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Anne Vincent - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of G protein-gated K + channels by Tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
Scientific reports, 2020Co-Authors: Isabelle Bidaud, Agnès Carcouët, S. De Waard, Michel Ronjat, M. De Waard, Flavien Charpentier, Kevin Wickman, Antony Chung You Chong, Dirk Isbrandt, Anne VincentAbstract:Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Cav1.3 (Cav1.3-/-), T-type Cav3.1 (Cav3.1-/-), or both (Cav1.3-/-/Cav3.1-/-). We also studied mice haplo-insufficient for the Na+ channel Nav1.5 (Nav1.5+/) and mice in which the cAMP-dependent regulation of hyperpolarization-activated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K+ current (IKACh) by the peptide Tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Cav1.3-/- (19%), Cav1.3-/-/Cav3.1-/- (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Nav1.5+/- mice by 24%. Our data suggest that the development of pharmacological IKACh inhibitors for the management of SND and conduction disease is a viable approach.
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Inhibition of G protein-gated K^+ channels by Tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
Scientific Reports, 2020Co-Authors: Isabelle Bidaud, Agnès Carcouët, Michel Ronjat, Flavien Charpentier, Kevin Wickman, Antony Chung You Chong, Stephan De Waard, Michel De Waard, Dirk Isbrandt, Anne VincentAbstract:Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Ca_v1.3 (Ca_v1.3^−/−), T-type Ca_v3.1 (Ca_v3.1^−/−), or both (Ca_v1.3^−/−/Ca_v3.1^−/−). We also studied mice haplo-insufficient for the Na^+ channel Na_v1.5 (Na_v1.5^+/) and mice in which the cAMP-dependent regulation of hyperpolarization-activated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K^+ current ( I _ KACh ) by the peptide Tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Ca_v1.3^−/− (19%), Ca_v1.3^−/−/Ca_v3.1^−/− (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Na_v1.5^+/− mice by 24%. Our data suggest that the development of pharmacological I _ KACh inhibitors for the management of SND and conduction disease is a viable approach.
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Inhibition of G protein-gated K+ channels by Tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
Scientific Reports, 2020Co-Authors: Isabelle Bidaud, Agnès Carcouët, Michel Ronjat, Flavien Charpentier, Kevin Wickman, Antony Chung You Chong, Stephan De Waard, Michel De Waard, Dirk Isbrandt, Anne VincentAbstract:Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Cav1.3 (Cav1.3-/-), T-type Cav3.1 (Cav3.1-/-), or both (Cav1.3-/-/Cav3.1-/-). We also studied mice haplo-insufficient for the Na+ channel Nav1.5 (Nav1.5+/) and mice in which the cAMP-dependent regulation of hyperpolarization-activated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K+ current (IKACh) by the peptide Tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Cav1.3-/- (19%), Cav1.3-/-/Cav3.1-/- (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Nav1.5+/- mice by 24%. Our data suggest that the development of pharmacological IKACh inhibitors for the management of SND and conduction disease is a viable approach.
Chris P Bolter - One of the best experts on this subject based on the ideXlab platform.
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effects of Tertiapin q and zd7288 on changes in sinoatrial pacemaker rhythm during vagal stimulation
Autonomic Neuroscience: Basic and Clinical, 2015Co-Authors: Su Young Han, Chris P BolterAbstract:Heart rate slowing produced by cardiac parasympathetic (vagal) stimulation is thought to be the result of modulation of the acetylcholine-activated K(+) current (IK,ACh) and the pacemaker current (If) in sinoatrial (SAN) pacemaker cells. However, the contribution of these and other ion currents to vagal slowing is controversial. Here, we examined the contributions of IK,ACh and If to vagal slowing in 15 isolated, vagal-innervated preparations of guinea-pig atria, using 300 nM Tertiapin-Q (TQ) and 2 μM ZD7288 to obtain full and substantial block of these currents, respectively. Blocking IK,ACh alone reduced atrial rate responses to 10-s trains of regular vagal stimulation (supramaximal stimulation, 2-ms duration, 1-10 Hz) by ~50% (P<0.01; N=11); blocking If alone had no effect (N=7). Blocking both IK,ACh and If produced ~90% reduction (P<0.01; N=4). Atrial cycle length response to a single burst of vagal stimuli (3 stimuli at 50 Hz), delivered at the optimum phase of the cycle was strongly suppressed by blocking IK,ACh (reduced by 98%; P<0.01; N=9), and modestly reduced by blocking If alone (by ~43%; P=0.20; N=6). The response was abolished by combined block of IK,ACh and If (P=0.04; N=4). Our data show that modulation of IK,ACh and If is sufficient to account for all the vagal slowing observed in this preparation. The vagally-induced negative shift in activation potential for If will be opposed by hyperpolarisation of SAN through activation of IK,ACh. Thus removal of IK,ACh by TQ may have exaggerated the overall contribution of If to vagal slowing.
