| Abstract | 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 alpha2-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 alpha2-adrenoceptors, we have generated mice with a targeted deletion of all 3 alpha2-adrenoceptor subtypes (alpha2ABC-/-). Alpha2ABC-/- mice were completely unresponsive to the analgesic and hypnotic effects of clonidine; however, clonidine significantly lowered heart rate in alpha2ABC-/- mice by up to 150 bpm. Clonidine-induced bradycardia in conscious alpha2ABC-/- mice was 32.3% (10 microg/kg) and 26.6% (100 microg/kg) of the effect in wild-type mice. A similar bradycardic effect of clonidine was observed in isolated spontaneously beating right atria from alpha2ABC-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 alpha2ABC-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. |
| Authors | Anne Knaus, Xiangang Zong, Nadine Beetz, Roland Jahns, Martin J Lohse, Martin Biel, Lutz Hein
(Affiliation: Department of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.)
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| Journal | Circulation
(Circulation)
Vol. 115
Issue 7
Pg. 872-80
(Feb 20 2007)
ISSN: 1524-4539 United States |
| PMID | 17261653
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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| Chemical References |
- Cardiovascular Agents
- Cyclic Nucleotide-Gated Cation Channels
- HCN2 potassium channel
- HCN4 protein, human
- Ion Channels
- Muscle Proteins
- Clonidine
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| Topics |
- Animals
- Bradycardia
(chemically induced)
- Cardiovascular Agents
(pharmacology)
- Cell Line
- Clonidine
(pharmacology)
- Cyclic Nucleotide-Gated Cation Channels
- Female
- Ion Channels
(antagonists & inhibitors, drug effects)
- Male
- Mice
- Mice, Inbred Strains
- Muscle Proteins
(antagonists & inhibitors, drug effects)
- Sympathetic Nervous System
(drug effects)
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