%0 Journal Article %1 Knaus2007 %A Knaus, A. %A Zong, X. %A Beetz, N. %A Jahns, R. %A Lohse, M. J. %A Biel, M. %A Hein, L. %D 2007 %J Circulation %K & Agents/*pharmacology Animals Bradycardia/chemically Cardiovascular Cation Cell Channels Channels/*antagonists Clonidine/*pharmacology Cyclic Female Ion Line Male Mice Muscle Nervous Nucleotide-Gated Proteins/antagonists Strains Sympathetic System/*drug effects induced inhibitors/*drug %N 7 %P 872-80 %T Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by clonidine %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17261653 %V 115 %X 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.

@article{Knaus2007, 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.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Knaus, A. and Zong, X. and Beetz, N. and Jahns, R. and Lohse, M. J. and Biel, M. and Hein, L.}, biburl = {https://www.bibsonomy.org/bibtex/22476f223a7dbbe12be0d8510d55607c0/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {bfaa75cc6d14b37e28dfb8ba53716d77}, intrahash = {2476f223a7dbbe12be0d8510d55607c0}, issn = {1524-4539 (Electronic) 1524-4539 (Linking)}, journal = {Circulation}, keywords = {& Agents/*pharmacology Animals Bradycardia/chemically Cardiovascular Cation Cell Channels Channels/*antagonists Clonidine/*pharmacology Cyclic Female Ion Line Male Mice Muscle Nervous Nucleotide-Gated Proteins/antagonists Strains Sympathetic System/*drug effects induced inhibitors/*drug}, month = {Feb 20}, note = {Knaus, Anne Zong, Xiangang Beetz, Nadine Jahns, Roland Lohse, Martin J Biel, Martin Hein, Lutz Research Support, Non-U.S. Gov't United States Circulation Circulation. 2007 Feb 20;115(7):872-80. Epub 2007 Jan 29.}, number = 7, pages = {872-80}, shorttitle = {Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by clonidine}, timestamp = {2010-12-14T18:22:13.000+0100}, title = {Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by clonidine}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17261653}, volume = 115, year = 2007 }