Published Online
on January 29, 2007

A more recent version of this article appeared on February 20, 2007

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Submitted on October 1, 2006
Accepted on December 15, 2006

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide-Gated Pacemaker Channels by Clonidine

Anne Knaus , Xiangang Zong MD, Nadine Beetz , Roland Jahns MD, Martin J. Lohse MD, Martin Biel PhD, and Lutz Hein MD^*

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.

^* To whom correspondence should be addressed. E-mail: lutz.hein{at}pharmakol.uni-freiburg.de.

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 (I_f) in isolated sinoatrial node pacemaker cells and the I_f-generating hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 and HCN4 channels in transfected HEK293 cells. As a consequence of blocking I_f, 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.

Key words: receptors, adrenergic, alpha • heart rate • ion channels • pharmacology

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