The transient receptor potential melastatin 4 channel inhibitor 9‐phenanthrol modulates cardiac sodium channel

Hou, Jianwen; Fei, Yudong; Li, Wei; Chen, Yihe; Wang, Qian; Xiao, Ying; Wang, Yuepeng; Li, Yi‐Gang

doi:10.1111/bph.14490

Cited by 16 publications

(22 citation statements)

References 42 publications

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“…All reagents were purchased from Sigma unless otherwise indicated. Cells were patch-clamped using the whole-cell configuration as previously described 15, 16. For action potential recordings, patch pipettes (resistance 2 to 3 MΩ) were filled with pipette solution containing (in mM): 110 K-aspartate, 30 KCl, 5 NaCl, 0.1 EGTA,10 HEPES, 5 MgATP, 5 creatine phosphate, 0.05 cAMP, pH 7.2 with KOH.…”

Section: Methodsmentioning

confidence: 99%

Macrophages facilitate post myocardial infarction arrhythmias: roles of gap junction and KCa3.1

Fei¹,

Wang²,

Hou³

et al. 2019

Theranostics

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Effective therapeutic targets against post-myocardial infarction (MI) arrhythmias remain to be discovered. We aimed to investigate the role of macrophages in post-MI arrhythmias.Methods: Mononuclear cell accumulation, macrophage polarization from M0 to M1 subset, and gap junction formation were analyzed in MI patients and MI mice by flow cytometry, immunofluorescence and patch clamping. Differentially expressed genes were identified by RNA sequencing. Macrophages and cardiomyocytes were cocultured in vitro, and the effects of gap junction and KCa3.1 on electrophysiological properties were assessed by patch clamping. The effects of KCa3.1 inhibition on post-MI arrhythmias were assessed by intracardiac stimulation and ambulatory electrocardiograms in vivo.Results: Percentage of pro-inflammatory mononuclear cells were significantly elevated in patients with post-MI arrhythmias compared with MI patients without arrhythmias and healthy controls (p<0.001). Macrophages formed gap junction with cardiomyocytes in MI border zones of MI patient and mice, and pro-inflammatory macrophages were significantly increased 3 days post-MI (p<0.001). RNA sequencing identified Kcnn4 as the most differentially expressed gene encoding ion channel, and the upregulation is mainly attributed to macrophage accumulation and polarization into pro-inflammatory subset. In vitro coculture experiments demonstrated that connection with M0 macrophages via gap junction slightly shortened the action potential durations (APDs) of cardiomyocytes. However, the APD90 of cardiomyocytes connected with M1 macrophages were significantly prolonged (p<0.001), which were effectively attenuated by gap junction inhibition (p=0.002), KCa3.1 inhibition (p=0.008), KCa3.1 silencing (p<0.001) and store-operated Ca2+ channel inhibition (p=0.005). In vivo results demonstrated that KCa3.1 inhibition significantly decreased the QTc durations (p=0.031), intracardiac stimulation-induced ventricular arrhythmia durations (p=0.050) and incidence of premature ventricular contractions (p=0.030) in MI mice.Conclusion: Macrophage polarization leads to APD heterogeneity and post-MI arrhythmias via gap junction and KCa3.1 activation. The results provide evidences of a novel mechanism of post-MI heterogeneous repolarization and arrhythmias, rendering macrophages and KCa3.1 to be potential therapeutic targets.

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Section: Methodsmentioning

confidence: 99%

Macrophages facilitate post myocardial infarction arrhythmias: roles of gap junction and KCa3.1

Fei¹,

Wang²,

Hou³

et al. 2019

Theranostics

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“…It can become important if increased under pathological conditions (Saint, 2006). The study by (Hou et al 2018) shows little effect of 9-Phen in normal tissue but large effects when the late Na + current is enhanced by ATXII or by overexpression in CHO cells. Conditions that enhance late INa + did not apply to our experiments.…”

Section: Study Limitationsmentioning

confidence: 99%

“…(Chen et al, 1993;Dosdall et al, 2008;Myles et al, 2012) and we observed no effects of Lugol's on heart rate or pressure development (Table 2). 9-Phen was reported, to target late Na + current in some pathologies (Hou et al, 2018).…”

Section: Study Limitationsmentioning

confidence: 99%

Mechanical stimulation of endocardial Purkinje fibres can trigger ventricular arrhythmias

