Zusammenfassung
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.
Nutzer