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Effects of Tertiapin-Q and ZD7288 on changes in sinoatrial pacemaker rhythm during vagal stimulation.
Autonomic neuroscience : basic & clinical, 2015Co-Authors: Su Young Han, Chris P BolterAbstract:Heart rate slowing produced by cardiac parasympathetic (vagal) stimulation is thought to be the result of modulation of the acetylcholine-activated K(+) current (IK,ACh) and the pacemaker current (If) in sinoatrial (SAN) pacemaker cells. However, the contribution of these and other ion currents to vagal slowing is controversial. Here, we examined the contributions of IK,ACh and If to vagal slowing in 15 isolated, vagal-innervated preparations of guinea-pig atria, using 300 nM Tertiapin-Q (TQ) and 2 μM ZD7288 to obtain full and substantial block of these currents, respectively. Blocking IK,ACh alone reduced atrial rate responses to 10-s trains of regular vagal stimulation (supramaximal stimulation, 2-ms duration, 1-10 Hz) by ~50% (P
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The muscarinic-activated potassium channel always participates in vagal slowing of the guinea-pig sinoatrial pacemaker.
Autonomic neuroscience : basic & clinical, 2011Co-Authors: Su Young Han, Chris P BolterAbstract:Controversy persists regarding participation of the muscarinic-activated potassium current (c(KACh)) in small and moderate vagal bradycardia. We investigated this by (i) critical examination of earlier experimental data for mechanisms proposed to operate in modest vagal bradycardia (modulation of I(f) and inhibition of a junctional Na(+) current) and (ii) experiments performed on isolated vagally-innervated guinea-pig atria. In 8 superperfused preparations, 10-s trains of vagal stimulation (1 to 20Hz) produced a bradycardia that ranged from 1 to 80%. Hyperpolarisation of sinoatrial cells accompanied bradycardia in 65/67 observations (linear correlation between bradycardia and increase in maximum diastolic potential (mV)=0.076x%; R(2)=0.57; P<0.001). In bath-mounted preparations single supramaximal stimuli to the vagus immediately and briefly increased pacemaker cycle length in 7 of 18 preparations. This response was eliminated by 300nM Tertiapin-Q. Trains of 10 single supramaximal vagal stimuli applied at 1-s intervals caused progressive increase in overall cycle length during the train; immediate and brief increases in cycle length occurred following some stimuli. Immediate brief responses and part of the slower response to the stimulus train were removed by 300nM Tertiapin-Q. experimental data shows that small and modest vagal bradycardia is accompanied by hyperpolarisation of the pacemaker cell which is severely attenuated by Tertiapin-Q. These observations support the idea that activation of I(KACh) occurs at all levels of vagal bradycardia. Contradictory conclusions from earlier studies may be attributed to the nature of experimental models and experimental design. Copyright © 2011 Elsevier B.V. All rights reserved.
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Tertiapin-Q removes a mechanosensitive component of muscarinic control of the sinoatrial pacemaker in the rat.
