title: Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats.
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.
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Pytka
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Lustyk
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Żmudzka
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kotańska
authors.affiliation: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zygmunt
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dziedziczak
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Śniecikowska
authors.affiliation: Control and Robotics Group, Institute of Automatic Control, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology Gliwice, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Olczyk
authors.affiliation: Control and Robotics Group, Institute of Automatic Control, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology Gliwice, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Gałuszka
authors.affiliation: Systems Engineering Group, Institute of Automatic Control, Faculty of Automatic Control, Electronics and Informatics, Silesian University of Technology Gliwice, Poland.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Śmieja
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Waszkielewicz
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Henryk
authors.initials: H
authors.lastname: Marona
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.
authors.forename: Szczepan
authors.initials: S
authors.lastname: Mogilski
keywords: 2-methoxyphenylpiperazine; antiarrhythmic agents; arrhythmia; hypotensive; α1-adrenolytics; α1A-adrenoceptor antagonist; α1B-adrenoceptor antagonist; α1D-adrenoceptor antagonist