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Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats.
- Source :
- Frontiers in Pharmacology; 8/3/2016, p1-14, 14p
- Publication Year :
- 2016
-
Abstract
- Studies proved that among all a<subscript>1</subscript>-adrenoceptors, cardiac myocytes functionally express only a<subscript>1A</subscript>- and a<subscript>1B</subscript>-subtype. Scientists indicated that a<subscript>1A</subscript>-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of a<subscript>1</subscript>-adrenoceptors subtypes (i.e., a<subscript>1A</subscript> and a<subscript>1B</subscript>) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β<subscript>1</subscript>- and a<subscript>1</subscript>-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at a<subscript>1</subscript>-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 a<subscript>1</subscript>-adrenoceptors but no affinity for β<subscript>1</subscript> receptors. Biofunctional studies revealed that the tested compounds blocked a<subscript>1A</subscript>-stronger than a<subscript>1B</subscript>-adrenoceptors, but except for HBK-19 they antagonized a<subscript>1A</subscript>-adrenoceptor weaker than a<subscript>1D</subscript>-subtype. HBK-19 showed the greatest difference in pA<subscript>2</subscript> values--it blocked a<subscript>1A</subscript>-adrenoceptors around seven-fold stronger than a<subscript>1B</subscript> 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<subscript>50</subscript> = 0.18-0.21) was comparable to that of carvedilol (ED<subscript>50</subscript> = 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<subscript>84</subscript>. 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 a<subscript>1A</subscript>-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 a<subscript>1A</subscript>-receptor subtype is essential to attenuate adrenaline-induced arrhythmia. [ABSTRACT FROM AUTHOR]
- Subjects :
- ARRHYTHMIA treatment
ADRENERGIC receptors
Subjects
Details
- Language :
- English
- ISSN :
- 16639812
- Database :
- Complementary Index
- Journal :
- Frontiers in Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 117202795
- Full Text :
- https://doi.org/10.3389/fphar.2016.00229