Published online before print January 29, 2007, doi: 10.1161/CIRCULATIONAHA.106.667675
(Circulation. 2007;115:872-880.)
© 2007 American Heart Association, Inc.
Arrhythmia/Electrophysiology |
Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine
From the Department of Pharmacology and Toxicology (A.K., R.J., M.J.L.) and Department of Internal Medicine (R.J.), University of Würzburg, Würzburg, Germany; Department of Pharmacy–Center for Drug Research (X.Z., M.B.), Ludwig Maximilian University of Munich, München, Germany; and Institute of Experimental and Clinical Pharmacology and Toxicology (A.K., N.B., L.H.), University of Freiburg, Freiburg, Germany.
Correspondence to Lutz Hein, MD, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany. E-mail lutz.hein{at}pharmakol.uni-freiburg.de
Received October 1, 2006; accepted December 15, 2006.
Background— Inhibition of cardiac sympathetic tone represents an important strategy for treatment of cardiovascular disease, including arrhythmia, coronary heart disease, and chronic heart failure. Activation of presynaptic 
2-adrenoceptors is the most widely accepted mechanism of action of the antisympathetic drug clonidine; however, other target proteins have been postulated to contribute to the in vivo actions of clonidine.
Methods and Results— To test whether clonidine elicits pharmacological effects independent of 2-adrenoceptors, we have generated mice with a targeted deletion of all 3 2-adrenoceptor subtypes (2ABC–/–). 2ABC–/– mice were completely unresponsive to the analgesic and hypnotic effects of clonidine; however, clonidine significantly lowered heart rate in 2ABC–/– mice by up to 150 bpm. Clonidine-induced bradycardia in conscious 2ABC–/– mice was 32.3% (10 µg/kg) and 26.6% (100 µg/kg) of the effect in wild-type mice. A similar bradycardic effect of clonidine was observed in isolated spontaneously beating right atria from 2ABC-knockout and wild-type mice. Clonidine inhibited the native pacemaker current (If) in isolated sinoatrial node pacemaker cells and the If-generating hyperpolarization-activated cyclic nucleotide–gated (HCN) 2 and HCN4 channels in transfected HEK293 cells. As a consequence of blocking If, clonidine reduced the slope of the diastolic depolarization and the frequency of pacemaker potentials in sinoatrial node cells from wild-type and 2ABC-knockout mice.
Conclusions— Direct inhibition of cardiac HCN pacemaker channels contributes to the bradycardic effects of clonidine gene-targeted mice in vivo, and thus, clonidine-like drugs represent novel structures for future HCN channel inhibitors.
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