Abstract:Background-New therapeutic approaches to improve cardiac contractility without severe risk would improve the management of acute heart failure. Increasing systolic sodium influx can increase cardiac contractility, but most sodium channel activators have proarrhythmic effects that limit their clinical use. Here, we report the cardiac effects of a novel positive inotropic peptide isolated from the toxin of the Black Judean scorpion that activates neuronal tetrodotoxinsensitive sodium channels. Methods and Result… Show more
“…Previous studies have reported ZD7288 as a potent blocker of Nav1.4 (Wu et al Wu et al 2012 ) and in higher concentrations (> 100 µM) of low-voltage-activated calcium channels (Felix et al 2003 ; Sánchez-Alonso et al 2008 ), thereby characterizing this drug as a non-selective blocker for HCN channels. Considering that Nav1.4 channels are not present in rodent thalamic neurons (Kirchhof et al 2015 ) and based on the fact that we applied 10 µM ZD7288 (thus having little effect on low-voltage-activated calcium channels), the reduction of tonic firing of TC neurons seems to be mainly based on the block of HCN channels. Fig.…”
Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels have important functions in controlling neuronal excitability and generating rhythmic oscillatory activity. The role of tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) in regulation of hyperpolarization-activated inward current, I
h, in the thalamocortical system and its functional relevance for the physiological thalamocortical oscillations were investigated. A significant decrease in I
h current density, in both thalamocortical relay (TC) and cortical pyramidal neurons was found in TRIP8b-deficient mice (TRIP8b−/−). In addition basal cAMP levels in the brain were found to be decreased while the availability of the fast transient A-type K+ current, I
A, in TC neurons was increased. These changes were associated with alterations in intrinsic properties and firing patterns of TC neurons, as well as intrathalamic and thalamocortical network oscillations, revealing a significant increase in slow oscillations in the delta frequency range (0.5–4 Hz) during episodes of active-wakefulness. In addition, absence of TRIP8b suppresses the normal desynchronization response of the EEG during the switch from slow-wave sleep to wakefulness. It is concluded that TRIP8b is necessary for the modulation of physiological thalamocortical oscillations due to its direct effect on HCN channel expression in thalamus and cortex and that mechanisms related to reduced cAMP signaling may contribute to the present findings.Electronic supplementary materialThe online version of this article (10.1007/s00429-017-1559-z) contains supplementary material, which is available to authorized users.
“…Previous studies have reported ZD7288 as a potent blocker of Nav1.4 (Wu et al Wu et al 2012 ) and in higher concentrations (> 100 µM) of low-voltage-activated calcium channels (Felix et al 2003 ; Sánchez-Alonso et al 2008 ), thereby characterizing this drug as a non-selective blocker for HCN channels. Considering that Nav1.4 channels are not present in rodent thalamic neurons (Kirchhof et al 2015 ) and based on the fact that we applied 10 µM ZD7288 (thus having little effect on low-voltage-activated calcium channels), the reduction of tonic firing of TC neurons seems to be mainly based on the block of HCN channels. Fig.…”
Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels have important functions in controlling neuronal excitability and generating rhythmic oscillatory activity. The role of tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) in regulation of hyperpolarization-activated inward current, I
h, in the thalamocortical system and its functional relevance for the physiological thalamocortical oscillations were investigated. A significant decrease in I
h current density, in both thalamocortical relay (TC) and cortical pyramidal neurons was found in TRIP8b-deficient mice (TRIP8b−/−). In addition basal cAMP levels in the brain were found to be decreased while the availability of the fast transient A-type K+ current, I
A, in TC neurons was increased. These changes were associated with alterations in intrinsic properties and firing patterns of TC neurons, as well as intrathalamic and thalamocortical network oscillations, revealing a significant increase in slow oscillations in the delta frequency range (0.5–4 Hz) during episodes of active-wakefulness. In addition, absence of TRIP8b suppresses the normal desynchronization response of the EEG during the switch from slow-wave sleep to wakefulness. It is concluded that TRIP8b is necessary for the modulation of physiological thalamocortical oscillations due to its direct effect on HCN channel expression in thalamus and cortex and that mechanisms related to reduced cAMP signaling may contribute to the present findings.Electronic supplementary materialThe online version of this article (10.1007/s00429-017-1559-z) contains supplementary material, which is available to authorized users.
“…Thus, it is possible that Nav1.5 was also inhibited. Kirchhof and colleagues showed that selective activation of the brain-type Na + channel Nav1.3 can increase cardiac contractility without provoking arrhythmia [ 7 ]. In this context, our data suggest that Nav1.3 is a feasible target of the positive inotropic agent HNO.…”
Section: Discussionmentioning
confidence: 99%
“…Nav1.1, Nav1.3, and Nav1.6 are localized to t-tubules or near t-tubule openings [ 5 , 6 ]. Kirchhof et al reported that a peptide that activates Nav1.3 and Nav1.6 can induce positive inotropy without provoking arrhythmias [ 7 ]. We have previously demonstrated that Nav1.5 and brain-type subunits are differentially inhibited Na + channel inhibitors including local anesthetics [ 8 ].…”
An accumulation of reactive oxygen species (ROS) in cardiomyocytes can induce pro-arrhythmogenic late Na+ currents by removing the inactivation of voltage-gated Na+ channels including the tetrodotoxin (TTX)-resistant cardiac α-subunit Nav1.5 as well as TTX-sensitive α-subunits like Nav1.2 and Nav1.3. Here, we explored oxidant-induced late Na+ currents in mouse cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as well as in HEK 293 cells expressing Nav1.2, Nav1.3, or Nav1.5. Na+ currents in mouse cardiomyocytes and hiPSC-CMs treated with the oxidant chloramine T (ChT) developed a moderate reduction in peak current amplitudes accompanied by large late Na+ currents. While ChT induced a strong reduction in peak current amplitudes but only small persistent currents on Nav1.5, both Nav1.2 and Nav1.3 produced increased peak current amplitudes and large persistent currents following oxidation. TTX (300 nM) blocked ChT-induced late Na+ currents significantly stronger as compared to peak Na+ currents in both mouse cardiomyocytes and hiPSC-CMs. Similar differences between Nav1.2, Nav1.3, and Nav1.5 regarding ROS sensitivity were also evident when oxidation was induced with UVA-light (380 nm) or the cysteine-selective oxidant nitroxyl (HNO). To conclude, our data on TTX-sensitive Na+ channels expressed in cardiomyocytes may be relevant for the generation of late Na+ currents following oxidative stress.
“…Further, there is evidence that augmentation of Na + influx through nNa V in WT murine hearts may be potentially inotropic by increasing Ca 2+ transient amplitude (Kirchhof et al . ; Radwanski et al . ).…”
Section: The Interplay Between Sodium and Calciummentioning
Excitation-contraction coupling is the bridge between cardiac electrical activation and mechanical contraction. It is driven by the influx of Ca across the sarcolemma triggering Ca release from the sarcoplasmic reticulum (SR) - a process termed Ca -induced Ca release (CICR) - followed by re-sequestration of Ca into the SR. The Na /Ca exchanger inextricably couples the cycling of Ca and Na in cardiac myocytes. Thus, influx of Na via voltage-gated Na channels (Na ) has emerged as an important regulator of CICR both in health and in disease. Recent insights into the subcellular distribution of cardiac and neuronal Na isoforms and their ultrastructural milieu have important implications for the roles of these channels in mediating Ca -driven arrhythmias. This review will discuss functional insights into the role of neuronal Na isoforms vis-à-vis cardiac Na s in triggering such arrhythmias and their potential as therapeutic targets in the context of the aforementioned structural observations.
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