A Novel Pan-Negative-Gating Modulator of K<sub>Ca</sub>2/3 Channels, Fluoro-Di-Benzoate, RA-2, Inhibits Endothelium-Derived Hyperpolarization–Type Relaxation in Coronary Artery and Produces Bradycardia In Vivo

Oliván-Viguera, Aida; Valero, Marta Sofía; Coleman, Nicole; Brown, Brandon M.; Laría, Celia; Murillo, María Divina; Gálvez, José A.; Dı́az-de-Villegas, Marı́a D.; Wulff, Heike; Badorrey, Ramón; Köhler, Ralf

doi:10.1124/mol.114.095745

Cited by 20 publications

(11 citation statements)

References 62 publications

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“…An indirect impact of TRAM‐34 or clotrimazole on autonomic input to SA and AV nodes in vivo can be excluded because both blockers exert similar effects on isolated SAN cells. In line with these data, RA‐2, a structurally different molecule from TRAM‐34 and clotrimazole, with a mixed blocker activity toward SK4 and SK2 channels, induced bradycardia in mice, an effect abolished in SK4 knockout mice (Olivan‐Viguera et al , ).…”

Section: Discussionmentioning

confidence: 69%

SK 4 K ⁺ channels are therapeutic targets for the treatment of cardiac arrhythmias

et al. 2017

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress‐provoked ventricular arrhythmia, which also manifests sinoatrial node (SAN) dysfunction. We recently showed that SK4 calcium‐activated potassium channels are important for automaticity of cardiomyocytes derived from human embryonic stem cells. Here SK4 channels were identified in human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) from healthy and CPVT2 patients bearing a mutation in calsequestrin 2 (CASQ2‐D307H) and in SAN cells from WT and CASQ2‐D307H knock‐in (KI) mice. TRAM‐34, a selective blocker of SK4 channels, prominently reduced delayed afterdepolarizations and arrhythmic Ca2+ transients observed following application of the β‐adrenergic agonist isoproterenol in CPVT2‐derived hiPSC‐CMs and in SAN cells from KI mice. Strikingly, in vivo ECG recording showed that intraperitoneal injection of the SK4 channel blockers, TRAM‐34 or clotrimazole, greatly reduced the arrhythmic features of CASQ2‐D307H KI and CASQ2 knockout mice at rest and following exercise. This work demonstrates the critical role of SK4 Ca2+‐activated K+ channels in adult pacemaker function, making them promising therapeutic targets for the treatment of cardiac ventricular arrhythmias such as CPVT.

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Section: Discussionmentioning

confidence: 69%

SK 4 K ⁺ channels are therapeutic targets for the treatment of cardiac arrhythmias

et al. 2017

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“…B,C). The negative‐gating modulator, RA‐2 (1 μM), that directly suppresses positive‐gating modulation potently blocked all K Ca current (not shown) and a small TRAM‐34/UCL‐1684‐resistant K Ca current (fig. B,C), which may suggest incomplete block of porcine K Ca 3.1 by the pore blocker, TRAM‐34 .…”

Section: Resultsmentioning

confidence: 93%

Vascular Reactivity Profile of Novel K_Ca3.1‐Selective Positive‐Gating Modulators in the Coronary Vascular Bed

Oliván-Viguera

Valero

Pinilla

et al. 2016

Basic Clin Pharma Tox

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Opening of intermediate-conductance calcium-activated potassium channels (KCa3.1) produces membrane hyperpolarization in the vascular endothelium. Here, we studied the ability of two new KCa3.1-selective positive-gating modulators, SKA-111 and SKA-121, to (1) evoke porcine endothelial cell KCa3.1 membrane hyperpolarization, (2) induce endothelium-dependent and, particularly, endothelium-derived hyperpolarization (EDH)-type relaxation in porcine coronary arteries (PCA) and (3) influence coronary artery tone in isolated rat hearts. In whole-cell patch-clamp experiments on endothelial cells of PCA (PCAEC), KCa currents evoked by bradykinin (BK) were potentiated ≈7-fold by either SKA-111 or SKA-121 (both at 1 μM) and were blocked by a KCa3.1 blocker, TRAM-34. In membrane potential measurements, SKA-111 and SKA-121 augmented bradykinin-induced hyperpolarization. Isometric tension measurements in large- and small-calibre PCA showed that SKA-111 and SKA-121 potentiated endothelium-dependent relaxation with intact NO synthesis and EDH-type relaxation to BK by ≈2-fold. Potentiation of the BK response was prevented by KCa3.1 inhibition. In Langendorff-perfused rat hearts, SKA-111 potentiated coronary vasodilation elicited by BK. In conclusion, our data show that positive-gating modulation of KCa3.1 channels improves BK-induced membrane hyperpolarization and endothelium-dependent relaxation in small and large PCA as well as in the coronary circulation of rats. Positive-gating modulators of KCa3.1 could be therapeutically useful to improve coronary blood flow and counteract impaired coronary endothelial dysfunction in cardiovascular disease.

