Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated
pacemaker channels by clonidine
A. Knaus, X. Zong, N. Beetz, R. Jahns, M. Lohse, M. Biel, and L. Hein. Circulation, 115 (7):
872-80(February 2007)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..
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.
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.
%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
}