AUTHOR=Pytka Karolina , Lustyk Klaudia , Żmudzka Elżbieta , Kotańska Magdalena , Siwek Agata , Zygmunt Małgorzata , Dziedziczak Agnieszka , Śniecikowska Joanna , Olczyk Adrian , Gałuszka Adam , Śmieja Jarosław , Waszkielewicz Anna M. , Marona Henryk , Filipek Barbara , Sapa Jacek , Mogilski Szczepan 

TITLE=Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats

JOURNAL=Frontiers in Pharmacology

VOLUME=7

YEAR=2016

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2016.00229

DOI=10.3389/fphar.2016.00229

ISSN=1663-9812

ABSTRACT=<p>Studies proved that among all α<sub>1</sub>-adrenoceptors, cardiac myocytes functionally express only α<sub>1A</sub>- and α<sub>1B</sub>-subtype. Scientists indicated that α<sub>1A</sub>-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α<sub>1</sub>-adrenoceptors subtypes (i.e., α<sub>1A</sub> and α<sub>1B</sub>) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β<sub>1</sub>- and α<sub>1</sub>-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α<sub>1</sub>-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 α<sub>1</sub>-adrenoceptors but no affinity for β<sub>1</sub> receptors. Biofunctional studies revealed that the tested compounds blocked α<sub>1A</sub>-stronger than α<sub>1B</sub>-adrenoceptors, but except for HBK-19 they antagonized α<sub>1A</sub>-adrenoceptor weaker than α<sub>1D</sub>-subtype. HBK-19 showed the greatest difference in pA<sub>2</sub> values—it blocked α<sub>1A</sub>-adrenoceptors around seven-fold stronger than α<sub>1B</sub> 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 (ED<sub>50</sub> = 0.18–0.21) was comparable to that of carvedilol (ED<sub>50</sub> = 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 ED<sub>84</sub>. 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 α<sub>1A</sub>-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 α<sub>1A</sub>-receptor subtype is essential to attenuate adrenaline-induced arrhythmia.</p>