White

Walton

Kaur

et al. 2020

Preprint

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Acute ventricular dilation can evoke mechanically-induced arrhythmias, our study investigated whether Purkinje fibres (PFs) may play a role. Changes in left ventricular (LV) pressure and pseudo-ECGs were measured in isolated, Langendorff-perfused, male Wistar rat hearts in sinus rhythm. The LV endocardial surface was irrigated with experimental agents, via an indwelling catheter. Mechanically-induced arrhythmias were triggered by LV lumen inflation (100μl in 2s) via an indwelling balloon. Arrhythmias occurred as the LV volume was increased and spontaneously ceased within 20s of the onset of LV inflation. Arrhythmias were indexed as an increase in the standard deviation of all R-R intervals (SDRR), the number of ectopic activations and the period of these activations. Following 10s LV endocardial irrigation with Lugol’s solution (IK/I2) to chemically ablate surface PFs or with 0 Na+ Tyrode, there was a statistically significant attenuation of mechanically-induced arrhythmias. Lugol’s reduced the mechanically-induced increase in SDRR (Tyrode pre-stretch 3.5±1.7ms to 113.8±15.1ms during stretch vs Lugol pre-stretch 3.3±0.5ms to 39.9±14.5ms during stretch n=8, P < 0.05). There was also a reduction in the number (21.2±2.0 to 1.5±0.7, P<0.001) and period (5.9±0.71s to 1.7±0.85s, P< 0.01) of ectopic activations. The experiment was repeated using LV lumen irrigation with either 1µM GsMTx4, a peptide that blocks stretch-activated channels or 50µM 9-Phenanthrol (9-Phen), a blocker of TRPM4 channels. GsMTx4 did not attenuate mechanically-activated arrhythmias while 9-Phen had a partial effect. 9-Phen statistically reduced the number and period of ectopic activations but did not attenuate the mechanically-induced increase in SDRR (n=6-11 for each intervention). In further studies, in situ focal mechanical stimulation of individual PFs, caused ectopic activations, in each of 4 sheep LV preparations (0.2±0.1 ectopics in 10s pre-mechanical stimulation vs 2.1±0.2 ectopics in 10s during mechanical stimulation, P<0.001). We interpret our observations in rat and sheep hearts as evidence for a role of PFs in the generation of some mechanically-induced arrhythmia.

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“…In either case, the cardiac action potentials (APs) were shortened suggesting a role of TRPM4 in the repolarization phase. However, discrepancies exist in these studies regarding their baseline cardiac phenotypes and doubts regarding the lack of specificity of 9-phenanthrol [21][22][23].…”

Section: Deletion Of Trpm4 Alters the Function And Expression Of Na Vmentioning

confidence: 99%

Deletion ofTrpm4alters the function and expression of Na_V1.5 channel in murine cardiac myocytes

Ozhathil

Rougier

Arullampalam

et al. 2020

Preprint

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AbstractTransient receptor potential melastatin member 4 (TRPM4) encodes a Ca+ -activated non-selective cation channel that is functionally expressed in several tissues including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases including conduction block and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized. To study the functional consequences of Trpm4 deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunohistochemistry studies on isolated atrial and ventricular cardiac myocytes and surface, pseudo and intracardiac ECGs either in vivo or on Langendorff-perfused explanted mouse hearts. We observed that Trpm4 is expressed in atrial and ventricular cardiac myocytes and that deletion of Trpm4 unexpectedly reduces the peak Na+ currents in the myocytes. Hearts from Trpm4-/- mice presented increased sensitivity towards mexiletine, a Na+ channel blocker, and slower intraventricular conduction, consistent with the reduction of peak Na+ current observed in the isolated cardiac myocytes. This reduction in Na+ current is explained by the observed decrease in protein expression of NaV1.5 in Trpm4-/- mice. This study suggests that Trpm4 expression impacts Na+ current in murine cardiac myocytes and points towards a novel function of Trpm4 regulating the NaV1.5 expression in murine cardiac myocytes.

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The transient receptor potential melastatin 4 channel inhibitor 9‐phenanthrol modulates cardiac sodium channel

Abstract: Our results indicate that 9-phenanthrol modulates the gating properties of cardiac sodium channels and inhibits I and I , which may contribute to its antiarrhythmic and cardioprotective effects.

Cited by 16 publications

References 42 publications

Macrophages facilitate post myocardial infarction arrhythmias: roles of gap junction and KCa3.1

Macrophages facilitate post myocardial infarction arrhythmias: roles of gap junction and KCa3.1

Mechanical stimulation of endocardial Purkinje fibres can trigger ventricular arrhythmias

Deletion ofTrpm4alters the function and expression of Na_V1.5 channel in murine cardiac myocytes

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The transient receptor potential melastatin 4 channel inhibitor 9‐phenanthrol modulates cardiac sodium channel

Abstract: Our results indicate that 9-phenanthrol modulates the gating properties of cardiac sodium channels and inhibits I and I , which may contribute to its antiarrhythmic and cardioprotective effects.

Cited by 16 publications

References 42 publications

Macrophages facilitate post myocardial infarction arrhythmias: roles of gap junction and KCa3.1

Macrophages facilitate post myocardial infarction arrhythmias: roles of gap junction and KCa3.1

Mechanical stimulation of endocardial Purkinje fibres can trigger ventricular arrhythmias

Deletion ofTrpm4alters the function and expression of NaV1.5 channel in murine cardiac myocytes

Contact Info

Product

Resources

About

Deletion ofTrpm4alters the function and expression of Na_V1.5 channel in murine cardiac myocytes