更新于：2024-11-01

PDE4 x PDE3 x calcium channel

更新于：2024-11-01

基本信息

关联

项与 PDE4 x PDE3 x calcium channel 相关的药物

ORG-30029

靶点

PDE3 x PDE4 x calcium channel

作用机制

PDE3抑制剂 [+2]

在研机构-

原研机构

Akzo Nobel NV

在研适应症-

非在研适应症

心脏衰竭

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PDE4 x PDE3 x calcium channel 相关的临床结果

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100 项与 PDE4 x PDE3 x calcium channel 相关的转化医学

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0 项与 PDE4 x PDE3 x calcium channel 相关的专利（医药）

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项与 PDE4 x PDE3 x calcium channel 相关的文献（医药）

2024-06-18·Journal of the American Heart Association

Differential Downregulation of β ₁ ‐Adrenergic Receptor Signaling in the Heart

Article

作者: Bahriz, Sherif ; Wang, Ying ; Salemme, Victoria R ; Xu, Bing ; Zhao, Meimi ; Xiang, Yang K ; Zhu, Chaoqun

Background Chronic sympathetic stimulation drives desensitization and downregulation of β1 adrenergic receptor (β 1 AR) in heart failure. We aim to explore the differential downregulation subcellular pools of β 1 AR signaling in the heart. Methods and Results We applied chronic infusion of isoproterenol to induced cardiomyopathy in male C57BL/6J mice. We applied confocal and proximity ligation assay to examine β 1 AR association with L‐type calcium channel, ryanodine receptor 2, and SERCA2a ((Sarco)endoplasmic reticulum calcium ATPase 2a) and Förster resonance energy transfer‐based biosensors to probe subcellular β 1 AR‐PKA (protein kinase A) signaling in ventricular myocytes. Chronic infusion of isoproterenol led to reduced β 1 AR protein levels, receptor association with L‐type calcium channel and ryanodine receptor 2 measured by proximity ligation (puncta/cell, 29.65 saline versus 14.17 isoproterenol, P <0.05), and receptor‐induced PKA signaling at the plasma membrane (Förster resonance energy transfer, 28.9% saline versus 1.9% isoproterenol, P <0.05) and ryanodine receptor 2 complex (Förster resonance energy transfer, 30.2% saline versus 10.6% isoproterenol, P <0.05). However, the β 1 AR association with SERCA2a was enhanced (puncta/cell, 51.4 saline versus 87.5 isoproterenol, P <0.05), and the receptor signal was minimally affected. The isoproterenol‐infused hearts displayed decreased PDE4D (phosphodiesterase 4D) and PDE3A and increased PDE2A, PDE4A, and PDE4B protein levels. We observed a reduced role of PDE4 and enhanced roles of PDE2 and PDE3 on the β 1 AR‐PKA activity at the ryanodine receptor 2 complexes and myocyte shortening. Despite the enhanced β 1 AR association with SERCA2a, the endogenous norepinephrine‐induced signaling was reduced at the SERCA2a complexes. Inhibiting monoamine oxidase A rescued the norepinephrine‐induced PKA signaling at the SERCA2a and myocyte shortening. Conclusions This study reveals distinct mechanisms for the downregulation of subcellular β 1 AR signaling in the heart under chronic adrenergic stimulation.

2021-01-01·Journal of Molecular and Cellular Cardiology2区 · 医学

Selective changes in cytosolic β-adrenergic cAMP signals and L-type Calcium Channel regulation by Phosphodiesterases during cardiac hypertrophy

2区 · 医学

Article

作者: Fischmeister, Rodolphe ; Abi-Gerges, Aniella ; Leroy, Jérôme ; Vandecasteele, Grégoire ; Domergue, Valérie ; Castro, Liliana

Background In cardiomyocytes, phosphodiesterases (PDEs) type 3 and 4 are the predominant enzymes that degrade cAMP generated by β-adrenergic receptors (β-ARs), impacting notably the regulation of the L-type Ca²⁺ current (I_Ca,L). Cardiac hypertrophy (CH) is accompanied by a reduction in PDE3 and PDE4, however, whether this affects the dynamic regulation of cytosolic cAMP and I_Ca,L is not known. Methods and Results CH was induced in rats by thoracic aortic banding over a time period of five weeks and was confirmed by anatomical measurements. Left ventricular myocytes (LVMs) were isolated from CH and sham-operated (SHAM) rats and transduced with an adenovirus encoding a Förster resonance energy transfer (FRET)-based cAMP biosensor or subjected to the whole-cell configuration of the patch-clamp technique to measure I_Ca,L. Aortic stenosis resulted in a 46% increase in heart weight to body weight ratio in CH compared to SHAM. In SHAM and CH LVMs, a short isoprenaline stimulation (Iso, 100 nM, 15 s) elicited a similar transient increase in cAMP with a half decay time (t_1/2off) of ~50 s. In both groups, PDE4 inhibition with Ro 20-1724 (10 μM) markedly potentiated the amplitude and slowed the decline of the cAMP transient, this latter effect being more pronounced in SHAM (t_1/2off ~ 250 s) than in CH (t_1/2off ~ 150 s, P < 0.01). In contrast, PDE3 inhibition with cilostamide (1 μM) had no effect on the amplitude of the cAMP transient and a minimal effect on its recovery in SHAM, whereas it potentiated the amplitude and slowed the decay in CH (t_1/2off ~ 80 s). Iso pulse stimulation also elicited a similar transient increase in I_Ca,L in SHAM and CH, although the duration of the rising phase was delayed in CH. Inhibition of PDE3 or PDE4 potentiated I_Ca,L amplitude in SHAM but not in CH. Besides, while only PDE4 inhibition slowed down the decline of I_Ca,L in SHAM, both PDE3 and PDE4 contributed in CH. Conclusion These results identify selective alterations in cytosolic cAMP and I_Ca,L regulation by PDE3 and PDE4 in CH, and show that the balance between PDE3 and PDE4 for the regulation of β-AR responses is shifted toward PDE3 during CH.

2019-11-01·Canadian Journal of Physiology and Pharmacology4区 · 医学

The contribution of phosphodiesterases to cardiac dysfunction in rats with metabolic syndrome induced by a high-carbohydrate diet

4区 · 医学

Article

作者: Turan, Belma ; Okatan, Esma N.

Metabolic syndrome (MetS) is a cluster of risk factors, including insulin resistance among others, underlying the development of diabetes and (or) cardiovascular diseases. Studies show a close relationship between cardiac dysfunction and abnormal cAMP catabolism, which contributes to pathological remodelling. Stimulating the synthesis of cAMP via suppression of phosphodiesterases (PDEs) has positive therapeutic effects. Therefore, we examined the role of PDEs on cardiac dysfunction in high-carbohydrate diet-induced MetS rats. We first demonstrated significantly high expression levels of PDE3 and PDE4, the most highly expressed subtypes, together with depressed cAMP levels in heart tissue from MetS rats. Second, we demonstrated the activity of these PDEs by using either their basal or PDE inhibitor-induced intracellular levels of cAMP and Ca2+, the transient intracellular Ca2+ changes under electrical stimulation, isometric contractions in papillary muscle strips and some key signalling proteins (such as RyR2, PLN, PP1A, and PKA) are responsible for the Ca2+ homeostasis in isolated cardiomyocytes from MetS rats. The clear recovery in decreased basal cAMP levels, increased protein expression levels of PDE3 and PDE4, and positive responses in the altered Ca2+ homeostasis to PDE inhibitors as seen in our study can provide important insights about the roles of activated PDEs in depressed contractile activity in hearts from MetS rats.