The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α<sub>1</sub>-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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| Format: | Article |
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/18/10381 |
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| author | Klaudia Lustyk Kinga Sałaciak Agata Siwek Jacek Sapa Paula Zaręba Adam Gałuszka Karolina Pytka |
| author_facet | Klaudia Lustyk Kinga Sałaciak Agata Siwek Jacek Sapa Paula Zaręba Adam Gałuszka Karolina Pytka |
| author_sort | Klaudia Lustyk |
| collection | DOAJ |
| 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<sub>1</sub>-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<sub>1</sub>-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with β<sub>1</sub>-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<sub>1</sub>-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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| language | English |
| last_indexed | 2024-03-09T23:48:07Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c9cbaf30ee914089a439b9f161ab31ac2023-11-23T16:40:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123181038110.3390/ijms231810381The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α<sub>1</sub>-Adrenolytic PropertiesKlaudia Lustyk0Kinga Sałaciak1Agata Siwek2Jacek Sapa3Paula Zaręba4Adam Gałuszka5Karolina Pytka6Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Physiochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Automatic Control and Robotics, Silesian University of Technology, Akademicka 2A, 44-100 Gliwice, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandHeart 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<sub>1</sub>-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<sub>1</sub>-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with β<sub>1</sub>-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<sub>1</sub>-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.https://www.mdpi.com/1422-0067/23/18/10381alpha-1 adrenergic receptoralpha-1 adrenolyticspyrrolidin-2-onearrhythmiaadrenaline-induced arrhythmia |
| spellingShingle | Klaudia Lustyk Kinga Sałaciak Agata Siwek Jacek Sapa Paula Zaręba Adam Gałuszka Karolina Pytka The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α<sub>1</sub>-Adrenolytic Properties International Journal of Molecular Sciences alpha-1 adrenergic receptor alpha-1 adrenolytics pyrrolidin-2-one arrhythmia adrenaline-induced arrhythmia |
| title | The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α<sub>1</sub>-Adrenolytic Properties |
| title_full | The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α<sub>1</sub>-Adrenolytic Properties |
| title_fullStr | The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α<sub>1</sub>-Adrenolytic Properties |
| title_full_unstemmed | The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α<sub>1</sub>-Adrenolytic Properties |
| title_short | The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α<sub>1</sub>-Adrenolytic Properties |
| title_sort | antiarrhythmic and hypotensive effects of s 61 and s 73 the pyrrolidin 2 one derivatives with α sub 1 sub adrenolytic properties |
| topic | alpha-1 adrenergic receptor alpha-1 adrenolytics pyrrolidin-2-one arrhythmia adrenaline-induced arrhythmia |
| url | https://www.mdpi.com/1422-0067/23/18/10381 |
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