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The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α(1)-Adrenolytic Properties

Heart rhythm abnormalities are a cause of many deaths worldwide. Unfortunately, the available antiarrhythmic drugs show limited efficacy and proarrhythmic potential. Thus, efforts should be made to search for new, more effective, and safer pharmacotherapies. Several studies suggested that blocking t...

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Autores principales: Lustyk, Klaudia, Sałaciak, Kinga, Siwek, Agata, Sapa, Jacek, Zaręba, Paula, Gałuszka, Adam, Pytka, Karolina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499458/
https://www.ncbi.nlm.nih.gov/pubmed/36142287
http://dx.doi.org/10.3390/ijms231810381
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author Lustyk, Klaudia
Sałaciak, Kinga
Siwek, Agata
Sapa, Jacek
Zaręba, Paula
Gałuszka, Adam
Pytka, Karolina
author_facet Lustyk, Klaudia
Sałaciak, Kinga
Siwek, Agata
Sapa, Jacek
Zaręba, Paula
Gałuszka, Adam
Pytka, Karolina
author_sort Lustyk, Klaudia
collection PubMed
description Heart rhythm abnormalities are a cause of many deaths worldwide. Unfortunately, the available antiarrhythmic drugs show limited efficacy and proarrhythmic potential. Thus, efforts should be made to search for new, more effective, and safer pharmacotherapies. Several studies suggested that blocking the α(1)-adrenoceptors could restore normal heart rhythm in arrhythmia. In this study, we aimed to assess the antiarrhythmic potential of S-61 and S-73, two novel pyrrolidin-2-one derivatives with high affinity for α(1)-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with β(1)-adrenoceptors. Next, we assessed whether S-61 and S-73 could protect rats against arrhythmia in adrenaline-, calcium chloride- and aconitine-induced arrhythmia models. Both compounds showed potent prophylactic antiarrhythmic properties in the adrenaline-induced arrhythmia model, but the effect of S-61 was more pronounced. None of the compounds displayed antiarrhythmic effects in calcium chloride- or aconitine-induced arrhythmia models. Interestingly, both derivatives revealed therapeutic antiarrhythmic activity in the adrenaline-induced arrhythmia, diminishing heart rhythm irregularities. Neither S-61 nor S-73 showed proarrhythmic potential in rats. Finally, the compounds decreased blood pressure in rodents. The hypotensive effects were not observed after coadministration with methoxamine, which suggests the α(1)-adrenolytic properties of both compounds. Our results confirm that pyrrolidin-2-one derivatives possess potent antiarrhythmic properties. Given the promising results of our experiments, further studies on pyrrolidin-2-one derivatives might result in the development of a new class of antiarrhythmic drugs.
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spelling pubmed-94994582022-09-23 The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α(1)-Adrenolytic Properties Lustyk, Klaudia Sałaciak, Kinga Siwek, Agata Sapa, Jacek Zaręba, Paula Gałuszka, Adam Pytka, Karolina Int J Mol Sci Article Heart rhythm abnormalities are a cause of many deaths worldwide. Unfortunately, the available antiarrhythmic drugs show limited efficacy and proarrhythmic potential. Thus, efforts should be made to search for new, more effective, and safer pharmacotherapies. Several studies suggested that blocking the α(1)-adrenoceptors could restore normal heart rhythm in arrhythmia. In this study, we aimed to assess the antiarrhythmic potential of S-61 and S-73, two novel pyrrolidin-2-one derivatives with high affinity for α(1)-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with β(1)-adrenoceptors. Next, we assessed whether S-61 and S-73 could protect rats against arrhythmia in adrenaline-, calcium chloride- and aconitine-induced arrhythmia models. Both compounds showed potent prophylactic antiarrhythmic properties in the adrenaline-induced arrhythmia model, but the effect of S-61 was more pronounced. None of the compounds displayed antiarrhythmic effects in calcium chloride- or aconitine-induced arrhythmia models. Interestingly, both derivatives revealed therapeutic antiarrhythmic activity in the adrenaline-induced arrhythmia, diminishing heart rhythm irregularities. Neither S-61 nor S-73 showed proarrhythmic potential in rats. Finally, the compounds decreased blood pressure in rodents. The hypotensive effects were not observed after coadministration with methoxamine, which suggests the α(1)-adrenolytic properties of both compounds. Our results confirm that pyrrolidin-2-one derivatives possess potent antiarrhythmic properties. Given the promising results of our experiments, further studies on pyrrolidin-2-one derivatives might result in the development of a new class of antiarrhythmic drugs. MDPI 2022-09-08 /pmc/articles/PMC9499458/ /pubmed/36142287 http://dx.doi.org/10.3390/ijms231810381 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lustyk, Klaudia
Sałaciak, Kinga
Siwek, Agata
Sapa, Jacek
Zaręba, Paula
Gałuszka, Adam
Pytka, Karolina
The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α(1)-Adrenolytic Properties
title The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α(1)-Adrenolytic Properties
title_full The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α(1)-Adrenolytic Properties
title_fullStr The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α(1)-Adrenolytic Properties
title_full_unstemmed The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α(1)-Adrenolytic Properties
title_short The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α(1)-Adrenolytic Properties
title_sort antiarrhythmic and hypotensive effects of s-61 and s-73, the pyrrolidin-2-one derivatives with α(1)-adrenolytic properties
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499458/
https://www.ncbi.nlm.nih.gov/pubmed/36142287
http://dx.doi.org/10.3390/ijms231810381
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