Efficient and specific cardiac IK1 inhibition by a new pentamidine analogue

Takanari, Hiroki; Nalos, Lukáš; Stary-Weinzinger, Anna; de, Kathy C G; Varkevisser, Rosanne; Linder, Tobias; Houtman, Marien J C; Peschar, Maaike; Boer, Teun P. de; Tidwell, Richard R.; Rook, Martin B.; Vos, Marc A.; Heyden, Marcel A.G. van der

doi:10.1093/cvr/cvt103

Cited by 38 publications

(64 citation statements)

References 46 publications

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“…To illustrate, consider the partial inhibition of K + currents (for increasing APD 90 and thus ERP), in combination with drugs aimed at increasing CaT amp (for restoring contractility). Partial block of NKA with digoxin, combined with reduced RyR Ca 2+ leak using a calmodulin kinase II inhibitor, appeared to be beneficial in single cell simulations (Figure S11) and may actually become feasible in the near future, as novel specific blockers of I K1 are being developed [34]. The 1D restitution results (Figure S12) also illustrated increases in APD, ERP, CV and WL, which may be desirable in terms of protecting against arrhythmia.…”

Section: Discussionmentioning

confidence: 99%

In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation

et al. 2014

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Chronic atrial fibrillation (AF) is a complex disease with underlying changes in electrophysiology, calcium signaling and the structure of atrial myocytes. How these individual remodeling targets and their emergent interactions contribute to cell physiology in chronic AF is not well understood. To approach this problem, we performed in silico experiments in a computational model of the human atrial myocyte. The remodeled function of cellular components was based on a broad literature review of in vitro findings in chronic AF, and these were integrated into the model to define a cohort of virtual cells. Simulation results indicate that while the altered function of calcium and potassium ion channels alone causes a pronounced decrease in action potential duration, remodeling of intracellular calcium handling also has a substantial impact on the chronic AF phenotype. We additionally found that the reduction in amplitude of the calcium transient in chronic AF as compared to normal sinus rhythm is primarily due to the remodeling of calcium channel function, calcium handling and cellular geometry. Finally, we found that decreased electrical resistance of the membrane together with remodeled calcium handling synergistically decreased cellular excitability and the subsequent inducibility of repolarization abnormalities in the human atrial myocyte in chronic AF. We conclude that the presented results highlight the complexity of both intrinsic cellular interactions and emergent properties of human atrial myocytes in chronic AF. Therefore, reversing remodeling for a single remodeled component does little to restore the normal sinus rhythm phenotype. These findings may have important implications for developing novel therapeutic approaches for chronic AF.

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Section: Discussionmentioning

confidence: 99%

In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation

et al. 2014

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“…24 This study indicates that KCNJ2 is similarly predominant in fibroblasts: DN-KCNJ2 almost completely eliminated fibroblast I K1 ( Figure 5B, inset). I K1 blockers are being developed as potential antiarrhythmic molecules, 25,26 based on their ability to inhibit cardiomyocyte I K1 and destabilize AF-maintaining rotors. 26,27 An additional potentially interesting consequence, based on the work reported here, might be the suppression of atrial fibrosis.…”

Section: Novel Elements and Potential Significancementioning

confidence: 99%

Fibroblast Inward-Rectifier Potassium Current Upregulation in Profibrillatory Atrial Remodeling

Huang

Ördög

et al. 2015

Circulation Research

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Rationale: Fibroblasts are involved in cardiac arrhythmogenesis and contribute to the atrial fibrillation substrate in congestive heart failure (CHF) by generating tissue fibrosis. Fibroblasts display robust ion currents, but their functional importance is poorly understood. Objective: To characterize atrial fibroblast inward-rectifier K + current ( I K1 ) remodeling in CHF and its effects on fibroblast properties. Methods and Results: Freshly isolated left atrial fibroblasts were obtained from controls and dogs with CHF (ventricular tachypacing). Patch clamp was used to record resting membrane potential (RMP) and I K1 . RMP was significantly increased by CHF (from −43.2±0.8 mV, control, to −55.5±0.9 mV). CHF upregulated I K1 (eg, at −90 mV from −1.1±0.2 to −2.7±0.5 pA/pF) and increased the expression of KCNJ2 mRNA (by 52%) and protein (by 80%). Ba 2+ (300 μmol/L) decreased the RMP and suppressed the RMP difference between controls and dogs with CHF. Store-operated Ca 2+ entry (Fura-2-acetoxymethyl ester) and fibroblast proliferation (flow cytometry) were enhanced by CHF. Lentivirus-mediated overexpression of KCNJ2 enhanced I K1 and hyperpolarized fibroblasts. Functional KCNJ2 suppression by lentivirus-mediated expression of a dominant negative KCNJ2 construct suppressed I K1 and depolarized RMP. Overexpression of KCNJ2 increased Ca 2+ entry and fibroblast proliferation, whereas the dominant negative KCNJ2 construct had opposite effects. Fibroblast hyperpolarization to mimic CHF effects on RMP enhanced the Ca 2+ entry. MicroRNA-26a, which targets KCNJ2, was downregulated in CHF fibroblasts. Knockdown of endogenous microRNA-26 to mimic CHF effects unregulated I K1 . Conclusions: CHF upregulates fibroblast KCNJ2 expression and currents, thereby hyperpolarizing RMP, increasing Ca 2+ entry, and enhancing atrial fibroblast proliferation. These effects are likely mediated by microRNA-26a downregulation. Remodeling-induced fibroblast KCNJ2 expression changes may play a role in atrial fibrillation promoting fibroblast remodeling and structural/arrhythmic consequences.

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“…In an effort to develop more specific Kir2.1 probes, the investigators analyzed a series of pentamidine analogs for activity toward Kir2.x and several other cardiac ion channels [27]. One compound termed PA-6 exhibited ~15 nM affinity toward Kir2.1, Kir2.2, and Kir2.3, but no discernible activity toward cardiac sodium, calcium, and potassium currents.…”

Section: Cardiac Kir2x Channelsmentioning

confidence: 99%

“…chloroquine [18], pentamidine [25,27], flecainide [33], fluoxetine [46,56], and nortriptyline [47]; Table 1) exhibiting Kir channel-directed activity creates opportunities for engineering more potent and selective Kir channel modulators from these chemical scaffolds (e.g. [27]). Chemically unique Kir channel inhibitors have been discovered in publically funded, large-scale screens of diverse chemical libraries, the results of which are deposited in well-annotated databases (http://pubchem.ncbi.nlm.nih.gov/).…”

Section: Cardiac Kir2x Channelsmentioning

confidence: 99%

Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

Swale¹,

Kharade²,

Denton³

2014

Current Opinion in Pharmacology

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Inward rectifier potassium (Kir) channels play fundamental roles in cardiac and renal function and may represent unexploited drug targets for cardiovascular diseases. However, the limited pharmacology of Kir channels has slowed progress toward exploring their integrative physiology and therapeutic potential. Here, we review recent progress toward developing the small-molecule pharmacology for Kir2.x, Kir4.1, and Kir7.1 and discuss common mechanistic themes that may help guide future Kir channel-directed drug discovery efforts.

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Efficient and specific cardiac IK1 inhibition by a new pentamidine analogue

Abstract: PA-6 has higher efficiency and specificity to KIR2.x-mediated current than P, lengthens action potential duration, and does not affect channel trafficking at concentrations relevant for complete IK₁ block.

Cited by 38 publications

References 46 publications

In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation

In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation

Fibroblast Inward-Rectifier Potassium Current Upregulation in Profibrillatory Atrial Remodeling

Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

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