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

frontiers in pharmacology

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