Abstract
The cellular mechanism of action of tedisamil (KC-8857) (TED), a novel antiarrhythmic / antifibrillatory compound, was studied on transmembrane currents in guinea pig, rabbit and dog ventricular myocytes by applying the patch-clamp and the conventional microelectrode technique. In guinea pig myocytes the rapid component of the delayed rectifier potassium current (IKr) was largely diminished by 1 μM TED (from 0.88±0.17 to 0.23±0.07 pA / pF, n=5, p < 0.05), while its slow component (IKs) was reduced only by 5 μM TED (from 8.1±0.3 to 4.23±0.07 pA / pF, n=5, p < 0.05). TED did not significantly change the IKr and IKs kinetics. In rabbit myocytes 1 μM TED decreased the amplitude of the transient outward current (Ito) from 20.3±4.9 to 13.9±2.8 pA / pF (n=5, p < 0.05), accelerated its fast inactivation time constant from 8.3±0.6 to 3.5±0.5 ms (n=5, p < 0.05) and reduced the ATP-activated potassium current (IKATP) from 38.2±11.8 to 18.4±4.7 pA / pF (activator: 50 μM cromakalim; n=5, p < 0.05). In dog myocytes 2 μM TED blocked the fast sodium current (INa) with rapid onset and moderately slow offset kinetics, while the inward rectifier potassium (IK1), the inward calcium (ICa) and even the Ito currents were not affected by TED in concentration as high as 10 μM. The differences in Ito responsiveness between dog and rabbit are probably due to the different α-subunits of Ito in these species. It is concluded that inhibition of several transmembrane currents, including IKr, IKs, Ito, IKATP and even INa, can contribute to the high antiarrhythmic / antifibrillatory potency of TED, underlying predominant Class III combined with I A / B type antiarrhythmic characteristics.
Keywords: tedisamil (kc-8857), cellular mechanism of action, transmembrane ion currents, cardiomyocytes
Current Medicinal Chemistry
Title: Effect of the Antifibrillatory Compound Tedisamil (KC-8857) on Transmembrane Currents in Mammalian Ventricular Myocytes
Volume: 11 Issue: 24
Author(s): N. Jost, L. Virag, O. Hala, A. Varro, D. Thormahlen and J. Gy. Papp
Affiliation:
Keywords: tedisamil (kc-8857), cellular mechanism of action, transmembrane ion currents, cardiomyocytes
Abstract: The cellular mechanism of action of tedisamil (KC-8857) (TED), a novel antiarrhythmic / antifibrillatory compound, was studied on transmembrane currents in guinea pig, rabbit and dog ventricular myocytes by applying the patch-clamp and the conventional microelectrode technique. In guinea pig myocytes the rapid component of the delayed rectifier potassium current (IKr) was largely diminished by 1 μM TED (from 0.88±0.17 to 0.23±0.07 pA / pF, n=5, p < 0.05), while its slow component (IKs) was reduced only by 5 μM TED (from 8.1±0.3 to 4.23±0.07 pA / pF, n=5, p < 0.05). TED did not significantly change the IKr and IKs kinetics. In rabbit myocytes 1 μM TED decreased the amplitude of the transient outward current (Ito) from 20.3±4.9 to 13.9±2.8 pA / pF (n=5, p < 0.05), accelerated its fast inactivation time constant from 8.3±0.6 to 3.5±0.5 ms (n=5, p < 0.05) and reduced the ATP-activated potassium current (IKATP) from 38.2±11.8 to 18.4±4.7 pA / pF (activator: 50 μM cromakalim; n=5, p < 0.05). In dog myocytes 2 μM TED blocked the fast sodium current (INa) with rapid onset and moderately slow offset kinetics, while the inward rectifier potassium (IK1), the inward calcium (ICa) and even the Ito currents were not affected by TED in concentration as high as 10 μM. The differences in Ito responsiveness between dog and rabbit are probably due to the different α-subunits of Ito in these species. It is concluded that inhibition of several transmembrane currents, including IKr, IKs, Ito, IKATP and even INa, can contribute to the high antiarrhythmic / antifibrillatory potency of TED, underlying predominant Class III combined with I A / B type antiarrhythmic characteristics.
Export Options
About this article
Cite this article as:
Jost N., Virag L., Hala O., Varro A., Thormahlen D. and Papp Gy. J., Effect of the Antifibrillatory Compound Tedisamil (KC-8857) on Transmembrane Currents in Mammalian Ventricular Myocytes, Current Medicinal Chemistry 2004; 11 (24) . https://dx.doi.org/10.2174/0929867043363631
DOI https://dx.doi.org/10.2174/0929867043363631 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The HVJ-Envelope as an Innovative Vector System for Cardiovascular Disease
Current Gene Therapy Oral IIa and Xa Inhibitors for Prevention of Stroke in Atrial Fibrillation: Clinical Studies and Regulatory Considerations
Current Clinical Pharmacology Genetics of Atrial Fibrilation: In Search of Novel Therapeutic Targets
Cardiovascular & Hematological Disorders-Drug Targets Retraction Notice: Prevention of Emetic Episodes During Cesarean Delivery Performed Under Regional Anesthesia in Parturients
Current Drug Safety Material-Based Engineering Strategies for Cardiac Regeneration
Current Pharmaceutical Design Peripartum Cardiomyopathy: An Intensivist's Perspective
Current Women`s Health Reviews Genetic Aspects of Lone Atrial Fibrillation: What Do We Know?
Current Pharmaceutical Design Stem Cells in Cardiovascular Regeneration: From Preservation of Endogenous Repair to Future Cardiovascular Therapies
Current Pharmaceutical Design Colorectal Cancer in Elderly Patients: From Best Supportive Care to Cure
Anti-Cancer Agents in Medicinal Chemistry Potassium Channels: Novel Emerging Biomarkers and Targets for Therapy in Cancer
Recent Patents on Anti-Cancer Drug Discovery Pleiotropic Effects of Cardioactive Glycosides
Current Medicinal Chemistry Trimetazidine: Does it Actually Reduce QT Dispersion After First Acute Myocardial Infarction?
Current Drug Therapy New Strategies and Drugs in the Treatment of Hypertension: Monotherapy or Combination?
Recent Patents on Cardiovascular Drug Discovery Dysfunctions of the Diffusional Membrane Pathways Mediated Hemichannels in Inherited and Acquired Human Diseases
Current Vascular Pharmacology Attention Deficit Hyperactive Disorder and Occurrence of Tic Disorders in Children and Adolescents—What is the Verdict
Current Pediatric Reviews Rewiring the Heart: Stem Cell Therapy to Restore Normal Cardiac Excitability and Conduction
Current Stem Cell Research & Therapy Omecamtiv Mecarbil: A Myosin Motor Activator Agent with Promising Clinical Performance and New in vitro Results
Current Medicinal Chemistry Human Embryonic and Induced Pluripotent Stem Cells in Cardiovascular Drug Discovery: Patents and Patented Uses
Recent Patents on Cardiovascular Drug Discovery Patent Annotations
Recent Patents on Anti-Infective Drug Discovery An Update on Peptide Drugs for Voltage-Gated Calcium Channels
Recent Patents on CNS Drug Discovery (Discontinued)