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Combination of Sildenafil and Ba(2+) at a Low Concentration Show a Significant Synergistic Inhibition of Inward Rectifier Potassium Current Resulting in Action Potential Prolongation
Sildenafil (Viagra) is a vasodilator mainly used in the treatment of erectile dysfunction. Atrial or ventricular fibrillation may rarely occur as a side effect during sildenafil therapy. Although changes in inward rectifier potassium currents including I (K1) are known to contribute to the pathogene...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081525/ https://www.ncbi.nlm.nih.gov/pubmed/35548367 http://dx.doi.org/10.3389/fphar.2022.829952 |
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author | Macháček, Martin Švecová, Olga Bébarová, Markéta |
author_facet | Macháček, Martin Švecová, Olga Bébarová, Markéta |
author_sort | Macháček, Martin |
collection | PubMed |
description | Sildenafil (Viagra) is a vasodilator mainly used in the treatment of erectile dysfunction. Atrial or ventricular fibrillation may rarely occur as a side effect during sildenafil therapy. Although changes in inward rectifier potassium currents including I (K1) are known to contribute to the pathogenesis of fibrillation, the effect of sildenafil on I (K1) has not been studied. In experiments, Ba(2+) is used as a specific inhibitor of I (K1) at high concentrations (usually 100 µM). Being an environmental contaminant, it is also present in the human body; Ba(2+) plasmatic concentrations up to 1.5 µM are usually reported in the general population. This study was primarily aimed to investigate changes of I (K1) induced by sildenafil in a wide range of concentrations (0.1–100 µM). Additionally, the effect of combination of sildenafil and Ba(2+) at selected clinically-relevant concentrations was tested, at 0.1 µM both on I (K1) and on the action potential duration (APD). Experiments were performed by the whole-cell patch-clamp technique on enzymatically isolated rat ventricular cardiomyocytes, mostly at 23°C with the exception of APD measurements which were performed at 37°C as well. Sildenafil caused a significant, reversible, and concentration-dependent inhibition of I (K1) that did not differ at −50 and −110 mV. Simultaneous application of sildenafil and Ba(2+) at 0.1 µM revealed a massive inhibition of both inward and outward components of I (K1) (this synergy was missing at other tested combinations). The combined effect at 0.1 µM (45.7 ± 5.7 and 43.0 ± 6.9% inhibition at −50 and −110 mV, respectively) was significantly higher than a simple sum of almost negligible effects of the individual substances and it led to a significant prolongation of APD at both 23 and 37°C. To our knowledge, similar potentiation of the drug-channel interaction has not been described. The observed massive inhibition of I (K1) induced by a combined action of the vasodilator sildenafil and environmental contaminant Ba(2+) at a low concentration and resulting in a significant APD prolongation may contribute to the genesis of arrhythmias observed in some patients treated with sildenafil. |
format | Online Article Text |
id | pubmed-9081525 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90815252022-05-10 Combination of Sildenafil and Ba(2+) at a Low Concentration Show a Significant Synergistic Inhibition of Inward Rectifier Potassium Current Resulting in Action Potential Prolongation Macháček, Martin Švecová, Olga Bébarová, Markéta Front Pharmacol Pharmacology Sildenafil (Viagra) is a vasodilator mainly used in the treatment of erectile dysfunction. Atrial or ventricular fibrillation may rarely occur as a side effect during sildenafil therapy. Although changes in inward rectifier potassium currents including I (K1) are known to contribute to the pathogenesis of fibrillation, the effect of sildenafil on I (K1) has not been studied. In experiments, Ba(2+) is used as a specific inhibitor of I (K1) at high concentrations (usually 100 µM). Being an environmental contaminant, it is also present in the human body; Ba(2+) plasmatic concentrations up to 1.5 µM are usually reported in the general population. This study was primarily aimed to investigate changes of I (K1) induced by sildenafil in a wide range of concentrations (0.1–100 µM). Additionally, the effect of combination of sildenafil and Ba(2+) at selected clinically-relevant concentrations was tested, at 0.1 µM both on I (K1) and on the action potential duration (APD). Experiments were performed by the whole-cell patch-clamp technique on enzymatically isolated rat ventricular cardiomyocytes, mostly at 23°C with the exception of APD measurements which were performed at 37°C as well. Sildenafil caused a significant, reversible, and concentration-dependent inhibition of I (K1) that did not differ at −50 and −110 mV. Simultaneous application of sildenafil and Ba(2+) at 0.1 µM revealed a massive inhibition of both inward and outward components of I (K1) (this synergy was missing at other tested combinations). The combined effect at 0.1 µM (45.7 ± 5.7 and 43.0 ± 6.9% inhibition at −50 and −110 mV, respectively) was significantly higher than a simple sum of almost negligible effects of the individual substances and it led to a significant prolongation of APD at both 23 and 37°C. To our knowledge, similar potentiation of the drug-channel interaction has not been described. The observed massive inhibition of I (K1) induced by a combined action of the vasodilator sildenafil and environmental contaminant Ba(2+) at a low concentration and resulting in a significant APD prolongation may contribute to the genesis of arrhythmias observed in some patients treated with sildenafil. Frontiers Media S.A. 2022-04-25 /pmc/articles/PMC9081525/ /pubmed/35548367 http://dx.doi.org/10.3389/fphar.2022.829952 Text en Copyright © 2022 Macháček, Švecová and Bébarová. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Macháček, Martin Švecová, Olga Bébarová, Markéta Combination of Sildenafil and Ba(2+) at a Low Concentration Show a Significant Synergistic Inhibition of Inward Rectifier Potassium Current Resulting in Action Potential Prolongation |
title | Combination of Sildenafil and Ba(2+) at a Low Concentration Show a Significant Synergistic Inhibition of Inward Rectifier Potassium Current Resulting in Action Potential Prolongation |
title_full | Combination of Sildenafil and Ba(2+) at a Low Concentration Show a Significant Synergistic Inhibition of Inward Rectifier Potassium Current Resulting in Action Potential Prolongation |
title_fullStr | Combination of Sildenafil and Ba(2+) at a Low Concentration Show a Significant Synergistic Inhibition of Inward Rectifier Potassium Current Resulting in Action Potential Prolongation |
title_full_unstemmed | Combination of Sildenafil and Ba(2+) at a Low Concentration Show a Significant Synergistic Inhibition of Inward Rectifier Potassium Current Resulting in Action Potential Prolongation |
title_short | Combination of Sildenafil and Ba(2+) at a Low Concentration Show a Significant Synergistic Inhibition of Inward Rectifier Potassium Current Resulting in Action Potential Prolongation |
title_sort | combination of sildenafil and ba(2+) at a low concentration show a significant synergistic inhibition of inward rectifier potassium current resulting in action potential prolongation |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081525/ https://www.ncbi.nlm.nih.gov/pubmed/35548367 http://dx.doi.org/10.3389/fphar.2022.829952 |
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