Clinical and experimental pharmacology & physiology, 2010Co-Authors: Su Young Han, Suzanne J. Wilson, Chris P BolterAbstract:1. In an isolated right atrial preparation, an increase in right atrial pressure (RAP) produces an increase in atrial rate. This rate response is larger and occurs faster when there is background vagal or muscarinic stimulation. 2. We hypothesized that in the latter situation, an increase in RAP antagonizes the effect of muscarinic stimulation through stretch inactivation of the mechanosensitive muscarinic potassium current I(K,ACh). 3. In two groups of bath-mounted right atria isolated from male Wistar rats (control n = 12; 300 nmol/L Tertiapin-Q treated (to block I(K,ACh)) n = 10), we examined the change in atrial rate when RAP was raised from 2 to 8 mmHg; oxotremorine-M (oxo-M; from 10 to 500 nmol/L) was added to incrementally activate muscarinic receptors. 4. In both control and Tertiapin-Q-treated groups, oxo-M reduced atrial rate, but its effect was less ( approximately 40-50%) in the latter group (P < 0.001). In control preparations, responses to an increase in RAP became progressively larger and quicker as the concentration of oxo-M was increased, whereas in Tertiapin-Q treated preparations oxo-M did not affect either the amplitude or the speed of the response (P < 0.0001 for both). 5. The results support the hypothesis that atrial stretch antagonizes muscarinic slowing by its effect on I(K,ACh). We suggest that through this mechanism, parasympathetic control of heart rate may be modulated continuously by RAP.
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Tertiapin-Q removes a large and rapidly acting component of vagal slowing of the guinea-pig cardiac pacemaker.
Autonomic Neuroscience: Basic and Clinical, 2009Co-Authors: Chris P Bolter, Michael J. TurnerAbstract:The participation of acetylcholine-activated potassium current (I(K,ACh)) and hyperpolarization-activated pacemaker current (I(f)) in vagal bradycardia were examined using vagally-innervated preparations of guinea-pig atria. Preparations were maintained in Krebs-Henseleit solution (36 degrees C). Before treatment, trains of vagal stimuli (10 s at 2, 5 and 10 Hz) produced graded bradycardias displaying rapid onset and offset. Tertiapin-Q (300 nM), which blocks I(K,ACh), had no effect on baseline atrial rate. In Tertiapin-Q, vagal bradycardia displayed a gradual onset and offset, with a peak response ~50% of that recorded in control conditions. Cumulative addition of 1 mM ZD7288 (blocker of I(f)) caused atrial rate to fall by ~60%, but had no further effect on the amplitude of the vagal bradycardia, while response onset and offset became slightly faster. From these observations, we argue that (i) vagal bradycardia was attributable primarily to activation of I(K,ACh), (ii) vagal modulation of I(f) had a minor influence on the rate of onset and offset of bradycardia, and (iii) removal of the influence of I(K,ACh) unmasked a slow response, of undetermined origin, to vagal stimulation. In a separate set of experiments we compared the effects of 1 mM Ba(2+) and 300 nM Tertiapin-Q on vagal bradycardia. Ba(2+) reduced baseline atrial rate and the response to vagal stimulation. Subsequent cumulative addition of Tertiapin-Q had no additional effect on baseline atrial rate, but caused further reduction in the amplitude of vagal bradycardia, suggesting that 1 mM Ba(2+) did not achieve a complete block of I(K,ACh) in this preparation.
Stanley Nattel - One of the best experts on this subject based on the ideXlab platform.
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Changes in I K, ACh single-channel activity with atrial tachycardia remodelling in canine atrial cardiomyocytes.
Cardiovascular research, 2007Co-Authors: Niels Voigt, Ursula Ravens, Dobromir Dobrev, Ange Maguy, Yung-hsin Yeh, Stanley NattelAbstract:Aims Although atrial tachycardia (AT) remodelling promotes agonist-independent, constitutively active, acetylcholine-regulated K+-current (IK,ACh) that increases susceptibility to atrial fibrillation (AF), the underlying changes in IK,Ach channel function are unknown. This study aimed to establish how AT remodelling affects IK,ACh single-channel function. Methods and results IK,ACh single-channel activity was studied via cell-attached patch-clamp in isolated left atrial cardiomyocytes of control and AT (7 days, 400 min−1) dogs. Atrial tachycardia prolonged the mean duration of induced AF from 44 ± 22 to 413 ± 167 s, and reduced atrial effective refractory period at a 360 ms cycle length from 126 ± 3 to 74 ± 5 ms ( n = 9/group, P < 0.001). In the absence of cholinergic stimulation, single-channel openings with typical IK,ACh conductance and rectification properties were sparse under control conditions. Atrial tachycardia induced prominent agonist-independent IK,ACh activity because of increased opening frequency ( f o) and open probability ( P o: approximately seven- and 10-fold, respectively, vs. control), but did not alter open time-constant, single-channel conductance, and membrane density. With maximum IK,ACh activation (10 µmol/L carbachol), channel P o was enhanced much more in control cells (∼42-fold) than in AT-remodelled myocytes (approximately five-fold). The selective Kir3 current blocker Tertiapin-Q (100 nmol/L) reduced f o and P o at −100 mV by 48 and 51%, respectively ( P < 0.05 for each), without altering other channel properties, confirming the identity of IK,ACh. Atrial tachycardia had no significant effect on mRNA or protein expression of either of the subunits (Kir3.1, Kir3.4) underlying IK,ACh. Conclusion Atrial tachycardia increases agonist-independent constitutive IK,ACh single-channel activity by enhancing spontaneous channel opening, providing a molecular basis for AT effects on macroscopic IK,ACh observed in previous studies, as well as associated refractoriness abbreviation and Tertiapin-suppressible AF promotion. These results suggest an important role for constitutive IK,Ach channel opening in AT remodelling and support its interest as a potential target for AF therapy.
