Abstract
Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques.
In histidine-decarboxylase knockout mice as well as in their wild types R (1-30 μM) shortened AP duration at 90% level of repolarization (APD90) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1-30 μM) caused a significant reduction of APA and maximum velocity of depolarization (Vmax) which was accompanied by lengthening of APD90.
In single canine ventricular myocytes at concentrations ≥10 μM R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced Vmax. R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC50 value for this inhibition was 25.2±2.7 μM for the transient outward K+ current (Ito), 72.3±9.3 μM for the rapid delayed rectifier K+ current (IKr), and 82.5±9.4 μM for the L-type Ca2+ current (ICa) with Hill coefficients close to unity. The inward rectifier K+ current (IK1) was not affected by R up to concentrations of 100 μM. Suppression of Ito, IKr, and ICa has been confirmed under action potential voltage clamp conditions as well.
The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patients.
Keywords: Antidiabetic agents, rosiglitazone, action potential, ion currents, cardiovascular adverse, ventricular papillary muscle, ventricular myocytes, microelectrode, repolarization, Suppression of Ito, Ikr and Ica
Current Medicinal Chemistry
Title: Can the Electrophysiological Action of Rosiglitazone Explain its Cardiac Side Effects?
Volume: 18 Issue: 24
Author(s): A. Szebeni, N. Szentandrassy, P. Pacher, J. Simko, P. P. Nanasi and V. Kecskemeti
Affiliation:
Keywords: Antidiabetic agents, rosiglitazone, action potential, ion currents, cardiovascular adverse, ventricular papillary muscle, ventricular myocytes, microelectrode, repolarization, Suppression of Ito, Ikr and Ica
Abstract: Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques.
In histidine-decarboxylase knockout mice as well as in their wild types R (1-30 μM) shortened AP duration at 90% level of repolarization (APD90) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1-30 μM) caused a significant reduction of APA and maximum velocity of depolarization (Vmax) which was accompanied by lengthening of APD90.
In single canine ventricular myocytes at concentrations ≥10 μM R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced Vmax. R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC50 value for this inhibition was 25.2±2.7 μM for the transient outward K+ current (Ito), 72.3±9.3 μM for the rapid delayed rectifier K+ current (IKr), and 82.5±9.4 μM for the L-type Ca2+ current (ICa) with Hill coefficients close to unity. The inward rectifier K+ current (IK1) was not affected by R up to concentrations of 100 μM. Suppression of Ito, IKr, and ICa has been confirmed under action potential voltage clamp conditions as well.
The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patients.
Export Options
About this article
Cite this article as:
Szebeni A., Szentandrassy N., Pacher P., Simko J., P. Nanasi P. and Kecskemeti V., Can the Electrophysiological Action of Rosiglitazone Explain its Cardiac Side Effects?, Current Medicinal Chemistry 2011; 18 (24) . https://dx.doi.org/10.2174/092986711796642364
DOI https://dx.doi.org/10.2174/092986711796642364 |
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
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...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
- 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
-
Potential Therapeutic Advantages of Doxorubicin when Activated by Formaldehyde to Function as a DNA Adduct-Forming Agent
Current Topics in Medicinal Chemistry Mast Cells and Inflammatory Heart Disease: Potential Drug Targets
Cardiovascular & Hematological Disorders-Drug Targets A Review on Novel Ligand Targeted Delivery for Cardiovascular Disorder
Current Drug Delivery Natriuretic Peptide Guided Heart Failure Management
Current Clinical Pharmacology MicroRNAs and Peroxisome Proliferator-Activated Receptors Governing the Differentiation of Mesenchymal Stem Cells
Current Stem Cell Research & Therapy Kinin Receptors in Vascular Biology and Pathology
Current Vascular Pharmacology Why is the Inhibition of the Renin-Angiotensin System Effective for Preventing Cardiac Events in Patients with Coronary Risk Factors or Coronary Artery Disease?
Current Cardiology Reviews Plasma Glucose Concentrations and Cardiac Hypertrophy in Essential Hypertension
Current Hypertension Reviews Adult Stem Cells and Skeletal Muscle Regeneration
Current Gene Therapy Role of the Renin-Angiotensin-Aldosterone System in the Pathogenesis of Atherosclerosis
Current Pharmaceutical Design Enzyme Replacement Therapy in Fabry Disease: Influence on Cardiac Manifestations
Current Medicinal Chemistry Cerebrovascular Complications After Heart Transplantation
Current Cardiology Reviews Animal Mitochondria: Evolution, Function, and Disease
Current Molecular Medicine Treating Heart Failure with Preserved Ejection Fraction Related to Arterial Stiffness. Can we Kill Two Birds With One Stone?
Current Vascular Pharmacology Anderson-Fabry Disease in Children
Current Pharmaceutical Design Editorial: Targeting Neuregulin1 and HER Receptor Tyrosine Kinases for Therapy of Breast Cancer and Heart Failure
Current Pharmaceutical Design Forms of Iron Binding in the Cells and the Chemical Features of Chelation Therapy
Mini-Reviews in Medicinal Chemistry Cell Penetrating Peptide Delivery of Splice Directing Oligonucleotides as a Treatment for Duchenne Muscular Dystrophy
Current Pharmaceutical Design Meet Our Regional Editor
Current Vascular Pharmacology Interatrial Block in the Modern Era
Current Cardiology Reviews