Abstract:
:Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e., α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 μg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity toward α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A-stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values-it blocked α1A-adrenoceptors around seven-fold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18, and HBK-19 (ED50 = 0.18-0.21) was comparable to that of carvedilol (ED50 = 0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18, and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18, and HBK-19 decreased heart rhythm at ED84. All compounds significantly lowered blood pressure in normotensive rats. HBK-18 showed the strongest hypotensive properties (the lowest active dose: 0.01 mg/kg). HBK-19 was the only compound in the group, which did not show hypotensive effect at antiarrhythmic doses. HBK-16, HBK-17, HBK-18, HBK-19 showed weak antioxidant properties. Our results indicate that the studied 2-methoxyphenylpiperazine derivatives that possessed stronger α1A-adrenolytic properties (i.e., HBK-16, HBK-17, HBK-18, and HBK-19) were the most active compounds in adrenaline-induced arrhythmia. Thus, we suggest that the potent blockade of α1A-receptor subtype is essential to attenuate adrenaline-induced arrhythmia.
journal_name
Front Pharmacoljournal_title
Frontiers in pharmacologyauthors
Pytka K,Lustyk K,Żmudzka E,Kotańska M,Siwek A,Zygmunt M,Dziedziczak A,Śniecikowska J,Olczyk A,Gałuszka A,Śmieja J,Waszkielewicz AM,Marona H,Filipek B,Sapa J,Mogilski Sdoi
10.3389/fphar.2016.00229subject
Has Abstractpub_date
2016-08-03 00:00:00pages
229issn
1663-9812journal_volume
7pub_type
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pub_type: 杂志文章,评审
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doi:10.3389/fphar.2017.00800
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pub_type: 杂志文章
doi:10.3389/fphar.2012.00152
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doi:10.3389/fphar.2020.561306
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journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2020.00841
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journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2019.00246
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pub_type: 杂志文章,已发布勘误
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pub_type: 撤回出版物
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journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2016.00197
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doi:10.3389/fphar.2019.00355
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pub_type: 杂志文章
doi:10.3389/fphar.2018.00064
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pub_type: 杂志文章,评审
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