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Abstract 950: Direct Evidence for an Important Role of Agonist-independent Constitutive IK,ACh Channel Activity in Atrial Tachycardia Remodeling
Circulation, 2007Co-Authors: Niels Voigt, Ursula Ravens, Dobromir Dobrev, Ange Maguy, Yung-hsin Yeh, Stanley NattelAbstract:Background: Although atrial tachycardia (AT) appears to promote agonist-independent constitutively active I K,ACh that increases susceptibility to AF, direct demonstration of dysregulated I K,ACh channel function is lacking. We studied AT effects on single I K,ACh channel activity in dog atria. Methods: I K,ACh channel activity was recorded with cell-attached patch clamp in isolated atrial myocytes of control (CTL) and AT (7 days, 400 min −1 ) dogs. Results : AT prolonged inducible AF duration from 44±22 to 413±167 s; N=9 dogs/gp, P K,ACh conductance and rectification were observed in CTL and AT (Figure). AT produced prominent agonist-independent I K,ACh activity due to 7-fold increased opening frequency (f o ) and 10-fold increased open probability (P o ) vs CTL (P K,ACh activation (10 μm carbachol, CCh), f o was 38% lower, open time constant 25% higher, and P o and unitary conductance unchanged for AT vs CTL. The selective Kir3 blocker Tertiapin (100 nM) reduced f o and P o by 48% and 51% (P I K,ACh. Conclusions : AT produces prominent agonist-independent constitutive single-channel I K,ACh activity, providing a molecular basis for previously-observed AT-enhanced macroscopic I K,ACh , as well as associated AP-shortening and Tertiapin-suppressible AF promotion. These results suggest an important role for constitutively active I K,ACh channels in AT-remodeling and support their interest as a potential novel AF-therapy target.
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kir3 based inward rectifier potassium current potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias
Circulation, 2006Co-Authors: Joachim R Ehrlich, Denis Chartier, Xiaoyan Qi, Ling Xiao, Stanley NattelAbstract:Background We previously characterized a novel K+ current (IKH) with properties of constitutively active acetylcholine-related current in dog atrium. I(KH) is sensitive to Tertiapin-Q (IC50 approximately 10 nmol/L), a highly selective Kir3 current blocker. This study assessed the role of IKH in atrial tachycardia (AT)-remodeled canine left atrium (LA) with the use of Tertiapin-Q as a probe. Methods and results Dogs were subjected to 7 to 13 days of AT (400 bpm). Coronary-perfused LA preparations were studied intact or subjected to cardiomyocyte isolation. IKH was recorded with patch-clamp methods. AT pacing increased time-dependent hyperpolarization-activated current (IKH) at -110 mV from -1.8+/-0.3 (control) to -3.4+/-0.5 pA/pF (AT) and the 100-nmol/L Tertiapin-sensitive component from -1.5+/-0.4 (control) to -3.3+/-0.6 pA/pF (AT). Prolonged atrial tachyarrhythmias could be induced with single extrastimuli in AT-remodeled, but not control, preparations, reflecting the atrial fibrillation-promoting effects of AT remodeling. In AT-remodeled preparations, tachyarrhythmia duration averaged 11.0+/-5.2 seconds, with a cycle length of 108+/-6 ms. Tertiapin-Q decreased tachyarrhythmia duration (to 0.6+/-0.1 second; P 20 minutes; Tertiapin-Q slowed and then terminated arrhythmia in both. Tertiapin had no effect on left ventricular cardiomyocyte currents or APD. Conclusions AT remodeling increases IKH, and a highly selective Kir3 current antagonist, Tertiapin-Q, increases APD and suppresses atrial tachyarrhythmias in AT-remodeled preparations without affecting ventricular electrophysiology. Constitutive acetylcholine-related K+ current contributes to AT-remodeling effects in dogs and is a potentially interesting antiarrhythmic target.
