Mechanisms of Sevoflurane-induced Myocardial Preconditioning in Isolated Human Right Atria In Vitro 

2003 ◽  
Vol 99 (1) ◽  
pp. 27-33 ◽  
Author(s):  
Alexandra Yvon ◽  
Jean-Luc Hanouz ◽  
Benoît Haelewyn ◽  
Xavier Terrien ◽  
Massimo Massetti ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
Adenosine Triphosphate ◽  
Human Myocardium ◽  
Right Atrial ◽  
Human Right ◽  
Myocardial Preconditioning ◽  
Right Atria

Background The authors examined the role of adenosine triphosphate-sensitive potassium channels and adenosine A(1) receptors in sevoflurane-induced preconditioning on isolated human myocardium. Methods The authors recorded isometric contraction of human right atrial trabeculae suspended in oxygenated Tyrode's solution (34 degrees C; stimulation frequency, 1 Hz). In all groups, a 30-min hypoxic period was followed by 60 min of reoxygenation. Seven minutes before hypoxia reoxygenation, muscles were exposed to 4 min of hypoxia and 7 min of reoxygenation or 15 min of sevoflurane at concentrations of 1, 2, and 3%. In separate groups, sevoflurane 2% was administered in the presence of 10 microm HMR 1098, a sarcolemmal adenosine triphosphate-sensitive potassium channel antagonist; 800 microm 5-hydroxy-decanoate, a mitochondrial adenosine triphosphate-sensitive potassium channel antagonist; and 100 nm 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A(1) receptor antagonist. Recovery of force at the end of the 60-min reoxygenation period was compared between groups (mean +/- SD). Results Hypoxic preconditioning (90 +/- 4% of baseline) and sevoflurane 1% (82 +/- 3% of baseline), 2% (92 +/- 5% of baseline), and 3% (85 +/- 7% of baseline) enhanced the recovery of force after 60 min of reoxygenation compared with the control groups (52 +/- 9% of baseline). This effect was abolished in the presence of 5-hydroxy-decanoate (55 +/- 14% of baseline) and 8-cyclopentyl-1,3-dipropylxanthine (58 +/- 16% of baseline) but was attenuated in the presence of HMR 1098 (73 +/- 10% of baseline). Conclusions In vitro, sevoflurane preconditions human myocardium against hypoxia through activation of adenosine triphosphate-sensitive potassium channels and stimulation of adenosine A(1) receptors.

Ketamine Preconditions Isolated Human Right Atrial Myocardium

2005 ◽  
Vol 102 (6) ◽  
pp. 1190-1196 ◽  
Author(s):  
Jean-Luc Hanouz ◽  
Lan Zhu ◽  
Emmanuel Persehaye ◽  
Massimo Massetti ◽  
Gerard Babatasi ◽  
...  
Keyword(s):  
Adenosine Triphosphate ◽  
Enhanced Recovery ◽  
Human Myocardium ◽  
Right Atrial ◽  
Control Group ◽  
Force Of Contraction ◽  
Human Right ◽  
Adrenoceptor Antagonist ◽  
Racemic Ketamine

Background The authors examined the effect of ketamine and its S(+) isomer on isolated human myocardium submitted to hypoxia-reoxygenation in vitro. Methods The authors studied isometric contraction of human right atrial trabeculae suspended in an oxygenated Tyrode's modified solution at 34 degrees C. Ten minutes before a 30-min hypoxic period followed by a 60-min reoxygenation, muscles were exposed for 15 min to racemic ketamine and its S(+) isomer at 10, 10, and 10 m alone or in the presence of 8.10 m 5-hydroxydecanoate, 10 m HMR 1098 (sarcolemmal adenosine triphosphate-sensitive potassium channel antagonist), 10 m phentolamine (alpha-adrenoceptor antagonist), and 10 m propranolol (beta-adrenoceptor antagonist). Force of contraction at the end of the 60-min reoxygenation period was compared between groups (mean +/- SD). Results Ketamine (10 m: 85 +/- 4%; 10 m: 95 +/- 10%; 10 m: 94 +/- 14% of baseline) and S(+)-ketamine (10-6 m: 85 +/- 4%; 10 m: 91 +/- 16%; 10 m: 93 +/- 14% of baseline) enhanced recovery of force of contraction at the end of the reoxygenation period as compared with the control group (47 +/- 10% of baseline; P < 0.001). Ketamine-induced preconditioning at 10 m was inhibited by 5-hydroxydecanoate (60 +/- 16%; P < 0.001), HMR 1098 (60 +/- 14%; P < 0.001), phentolamine (56 +/- 12%; P < 0.001), and propranolol (60 +/- 7%; P < 0.001). Conclusions In vitro, ketamine preconditions isolated human myocardium, at least in part, via activation of adenosine triphosphate-sensitive potassium channels and stimulation of alpha- and beta-adrenergic receptors.