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“…) or the novel negative‐gating modulator, the dibenzoate ester, RA‐2 (Olivan‐Viguera et al . ), may prevent lung oedema formation when applied from the bronchial side to minimize potential systemic effects on blood pressure. While this is hypothetical for the lung, there are studies on the brain that suggest such utilities for prevention of oedema: a cyclohexadiene compound efficiently reduces brain oedema in a rat acute subdural haematoma model (Mauler et al .…”

Section: Do Kca31 Blockers Have Therapeutic Utility Against Pulmonarmentioning

confidence: 99%

Emerging roles of calcium-activated K channels and TRPV4 channels in lung oedema and pulmonary circulatory collapse

et al. 2016

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It has been suggested that the transient receptor potential cation (TRP) channel subfamily V (vanilloid) type 4 (TRPV4) and intermediate conductance calcium-activated potassium (KCa3.1) channels contribute to endothelium-dependent vasodilation. Here, we summarize very recent evidence for a synergistic interplay of TRPV4 and KCa3.1 channels in lung disease. Among the endothelial Ca 2+ -permeable TRPs, TRPV4 is best characterized and produces arterial dilation by stimulating Ca 2+ -dependent nitric oxide synthesis and endothelium-dependent hyperpolarization. Besides these roles, some TRP channels control endothelial/epithelial barrier functions and vascular integrity, while KCa3.1 channels provide the driving force required for Cl À and water transport in some cells and most secretory epithelia. The three conditions, increased pulmonary venous pressure caused by left heart disease, high inflation pressure and chemically induced lung injury, may lead to activation of TRPV4 channels followed by Ca 2+ influx leading to activation of KCa3.1 channels in endothelial cells ultimately leading to acute lung injury. We find that a deficiency in KCa3.1 channels protects against TRPV4-induced pulmonary arterial relaxation, fluid extravasation, haemorrhage, pulmonary circulatory collapse and cardiac arrest in vivo. These data identify KCa3.1 channels as crucial molecular components in downstream TRPV4 signal transduction and as a potential target for the prevention of undesired fluid extravasation, vasodilatation and pulmonary circulatory collapse.

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A Novel Pan-Negative-Gating Modulator of K_Ca2/3 Channels, Fluoro-Di-Benzoate, RA-2, Inhibits Endothelium-Derived Hyperpolarization–Type Relaxation in Coronary Artery and Produces Bradycardia In Vivo

Cited by 20 publications

References 62 publications

SK 4 K ⁺ channels are therapeutic targets for the treatment of cardiac arrhythmias

SK 4 K ⁺ channels are therapeutic targets for the treatment of cardiac arrhythmias

Vascular Reactivity Profile of Novel K_Ca3.1‐Selective Positive‐Gating Modulators in the Coronary Vascular Bed

Emerging roles of calcium-activated K channels and TRPV4 channels in lung oedema and pulmonary circulatory collapse

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A Novel Pan-Negative-Gating Modulator of KCa2/3 Channels, Fluoro-Di-Benzoate, RA-2, Inhibits Endothelium-Derived Hyperpolarization–Type Relaxation in Coronary Artery and Produces Bradycardia In Vivo

Cited by 20 publications

References 62 publications

SK 4 K + channels are therapeutic targets for the treatment of cardiac arrhythmias

SK 4 K + channels are therapeutic targets for the treatment of cardiac arrhythmias

Vascular Reactivity Profile of Novel KCa3.1‐Selective Positive‐Gating Modulators in the Coronary Vascular Bed

Emerging roles of calcium-activated K channels and TRPV4 channels in lung oedema and pulmonary circulatory collapse

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A Novel Pan-Negative-Gating Modulator of K_Ca2/3 Channels, Fluoro-Di-Benzoate, RA-2, Inhibits Endothelium-Derived Hyperpolarization–Type Relaxation in Coronary Artery and Produces Bradycardia In Vivo

SK 4 K ⁺ channels are therapeutic targets for the treatment of cardiac arrhythmias

SK 4 K ⁺ channels are therapeutic targets for the treatment of cardiac arrhythmias

Vascular Reactivity Profile of Novel K_Ca3.1‐Selective Positive‐Gating Modulators in the Coronary Vascular Bed