Background-The antiarrhythmic drugs quinidine and verapamil are known to block ␣ 1 -adrenoceptors (␣ 1 ARs). ␣ 1 ARs are a heterogeneous family of three subtypes (␣ 1A , ␣ 1B , and ␣ 1D ), and little is known about the effects of quinidine and verapamil on the different human ␣ 1 AR subtypes. Methods and Results-Reverse transcriptase-polymerase chain reaction showed that all ␣ 1 AR subtypes are expressed in both human heart (atrium and ventricle) and the mesenteric artery. Pharmacological profiles of quinidine and verapamil actions on the ␣ 1 AR subtypes were characterized with Chinese hamster ovary cells stably expressing cloned human ␣ 1 AR subtypes. Radioligand binding studies showed that quinidine and verapamil had high affinities for all ␣ 1 AR subtypes. Also, both drugs synergistically inhibited ␣ 1 AR-mediated inositol 1,4,5-triphosphate production at the clinical effective concentration range (1 mol/L quinidine and 0.1 mol/L verapamil). Conclusions-The results show that all ␣ 1 AR subtypes are expressed in the human cardiovascular system and that quinidine and verapamil may have a potent, synergistic inhibitory effect on the ␣ 1 ARs. Clinically observed hypotension after quinidine plus verapamil can be explained by their synergistic inhibitory effects on human ␣ 1 ARs. (Circulation. 1998;97:1227-1230.)Key Words: receptors, adrenergic, alpha Ⅲ blood pressure Ⅲ catecholamines Ⅲ signal transduction Q uinidine is used for the treatment of ventricular arrhythmia and supraventricular tachycardia. 1 Verapamil is a calcium channel blocker that has been used in the treatment of vasospasm and supraventricular arrhythmia, and its vasodilator effect makes it useful for the treatment of other disorders, such as angina pectoris and hypertension.2 Because quinidine and verapamil are widely used for the treatment of a variety of cardiovascular disorders, their interaction is of potential significance. Serious hypotension, which responds to epinephrine, 3 has been reported after combined therapy with verapamil and quinidine, and radioligand binding studies using native tissues (rat heart and kidney for ␣ 1 AR and human platelets for ␣ 2 AR) have shown the interaction to be due to an additive blockade of ␣AR.
4,5␣ 1 ARs play an important role in human cardiovascular physiology. 6 Recently, the heterogeneity of ␣ 1 ARs has been recognized, 7,8 and three distinct cDNAs encoding human ␣ 1 AR subtypes (␣ 1A , ␣ 1B , and ␣ 1D ) have been cloned. 9 -11 Little is known, however, about the effects of quinidine and verapamil on each ␣ 1 AR subtype. The present study was therefore designed to assess this effect on human ␣ 1 AR subtypes by use of human cloned ␣ 1 ARs.
Methods
Reverse Transcriptase-Polymerase Chain ReactionAutopsy samples of myocardium and mesenteric artery were analyzed. Total RNA from each tissue was reverse transcribed, and first-strand cDNA was used as a template in PCR (94°C for 60 seconds, 55°C for 30 seconds, and 72°C for 60 seconds) as previously described. 9 The primers CATCGTGGTCGGCTGCT TCGTCCTCTGCTG (sens...