Mechanisms of Desflurane-induced Preconditioning in Isolated Human Right Atria In Vitro 

2002 ◽  
Vol 97 (1) ◽  
pp. 33-41 ◽  
Author(s):  
Jean-Luc Hanouz ◽  
Alexandra Yvon ◽  
Massimo Massetti ◽  
Olivier Lepage ◽  
Gérard Babatasi ◽  
...  
Keyword(s):  
Human Myocardium ◽  
Adenosine A1 Receptor ◽  
Right Atrial ◽  
Control Group ◽  
Human Right ◽  
Beta Adrenoceptors ◽  
Adrenoceptor Antagonist ◽  
Adenosine A1 ◽  
A1 Receptor

Background The authors examined the role of adenosine triphosphate-sensitive potassium (K(ATP)) channels, adenosine A1 receptor, and alpha and beta adrenoceptors in desflurane-induced preconditioning in human myocardium, in vitro. Methods The authors recorded isometric contraction of human right atrial trabeculae suspended in oxygenated Tyrode's solution (34 degrees C; stimulation frequency, 1 Hz). Before a 30-min anoxic period, 3, 6, and 9% desflurane was administered during 15 min. Desflurane, 6%, was also administered in the presence of 10 microm glibenclamide, a K(ATP) channels antagonist; 10 microm HMR 1098, a sarcolemmal K(ATP) channel antagonist; 800 microm 5-hydroxy-decanoate (5-HD), a mitochondrial K(ATP) channel antagonist; 1 microm phentolamine, an alpha-adrenoceptor antagonist; 1 microm propranolol, a beta-adrenoceptor antagonist; and 100 nm 8-cyclopentyl-1,3-dipropylxanthine (DPX), the adenosine A1 receptor antagonist. Developed force at the end of a 60-min reoxygenation period was compared (mean +/- SD). Results Desflurane at 3% (95 +/- 13% of baseline), 6% (86 +/- 6% of baseline), and 9% (82 +/- 6% of baseline) enhanced the recovery of force after 60 min of reoxygenation as compared with the control group (50 +/- 11% of baseline). Glibenclamide (60 +/- 12% of baseline), 5-HD (57 +/- 21% of baseline), DPX (63 +/- 19% of baseline), phentolamine (56 +/- 20% of baseline), and propranolol (63 +/- 13% of baseline) abolished desflurane-induced preconditioning. In contrast, HMR 1098 (85 +/- 12% of baseline) did not modify desflurane-induced preconditioning. Conclusions In vitro, desflurane preconditions human myocardium against simulated ischemia through activation of mitochondrial K(ATP) channels, adenosine A1 receptor, and alpha and beta adrenoceptors.

KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways

2021 ◽  
pp. 1-15
Author(s):  
Ping Xu ◽  
Xiao Mo ◽  
Ruixue Xia ◽  
Long Jiang ◽  
Chengfei Zhang ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Lung Adenocarcinoma ◽  
Potassium Channel ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Biology ◽  
Erk Signaling ◽  
Mesenchymal Transition

BACKGROUND: Potassium channels, encoded by more than seventy genes, are cell excitability transmembrane proteins and become evident to play essential roles in tumor biology. OBJECTIVE: The deregulation of potassium channel genes has been related to cancer development and patient prognosis. The objective of this study is to understand the role of potassium channels in lung cancer. METHODS: We examined all potassium channel genes and identified that KCNN4 is the most significantly overexpressed one in lung adenocarcinoma. The role and mechanism of KCNN4 in lung adenocarcinoma were further investigated by in vitro cell and molecular assay and in vivo mouse xenograft models. RESULTS: We revealed that the silencing of KCNN4 significantly inhibits cell proliferation, migration, invasion, and tumorigenicity of lung adenocarcinoma. Further studies showed that knockdown of KCNN4 promotes cell apoptosis, induces cell cycle arrested in the S phase, and is associated with the epithelial to mesenchymal transition (EMT) process. Most importantly, we demonstrated that KCNN4 regulates the progression of lung adenocarcinoma through P13K/AKT and MEK/ERK signaling pathways. The use of inhibitors that targeted AKT and ERK also significantly inhibit the proliferation and metastasis of lung adenocarcinoma cells. CONCLUSIONS: This study investigated the function and mechanism of KCNN4 in lung adenocarcinoma. On this basis, this means that KCNN4 can be used as a tumor marker for lung adenocarcinoma and is expected to become an important target for a potential drug.

