranilast (a TRPV2 inhibitor) or saline was given starting 1 day before PH establishment. PH increased the susceptibility to AF, with TRPV2 up-regulated in the right atria. Compared to PH rats, tranilast reduced AF inducibility and the prolongations of ERP and APD; mitigated cardiopulmonary remodeling and the increases in P-wave duration and P-R interval; partially reversed the down-regulation of ion channels such as Cav1.2, Nav1.5, Kv4.3, Kv4.2, Kv1.5, Kir2.1, Kir3.1, Kir3.4 as well as connexin (Cx) 40 and Cx43; improved right atrial (RA) fibrosis, enlargement, and myocardial hypertrophy; decreased the accumulation of inflammatory cells; down-regulated inflammatory indicators such as TNF-α, IL-1β, CXCL1, and CXCL2; and inhibited the activation of the PI3K-AKT-NF-κB signaling pathway. Our results reveal that TRPV2 participates in PH-induced AF, and TRPV2 inhibitor tranilast prevents PH-induced RA remodeling. TRPV2 might be a promising target for PH-induced AF.

2023-10-18·International journal of molecular sciences

The W101C KCNJ5 Mutation Induces Slower Pacing by Constitutively Active GIRK Channels in hiPSC-Derived Cardiomyocytes.

Article

作者: Šarić, Tomo ; Kayser, Anne ; Mearini, Giulia ; Dittmann, Sven ; Verkerk, Arie O ; Schulze-Bahr, Eric

Mutations in the KCNJ5 gene, encoding one of the major subunits of cardiac G-protein-gated inwardly rectifying K⁺ (GIRK) channels, have been recently linked to inherited forms of sinus node dysfunction. Here, the pathogenic mechanism of the W101C KCNJ5 mutation underlying sinus bradycardia in a patient-derived cellular disease model of sinus node dysfunction (SND) was investigated. A human-induced pluripotent stem cell (hiPSCs) line of a mutation carrier was generated, and CRISPR/Cas9-based gene targeting was used to correct the familial mutation as a control line. Both cell lines were further differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed GIRK channels which underly the acetylcholine-regulated K⁺ current (I_K,ACh). hiPSC-CMs with the W101C KCNJ5 mutation (hiPSC^W101C-CM) had a constitutively active I_K,ACh under baseline conditions; the application of carbachol was able to increase I_K,ACh, further indicating that not all available cardiac GIRK channels were open at baseline. Additionally, hiPSC^W101C-CM had a more negative maximal diastolic potential (MDP) and a slower pacing frequency confirming the bradycardic phenotype. Of note, the blockade of the constitutively active GIRK channel with XAF-1407 rescued the phenotype. These results provide further mechanistic insights and may pave the way for the treatment of SND patients with GIRK channel dysfunction.