Transient receptor potential melastatin 4 inhibitor 9‐phenanthrol abolishes arrhythmias induced by hypoxia and re‐oxygenation in mouse ventricle

Simard, Christophe; Sallé, Laurent; Rouet, René; Guinamard, Romain

doi:10.1111/j.1476-5381.2011.01715.x

Cited by 85 publications

(98 citation statements)

References 54 publications

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“…For example, TRPC (TRP-canonical) channels have been proposed to be critical regulators of microdomain Ca 2ϩ signaling in the heart to control pathological hypertrophy (38). Focusing on TRPM channels, although TRPM4 channels have been associated with conduction abnormalities, cardiac arrhythmias, and hypertension (8,9), to date there is limited understanding of TRPM2 channels in the heart (5,7,39,40). The present study provides evidence that TRPM2 channels were activated by ADPR (Fig.…”

Section: Discussionmentioning

confidence: 58%

TRPM2 Channels Protect against Cardiac Ischemia-Reperfusion Injury

Miller

Hoffman

Merali

et al. 2014

Journal of Biological Chemistry

126

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Background: TRPM2 channels are present in the heart, but their function is unknown. Results: Genetic ablation of TRPM2 results in cardiac mitochondrial dysfunction, enhanced ROS production, and exacerbated cardiac ischemic injury. Conclusion: TRPM2 channels preserve cardiac mitochondrial bioenergetics and protect cardiac myocytes from ischemic injury. Significance: TRPM2 is a rational target for treatment of ischemic heart disease.

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Section: Discussionmentioning

confidence: 58%

TRPM2 Channels Protect against Cardiac Ischemia-Reperfusion Injury

Miller

Hoffman

Merali

et al. 2014

Journal of Biological Chemistry

126

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“…Furthermore, 9-phenanthrol has been shown to block TRPM4 currents in cerebral blood vessels and evoke substantial hyperpolarization of vascular smooth muscle cell membrane potential and dilation of arteries with myogenic tone (17). In addition, 9-phenanthrol produced an antiarrhythmic effect in murine ventricle by reducing the frequency of early afterdepolarizations when applied for 10 min at a concentration of 10 M; this effect was attributed to TRPM4 channels (36). Collectively, these findings confirm that 9-phenanthrol is an important novel pharmacological tool that could be used to investigate the TRPM4 channel physiological role in DSM excitation-contraction coupling.…”

mentioning

confidence: 97%

Novel role for the transient potential receptor melastatin 4 channel in guinea pig detrusor smooth muscle physiology

Smith

Hristov

Cheng

et al. 2013

American Journal of Physiology-Cell Physiology

115

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Members of the transient receptor potential (TRP) channel superfamily, including the Ca(2+)-activated monovalent cation-selective TRP melastatin 4 (TRPM4) channel, have been recently identified in the urinary bladder. However, their expression and function at the level of detrusor smooth muscle (DSM) remain largely unexplored. In this study, for the first time we investigated the role of TRPM4 channels in guinea pig DSM excitation-contraction coupling using a multidisciplinary approach encompassing protein detection, electrophysiology, live-cell Ca(2+) imaging, DSM contractility, and 9-phenanthrol, a recently characterized selective inhibitor of the TRPM4 channel. Western blot and immunocytochemistry experiments demonstrated the expression of the TRPM4 channel in whole DSM tissue and freshly isolated DSM cells with specific localization on the plasma membrane. Perforated whole cell patch-clamp recordings and real-time Ca(2+) imaging experiments with fura 2-AM, both using freshly isolated DSM cells, revealed that 9-phenanthrol (30 μM) significantly reduced the cation current and decreased intracellular Ca(2+) levels. 9-Phenanthrol (0.1-30 μM) significantly inhibited spontaneous, 0.1 μM carbachol-induced, 20 mM KCl-induced, and nerve-evoked contractions in guinea pig DSM-isolated strips with IC50 values of 1-7 μM and 70-80% maximum inhibition. 9-Phenanthrol also reduced nerve-evoked contraction amplitude induced by continuous repetitive electrical field stimulation of 10-Hz frequency and shifted the frequency-response curve (0.5-50 Hz) relative to the control. Collectively, our data demonstrate the novel finding that TRPM4 channels are expressed in guinea pig DSM and reveal their critical role in the regulation of guinea pig DSM excitation-contraction coupling.

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“…Recently, 9-phenanthrol has received much attention as a TRPM4-specific antagonist. However, this compound also affects voltage-gated Ca 2+ and K + channels in primary myocytes, 31 which limits its usefulness as an agent to delineate the pharmacological potential of TRPM4 in living mice.…”

mentioning

confidence: 99%