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characterization of a hyperpolarization activated time dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium
The Journal of Physiology, 2004Co-Authors: Joachim R Ehrlich, Denis Chartier, Stanley Nattel, Taejoon Cha, Liming Zhang, Louis Villeneuve, Terence E HebertAbstract:Cardiomyocytes from the pulmonary vein sleeves (PVs) are known to play an important role in atrial fibrillation. PVs have been shown to exhibit time-dependent hyperpolarization-induced inward currents of uncertain nature. We observed a time-dependent K+ current upon hyperpolarization of PV and left atrial (LA) cardiomyocytes (IKH) and characterized its biophysical and pharmacological properties. The activation time constant was weakly voltage dependent, ranging from 386 ± 14 to 427 ± 37 ms between −120 and −90 mV, and the half-activation voltage averaged −93 ± 4 mV. IKH was larger in PV than LA cells (e.g. at −120 mV: −2.8 ± 0.3 versus−1.9 ± 0.2 pA pF−1, respectively, P < 0.01). The reversal potential was ∼−84 mV with 5.4 mm[K+]o and changed by 55.7 ± 2.4 mV per decade [K+]o change. IKH was exquisitely Ba2+ sensitive, with a 50% inhibitory concentration (IC50) of 2.0 ± 0.3 μm (versus 76.0 ± 17.9 μm for instantaneous inward-rectifier current, P < 0.01), and showed similar Cs+ sensitivity to instantaneous current. IKH was potently blocked by Tertiapin-Q, a selective Kir3-subunit channel blocker (IC50 10.0 ± 2.1 nm), was unaffected by atropine and was significantly increased by isoproterenol (isoprenaline), carbachol and the non-hydrolysable guanosine triphosphate analogue GTPγS. IKH activation by carbachol required GTP in the pipette and was prevented by pertussis toxin pretreatment. Tertiapin-Q delayed repolarization in atropine-exposed multicellular atrial preparations studied with standard microelectrodes (action potential duration pre- versus post-Tertiapin-Q: 190.4 ± 4.3 versus 234.2 ± 9.9 ms, PV; 202.6 ± 2.6 versus 242.7 ± 6.2 ms, LA; 2 Hz, P < 0.05 each). Seven-day atrial tachypacing significantly increased IKH (e.g. at −120 mV in PV: from −2.8 ± 0.3 to −4.5 ± 0.5 pA pF−1, P < 0.01). We conclude that IKH is a time-dependent, hyperpolarization-activated K+ current that likely involves Kir3 subunits and appears to play a significant role in atrial physiology.