Abstract P780: Myosin Light Chain Dephosphorylation by Ppp1r12c Promotes Atrial Hypocontractility in Atrial Fibrillation

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Perike Srikanth ◽  
Andrielle E Capote ◽  
Alsina Katherina M ◽  
Benjamin Levin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Abstract P458: Myosin Light Chain Dephosphorylation By Ppp1r12c Promotes Atrial Hypocontractility In Atrial Fibrillation

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Srikanth Perike ◽  
Frederick Damen ◽  
Andrielle Capote ◽  
Katherina M Alsina ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Introduction: Atrial fibrillation (AF), is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 2.7 million to 6.1 million and is predictive to increase to 12.1 million in 2030. AF increases the chances of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. Objective: The overexpression of PPP1R12C, causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), decreasing atrial contractility. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluated the role of PP1c-PPP1R12C interaction in MLC2a de-phosphorylation we used Western blots, coimmunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The Overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, that cause a reduction in atrial contractility and increases AF inducibility. All these discoveries advocate that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Desflurane-induced postconditioning of diabetic human right atrial myocardium in vitro

2010 ◽  
Vol 36 (1) ◽  
pp. 21-28 ◽  
Author(s):  
S. Lemoine ◽  
C. Durand ◽  
L. Zhu ◽  
C. Ivasceau ◽  
O. Lepage ◽  
...  
Keyword(s):  
Right Atrial ◽  
Atrial Myocardium ◽  
Human Right

scholarly journals K+ channel blockade in the NTS alters efficacy of two cardiorespiratory reflexes in vivo

1998 ◽  
Vol 274 (3) ◽  
pp. R677-R685 ◽  
Author(s):  
James W. Butcher ◽  
Julian F. R. Paton
Keyword(s):  
Potassium Channel ◽  
Neuronal Excitability ◽  
Baroreceptor Reflex ◽  
Right Atrial ◽  
K Channel ◽  
Reflex Bradycardia ◽  
Potassium Conductances ◽  
Voltage Dependent

We investigated the role of potassium conductances in the nucleus of the solitary tract (NTS) in determining the efficacy of the baroreceptor and cardiopulmonary reflexes in anesthetized rats. The baroreceptor reflex was elicited with an intravenous injection of phenylephrine to evoke a reflex bradycardia, and the cardiopulmonary reflex was evoked with a right atrial injection of phenylbiguanide. Microinjection of two Ca-dependent potassium channel antagonists (apamin and charybdotoxin) into the NTS potentiated the baroreceptor reflex bradycardia. This may reflect the increased neuronal excitability observed previously in vitro with these blockers. In contrast, the Ca-dependent potassium channel antagonists attenuated the cardiopulmonary reflex, whereas voltage-dependent potassium channel antagonists (4-aminopyridine and dendrotoxin) attenuated both the baro- and cardiopulmonary reflexes when microinjected into the NTS. The possibility that the reflex attenuation observed indicates a predominant distribution of certain potassium channels on γ-aminobutyric acid interneurons is discussed.

In vivo location and mechanism of EDHF-mediated vasodilation in canine coronary microcirculation

1999 ◽  
Vol 277 (3) ◽  
pp. H1252-H1259 ◽  
Author(s):  
Yasuhiro Nishikawa ◽  
David W. Stepp ◽  
William M. Chilian
Keyword(s):  
Nitric Oxide ◽  
Potassium Channels ◽  
Potassium Channel ◽  
Direct Evidence ◽  
Coronary Microcirculation ◽  
Combined Administration ◽  
Cytochrome P 450 ◽  
Coronary Arterioles

Responses of epicardial coronary arterioles to ACh were measured using stroboscopic fluorescence microangiography in dogs ( n = 38). ACh (0.1 and 0.5 μg ⋅ kg−1 ⋅ min−1ic) dilated small (<100 μm, 11 ± 2 and 19 ± 2%, respectively) and large (>100 μm, 6 ± 3 and 13 ± 3%, respectively) arterioles at baseline. Combined administration of N ω-monomethyl-l-arginine (l-NMMA; 1.0 μmol/min ic) and indomethacin (10 mg/kg iv) eliminated ACh-induced dilation in large coronary arterioles but only partially attenuated that in small arterioles. Suffusion of a buffer containing 60 mM KCl (high KCl) completely abolished cromakalim-induced dilation in arterioles and in combination with l-NMMA plus indomethacin completely blocked ACh-induced dilation in small arterioles. This indicated that the vasodilation to ACh that persists in small arterioles after administration of l-NMMA and indomethacin is mediated via a hyperpolarizing factor. The ACh-induced vasodilation remaining after l-NMMA and indomethacin was completely blocked by the large-conductance potassium-channel antagonist iberiotoxin or by epicardial suffusion of miconazole or metyrapone, inhibitors of cytochrome P-450 enzymes. These observations are consistent with the view that endothelium-derived hyperpolarizing factor (EDHF) is a product of cytochrome P-450 enzymes and produces vasodilation by the opening of large-conductance potassium channels. We conclude that ACh-induced dilation in large coronary arterioles is mediated mainly by nitric oxide (NO), whereas, in small arterioles both NO and EDHF mediate dilation to ACh. These data provide the first direct evidence for an in vivo role of EDHF in small coronary arterioles.

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