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1.
Herzschrittmacherther Elektrophysiol ; 26(3): 300-2, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26141412

ABSTRACT

BACKGROUND: A 57-year-old man presented with recurrent episodes of dizziness, weakness of legs, and presyncope. The electrocardiogram showed a sinus bradycardia and recurrent sinus pauses. RESULTS: Cardiac evaluation revealed a normal left ventricular ejection fraction without ischemic, structural, or valvular heart disease. Pronounced limb weakness prompted neurological consultation. Cranial magnetic resonance imaging showed a large right-sided intracranial tumor adjacent to the medial sphenoid wing. Surgical removal of the tumor was accomplished successfully after application of a transient cardiac pacemaker, while decision upon permanent pacemaker implantation was postponed. Histopathology provided evidence of a meningothelial meningioma. Postoperative assessment displayed the absence of sinus node dysfunction after tumor removal. CONCLUSION: Careful differential diagnostic assessment of patients with symptomatic bradycardias needs to rule out reversible causes before implantation of permanent devices.


Subject(s)
Bradycardia/etiology , Bradycardia/prevention & control , Meningeal Neoplasms/complications , Meningeal Neoplasms/surgery , Meningioma/complications , Meningioma/surgery , Adult , Bradycardia/diagnosis , Diagnosis, Differential , Humans , Male , Meningeal Neoplasms/diagnosis , Meningioma/diagnosis , Sphenoid Bone/surgery , Treatment Outcome
2.
Br J Pharmacol ; 171(23): 5182-94, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25168769

ABSTRACT

BACKGROUND AND PURPOSE: The ß-receptor antagonist carvedilol blocks a range of ion channels. K2P 2.1 (TREK1) and K2P 10.1 (TREK2) channels are expressed in the heart and regulated by alternative translation initiation (ATI) of their mRNA, producing functionally distinct channel variants. The first objective was to investigate acute effects of carvedilol on human K2P 2.1 and K2P 10.1 channels. Second, we sought to study ATI-dependent modulation of K2P K(+) current sensitivity to carvedilol. EXPERIMENTAL APPROACH: Using standard electrophysiological techniques, we recorded currents from wild-type and mutant K2P 2.1 and K2P 10.1 channels in Xenopus oocytes and HEK 293 cells. KEY RESULTS: Carvedilol concentration-dependently inhibited K2P 2.1 channels (IC50 ,oocytes = 20.3 µM; IC50 , HEK = 1.6 µM) and this inhibition was frequency-independent. When K2P 2.1 isoforms generated by ATI were studied separately in oocytes, the IC50 value for carvedilol inhibition of full-length channels (16.5 µM) was almost 5-fold less than that for the truncated channel variant (IC50 = 79.0 µM). Similarly, the related K2P 10.1 channels were blocked by carvedilol (IC50 ,oocytes = 24.0 µM; IC50 , HEK = 7.6 µM) and subject to ATI-dependent modulation of drug sensitivity. CONCLUSIONS AND IMPLICATIONS: Carvedilol targets K2P 2.1 and K2P 10.1 K(+) channels. This previously unrecognized mechanism supports a general role of cardiac K2P channels as antiarrhythmic drug targets. Furthermore, the work reveals that the sensitivity of the cardiac ion channels K2P 2.1 and K2P 10.1 to block was modulated by alternative mRNA translation initiation.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Carbazoles/pharmacology , Potassium Channels, Tandem Pore Domain/antagonists & inhibitors , Propanolamines/pharmacology , Animals , Carvedilol , Cells, Cultured , Female , HEK293 Cells , Humans , Oocytes , Potassium Channels, Tandem Pore Domain/physiology , Protein Biosynthesis , Xenopus laevis
3.
Br J Pharmacol ; 168(5): 1215-29, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23061993

ABSTRACT

BACKGROUND AND PURPOSE: Zolpidem, a short-acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome (LQTS) and torsade de pointes (TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether-a-go-go-related gene (hERG)/I(Kr) currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K(+) channels. EXPERIMENTAL APPROACH: Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration (APD) was assessed in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. KEY RESULTS: Zolpidem caused acute hERG channel blockade in oocytes (IC(50) = 61.5 µM) and in HEK 293 cells (IC(50) = 65.5 µM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage- and frequency-independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I-V relationships of steady-state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC-derived cardiomyocytes. CONCLUSIONS AND IMPLICATIONS: Zolpidem inhibits cardiac hERG K(+) channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose.


Subject(s)
Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Hypnotics and Sedatives/pharmacology , Long QT Syndrome/physiopathology , Myocytes, Cardiac/drug effects , Potassium Channel Blockers/pharmacology , Pyridines/pharmacology , Action Potentials/drug effects , Animals , Cells, Cultured , Ether-A-Go-Go Potassium Channels/physiology , HEK293 Cells , Humans , Induced Pluripotent Stem Cells/cytology , Long QT Syndrome/chemically induced , Myocytes, Cardiac/physiology , Oocytes/drug effects , Oocytes/physiology , Recombinant Proteins , Xenopus laevis , Zolpidem
4.
Dtsch Med Wochenschr ; 137(33): 1654-8, 2012 Aug.
Article in German | MEDLINE | ID: mdl-22875694

ABSTRACT

Uncontrolled electrical activity caused by ion channel dysfunction produces arrhythmia in the heart. Despite recent advances in pharmaceutical research and development, effective and safe pharmacological management of cardiac arrhythmia still remains an unmet medical need. The emerging family of two-pore-domain potassium (K2P) channels stabilizes the resting membrane potential and facilitates action potential repolarization. In the heart, genetic inactivation or inhibition of two-pore-domain K + (K2P) currents by class III antiarrhythmic drugs results in action potential prolongation. In particular, human K2P3.1 channels are selectively expressed in the atria and represent targets for the pharmacological management of atrial fibrillation. Furthermore, stretch-sensitive K2P2.1 channels are implicated in mechanoelectrical feedback and arrhythmogenesis. The current knowledge on function, regulation, and cardiac significance of K2P channels is summarized in this work, and potential therapeutic implications are highlighted.