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Characterization of a hyperpolarization‐activated time‐dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium
The Journal of Physiology, 2004Co-Authors: Joachim R Ehrlich, Denis Chartier, Taejoon Cha, Liming Zhang, Louis Villeneuve, Terence E Hebert, Stanley NattelAbstract:Cardiomyocytes from the pulmonary vein sleeves (PVs) are known to play an important role in atrial fibrillation. PVs have been shown to exhibit time-dependent hyperpolarization-induced inward currents of uncertain nature. We observed a time-dependent K+ current upon hyperpolarization of PV and left atrial (LA) cardiomyocytes (IKH) and characterized its biophysical and pharmacological properties. The activation time constant was weakly voltage dependent, ranging from 386 ± 14 to 427 ± 37 ms between −120 and −90 mV, and the half-activation voltage averaged −93 ± 4 mV. IKH was larger in PV than LA cells (e.g. at −120 mV: −2.8 ± 0.3 versus−1.9 ± 0.2 pA pF−1, respectively, P < 0.01). The reversal potential was ∼−84 mV with 5.4 mm[K+]o and changed by 55.7 ± 2.4 mV per decade [K+]o change. IKH was exquisitely Ba2+ sensitive, with a 50% inhibitory concentration (IC50) of 2.0 ± 0.3 μm (versus 76.0 ± 17.9 μm for instantaneous inward-rectifier current, P < 0.01), and showed similar Cs+ sensitivity to instantaneous current. IKH was potently blocked by Tertiapin-Q, a selective Kir3-subunit channel blocker (IC50 10.0 ± 2.1 nm), was unaffected by atropine and was significantly increased by isoproterenol (isoprenaline), carbachol and the non-hydrolysable guanosine triphosphate analogue GTPγS. IKH activation by carbachol required GTP in the pipette and was prevented by pertussis toxin pretreatment. Tertiapin-Q delayed repolarization in atropine-exposed multicellular atrial preparations studied with standard microelectrodes (action potential duration pre- versus post-Tertiapin-Q: 190.4 ± 4.3 versus 234.2 ± 9.9 ms, PV; 202.6 ± 2.6 versus 242.7 ± 6.2 ms, LA; 2 Hz, P < 0.05 each). Seven-day atrial tachypacing significantly increased IKH (e.g. at −120 mV in PV: from −2.8 ± 0.3 to −4.5 ± 0.5 pA pF−1, P < 0.01). We conclude that IKH is a time-dependent, hyperpolarization-activated K+ current that likely involves Kir3 subunits and appears to play a significant role in atrial physiology.
Isabelle Bidaud - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of G protein-gated K^+ channels by Tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
Scientific Reports, 2020Co-Authors: Isabelle Bidaud, Agnès Carcouët, Michel Ronjat, Flavien Charpentier, Kevin Wickman, Antony Chung You Chong, Stephan De Waard, Michel De Waard, Dirk Isbrandt, Anne VincentAbstract:Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Ca_v1.3 (Ca_v1.3^−/−), T-type Ca_v3.1 (Ca_v3.1^−/−), or both (Ca_v1.3^−/−/Ca_v3.1^−/−). We also studied mice haplo-insufficient for the Na^+ channel Na_v1.5 (Na_v1.5^+/) and mice in which the cAMP-dependent regulation of hyperpolarization-activated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K^+ current ( I _ KACh ) by the peptide Tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Ca_v1.3^−/− (19%), Ca_v1.3^−/−/Ca_v3.1^−/− (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Na_v1.5^+/− mice by 24%. Our data suggest that the development of pharmacological I _ KACh inhibitors for the management of SND and conduction disease is a viable approach.
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Inhibition of G protein-gated K + channels by Tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
Scientific reports, 2020Co-Authors: Isabelle Bidaud, Agnès Carcouët, S. De Waard, Michel Ronjat, M. De Waard, Flavien Charpentier, Kevin Wickman, Antony Chung You Chong, Dirk Isbrandt, Anne VincentAbstract:Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Cav1.3 (Cav1.3-/-), T-type Cav3.1 (Cav3.1-/-), or both (Cav1.3-/-/Cav3.1-/-). We also studied mice haplo-insufficient for the Na+ channel Nav1.5 (Nav1.5+/) and mice in which the cAMP-dependent regulation of hyperpolarization-activated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K+ current (IKACh) by the peptide Tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Cav1.3-/- (19%), Cav1.3-/-/Cav3.1-/- (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Nav1.5+/- mice by 24%. Our data suggest that the development of pharmacological IKACh inhibitors for the management of SND and conduction disease is a viable approach.
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Inhibition of G protein-gated K+ channels by Tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
Scientific Reports, 2020Co-Authors: Isabelle Bidaud, Agnès Carcouët, Michel Ronjat, Flavien Charpentier, Kevin Wickman, Antony Chung You Chong, Stephan De Waard, Michel De Waard, Dirk Isbrandt, Anne VincentAbstract:Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Cav1.3 (Cav1.3-/-), T-type Cav3.1 (Cav3.1-/-), or both (Cav1.3-/-/Cav3.1-/-). We also studied mice haplo-insufficient for the Na+ channel Nav1.5 (Nav1.5+/) and mice in which the cAMP-dependent regulation of hyperpolarization-activated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K+ current (IKACh) by the peptide Tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Cav1.3-/- (19%), Cav1.3-/-/Cav3.1-/- (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Nav1.5+/- mice by 24%. Our data suggest that the development of pharmacological IKACh inhibitors for the management of SND and conduction disease is a viable approach.
