BACKGROUND: The antiarrhythmic drugs quinidine and verapamil are known to block alpha1-adrenoceptors (alpha1ARs). Alpha1ARs are a heterogeneous family of three subtypes (alpha1A, alpha1B, and alpha1D), and little is known about the effects of quinidine and verapamil on the different human alpha1AR subtypes. METHODS AND RESULTS: Reverse transcriptase-polymerase chain reaction showed that all alpha1AR subtypes are expressed in both human heart (atrium and ventricle) and the mesenteric artery. Pharmacological profiles of quinidine and verapamil actions on the alpha1AR subtypes were characterized with Chinese hamster ovary cells stably expressing cloned human alpha1AR subtypes. Radioligand binding studies showed that quinidine and verapamil had high affinities for all alpha1AR subtypes. Also, both drugs synergistically inhibited alpha1AR-mediated inositol 1,4,5-triphosphate production at the clinical effective concentration range (1 micromol/L quinidine and 0.1 micromol/L verapamil). CONCLUSIONS: The results show that all alpha1AR subtypes are expressed in the human cardiovascular system and that quinidine and verapamil may have a potent, synergistic inhibitory effect on the alpha1ARs. Clinically observed hypotension after quinidine plus verapamil can be explained by their synergistic inhibitory effects on human alpha1ARs.
BACKGROUND: The antiarrhythmic drugs quinidine and verapamil are known to block alpha1-adrenoceptors (alpha1ARs). Alpha1ARs are a heterogeneous family of three subtypes (alpha1A, alpha1B, and alpha1D), and little is known about the effects of quinidine and verapamil on the different human alpha1AR subtypes. METHODS AND RESULTS: Reverse transcriptase-polymerase chain reaction showed that all alpha1AR subtypes are expressed in both human heart (atrium and ventricle) and the mesenteric artery. Pharmacological profiles of quinidine and verapamil actions on the alpha1AR subtypes were characterized with Chinese hamster ovary cells stably expressing cloned human alpha1AR subtypes. Radioligand binding studies showed that quinidine and verapamil had high affinities for all alpha1AR subtypes. Also, both drugs synergistically inhibited alpha1AR-mediated inositol 1,4,5-triphosphate production at the clinical effective concentration range (1 micromol/L quinidine and 0.1 micromol/L verapamil). CONCLUSIONS: The results show that all alpha1AR subtypes are expressed in the human cardiovascular system and that quinidine and verapamil may have a potent, synergistic inhibitory effect on the alpha1ARs. Clinically observed hypotension after quinidine plus verapamil can be explained by their synergistic inhibitory effects on human alpha1ARs.
Authors: Gizem Kaykı-Mutlu; Olga Papazisi; Meindert Palmen; A H Jan Danser; Martin C Michel; Ebru Arioglu-Inan Journal: Cells Date: 2020-11-04 Impact factor: 6.600