Subject(s)
Arrhythmias, Cardiac/physiopathology , Electrocardiography , Potassium Channels, Tandem Pore Domain/physiology , Animals , Anti-Arrhythmia Agents/adverse effects , Anti-Arrhythmia Agents/therapeutic use , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/genetics , Atrial Fibrillation/drug therapy , Atrial Fibrillation/genetics , Atrial Fibrillation/physiopathology , Electrocardiography/drug effects , Gene Silencing , Heart Atria/drug effects , Heart Atria/physiopathology , Heart Conduction System/drug effects , Heart Conduction System/physiopathology , Heart Ventricles/drug effects , Heart Ventricles/physiopathology , Humans , Mice , Potassium Channels, Tandem Pore Domain/drug effects , Potassium Channels, Tandem Pore Domain/genetics , Rats
5.
Cell Death Dis ; 2: e193, 2011 Aug 18.
Article in English | MEDLINE | ID: mdl-21850047

ABSTRACT

The human ether-a-go-go-related gene potassium channel (hERG, Kv11.1, KCNH2) has an essential role in cardiac action potential repolarization. Electrical dysfunction of the voltage-sensitive ion channel is associated with potentially lethal ventricular arrhythmias in humans. hERG K(+) channels are also expressed in a variety of cancer cells where they control cell proliferation and apoptosis. In this review, we discuss molecular mechanisms of hERG-associated cell cycle regulation and cell death. In addition, the significance of hERG K(+) channels as future drug target in anticancer therapy is highlighted.


Subject(s)
Apoptosis , Ether-A-Go-Go Potassium Channels/metabolism , Cell Proliferation/drug effects , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Neoplasms/metabolism , Potassium Channel Blockers/pharmacology
6.
Br J Pharmacol ; 163(5): 1099-110, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21410455

ABSTRACT

BACKGROUND AND PURPOSE: Human K(2P) 3.1 (TASK1) channels represent potential targets for pharmacological management of atrial fibrillation. K(2P) channels control excitability by stabilizing membrane potential and by expediting repolarization. In the heart, inhibition of K(2P) currents by class III antiarrhythmic drugs results in action potential prolongation and suppression of electrical automaticity. Carvedilol exerts antiarrhythmic activity and suppresses atrial fibrillation following cardiac surgery or cardioversion. The objective of this study was to investigate acute effects of carvedilol on human K(2P) 3.1 (hK(2P) 3.1) channels. EXPERIMENTAL APPROACH: Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hK(2P) 3.1 currents from Xenopus oocytes, Chinese hamster ovary (CHO) cells and human pulmonary artery smooth muscle cells (hPASMC). KEY RESULTS: Carvedilol concentration-dependently inhibited hK(2P) 3.1 currents in Xenopus oocytes (IC(50) = 3.8 µM) and in mammalian CHO cells (IC(50) = 0.83 µM). In addition, carvedilol sensitivity of native I(K2P3.1) was demonstrated in hPASMC. Channels were blocked in open and closed states in frequency-dependent fashion, resulting in resting membrane potential depolarization by 7.7 mV. Carvedilol shifted the current-voltage (I-V) relationship by -6.9 mV towards hyperpolarized potentials. Open rectification, characteristic of K(2P) currents, was not affected. CONCLUSIONS AND IMPLICATIONS: The antiarrhythmic drug carvedilol targets hK(2P) 3.1 background channels. We propose that cardiac hK(2P) 3.1 current blockade may suppress electrical automaticity, prolong atrial refractoriness and contribute to the class III antiarrhythmic action in patients treated with the drug.


Subject(s)
Carbazoles/pharmacology , Nerve Tissue Proteins/antagonists & inhibitors , Potassium Channel Blockers/pharmacology , Potassium Channels, Tandem Pore Domain/antagonists & inhibitors , Propanolamines/pharmacology , Animals , CHO Cells , Carvedilol , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Humans , Ion Channel Gating/drug effects , Membrane Potentials/drug effects , Muscle, Smooth, Vascular/cytology , Oocytes , Patch-Clamp Techniques , Pulmonary Artery/cytology , Transfection , Xenopus laevis
7.
Am J Sports Med ; 11(3): 111-5, 1983.
Article in English | MEDLINE | ID: mdl-6688155

ABSTRACT

In order to more accurately document the effects of meniscus removal, 20 children and adolescents with isolated meniscal tears were examined an average of 5.5 years after surgery. All patients with concomitant ligamentous injuries and a history of prior surgery on either knee, and those with bilateral knee pathology or knee pathology outside the meniscus, were excluded. At followup, 60% of the 20 study patients had unsatisfactory results. The clinical results did not correlate with the site of meniscectomy, the type of meniscal tear, the severity of radiographic changes, or whether the patient had total or partial meniscectomy. Evaluation of lower extremity muscle function revealed a statistically significant (P less than 0.05) decrease in hip abductor strength in patients with unsatisfactory results. This study indicates that meniscectomy in the child or adolescent is not a benign procedure, and that failure to rehabilitate hip abductor strength to normal levels significantly comprises the clinical end results.


Subject(s)
Athletic Injuries/surgery , Knee Injuries/surgery , Menisci, Tibial/surgery , Adolescent , Athletic Injuries/physiopathology , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Knee Injuries/physiopathology , Knee Joint/physiopathology , Male , Movement , Postoperative Complications , Tibial Meniscus Injuries
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