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Inhibition of KACh channels by the bee venom peptide Tertiapin-Q rescues inherited cardiac conduction defects and sino-atrial bradycardia and atrioventricular block in models of congenital dysfunction
Archives of Cardiovascular Diseases Supplements, 2018Co-Authors: A. Chung You Chong, Isabelle Bidaud, Agnès Carcouët, S. De Waard, Michel Ronjat, M. De Waard, Matteo E. Mangoni, P. Mesirca, Flavien CharpentierAbstract:Introduction Pacemaker activity of the sino-atrial node (SAN) generates the heart rate. SAN dysfunction leads to sick sinus syndrome (SSS) characterized by abnormally low heart rate (HR). The only currently available therapy for SSS is electronic pacemaker implantation. Mice lacking SAN L-type Cav1.3 Ca2+ channels (Cav1.3−/−) present symptoms similar to those observed of SSS in humans especially SAN bradycardia and atrioventricular (AV) block. Cardiac voltage-gated Na+ channels (Nav) are essential for SAN impulse conduction through the AV node and the working myocardium. Mutations in the α-subunit of the cardiac Nav1.5 channel isoform are associated with inherited dysfunction of heart impulse conduction. We recently showed that genetic ablation of muscarinic-gated K+ channels (IKAch) rescues bradycardia of Cav1.3−/− mice. Purpose We tested pharmacologic inhibition of IKAch by the peptide Tertiapine-Q to rescue SSS and conduction dysfunction in Cav1.3−/− mice having concurrent ablation of Cav1.3 and T-type Cav3.1 channels (Cav1.3−/−/Cav3.1−/−) and Nav1.5± mice, which present ECG profiles similar to individuals carrying congenital bradycardia and conduction defects. Methods We employed telemetric ECG recordings of SAN activity, HR and AV dysfunction in mice before and after administration of different doses of Tertiapin-Q. Results Tertiapin-Q significantly improves the HR of Cav1.3−/− (19%), Cav1.3−/−/Cav3.1−/− (23%) from doses of 0.1 to 5 mg/kg. HRs of Tertiapine-Q-treated mice were similar to those recorded in untreated wild-type mice. Tertiapin-Q also improved cardiac conduction of Nav1.5± mice by 24%. Conclusion Pharmacological inhibition of IKAch by Tertiapin-Q prevents SAN dysfunction and improves conduction in three models of congenital bradycardia and impulse conduction defects suggesting the possibility of IKACh pharmacologic targeting to manage SAN and conduction disease.
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Inhibition of G protein-gated K^+ channels by Tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
Scientific Reports, 2020Co-Authors: Isabelle Bidaud, Agnès Carcouët, Michel Ronjat, Flavien Charpentier, Kevin Wickman, Antony Chung You Chong, Stephan De Waard, Michel De Waard, Dirk Isbrandt, Anne VincentAbstract:Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Ca_v1.3 (Ca_v1.3^−/−), T-type Ca_v3.1 (Ca_v3.1^−/−), or both (Ca_v1.3^−/−/Ca_v3.1^−/−). We also studied mice haplo-insufficient for the Na^+ channel Na_v1.5 (Na_v1.5^+/) and mice in which the cAMP-dependent regulation of hyperpolarization-activated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K^+ current ( I _ KACh ) by the peptide Tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Ca_v1.3^−/− (19%), Ca_v1.3^−/−/Ca_v3.1^−/− (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Na_v1.5^+/− mice by 24%. Our data suggest that the development of pharmacological I _ KACh inhibitors for the management of SND and conduction disease is a viable approach.
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Inhibition of G protein-gated K + channels by Tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
Scientific reports, 2020Co-Authors: Isabelle Bidaud, Agnès Carcouët, S. De Waard, Michel Ronjat, M. De Waard, Flavien Charpentier, Kevin Wickman, Antony Chung You Chong, Dirk Isbrandt, Anne VincentAbstract:Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Cav1.3 (Cav1.3-/-), T-type Cav3.1 (Cav3.1-/-), or both (Cav1.3-/-/Cav3.1-/-). We also studied mice haplo-insufficient for the Na+ channel Nav1.5 (Nav1.5+/) and mice in which the cAMP-dependent regulation of hyperpolarization-activated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K+ current (IKACh) by the peptide Tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Cav1.3-/- (19%), Cav1.3-/-/Cav3.1-/- (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Nav1.5+/- mice by 24%. Our data suggest that the development of pharmacological IKACh inhibitors for the management of SND and conduction disease is a viable approach.
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Inhibition of G protein-gated K+ channels by Tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia
Scientific Reports, 2020Co-Authors: Isabelle Bidaud, Agnès Carcouët, Michel Ronjat, Flavien Charpentier, Kevin Wickman, Antony Chung You Chong, Stephan De Waard, Michel De Waard, Dirk Isbrandt, Anne VincentAbstract:Sinus node (SAN) dysfunction (SND) manifests as low heart rate (HR) and is often accompanied by atrial tachycardia or atrioventricular (AV) block. The only currently available therapy for chronic SND is the implantation of an electronic pacemaker. Because of the growing burden of SND in the population, new pharmacological therapies of chronic SND and heart block are desirable. We developed a collection of genetically modified mouse strains recapitulating human primary SND associated with different degrees of AV block. These mice were generated with genetic ablation of L-type Cav1.3 (Cav1.3-/-), T-type Cav3.1 (Cav3.1-/-), or both (Cav1.3-/-/Cav3.1-/-). We also studied mice haplo-insufficient for the Na+ channel Nav1.5 (Nav1.5+/) and mice in which the cAMP-dependent regulation of hyperpolarization-activated f-(HCN4) channels has been abolished (HCN4-CNBD). We analysed, by telemetric ECG recording, whether pharmacological inhibition of the G-protein-activated K+ current (IKACh) by the peptide Tertiapin-Q could improve HR and AV conduction in these mouse strains. Tertiapin-Q significantly improved the HR of Cav1.3-/- (19%), Cav1.3-/-/Cav3.1-/- (23%) and HCN4-CNBD (14%) mice. Tertiapin-Q also improved cardiac conduction of Nav1.5+/- mice by 24%. Our data suggest that the development of pharmacological IKACh inhibitors for the management of SND and conduction disease is a viable approach.
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G-protein-coupled inward rectifier potassium current contributes to ventricular repolarization
Cardiovascular research, 2013Co-Authors: Bo Liang, Jakob D. Nissen, Morten Laursen, Xiaodong Wang, Lasse Skibsbye, Matthew C. Hearing, Martin N. Andersen, Hanne B. Rasmussen, Kevin Wickman, Morten GrunnetAbstract:Aims The purpose of this study was to investigate the functional role of G-protein-coupled inward rectifier potassium (GIRK) channels in the cardiac ventricle. Methods and results Immunofluorescence experiments demonstrated that GIRK4 was localized in outer sarcolemmas and t-tubules in GIRK1 knockout (KO) mice, whereas GIRK4 labelling was not detected in GIRK4 KO mice. GIRK4 was localized in intercalated discs in rat ventricle, whereas it was expressed in intercalated discs and outer sarcolemmas in rat atrium. GIRK4 was localized in t-tubules and intercalated discs in human ventricular endocardium and epicardium, but absent in mid-myocardium. Electrophysiological recordings in rat ventricular tissue ex vivo showed that the adenosine A1 receptor agonist N 6-cyclopentyladenosine (CPA) and acetylcholine (ACh) shortened action potential duration (APD), and that the APD shortening was reversed by either the GIRK channel blocker Tertiapin-Q, the adenosine A1 receptor antagonist DPCPX or by the muscarinic M2 receptor antagonist AF-DX 116. Tertiapin-Q prolonged APD in the absence of the exogenous receptor activation. Furthermore, CPA and ACh decreased the effective refractory period and the effect was reversed by either Tertiapin-Q, DPCPX or AF-DX 116. Receptor activation also hyperpolarized the resting membrane potential, an effect that was reversed by Tertiapin-Q. In contrast, Tertiapin-Q depolarized the resting membrane potential in the absence of the exogenous receptor activation. Conclusion Confocal microscopy shows that among species GIRK4 is differentially localized in the cardiac ventricle, and that it is heterogeneously expressed across human ventricular wall. Electrophysiological recordings reveal that GIRK current may contribute significantly to ventricular repolarization and thereby to cardiac electrical stability.
