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-subunits
,Departments of Medicine, Cardiovascular Divisions of 1 Children's Hospital and 2 Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
Acetylcholine released on
parasympathetic stimulation slows heart rate through activation of
muscarinic receptors on the sinus nodal cells and subsequent opening of
the atrial muscarinic potassium channel (KACh).
KACh is directly activated by G protein 
-subunits. To
elucidate the physiological role of G for the regulation of heart
rate and electrophysiological function in vivo, we created transgenic
mice with a reduced amount of membrane-bound G protein by
overexpressing nonprenylated G2-subunits in their hearts
using the 
-myosin heavy chain promoter. At baseline and after
muscarinic stimulation with carbachol, heart rate and heart rate
variability were determined with electrocardiogram telemetry in
conscious mice and in vivo intracardiac electrophysiological studies in anesthetized mice. Reduction of the amount of functional G
protein by >50% caused a pronounced blunting of the carbachol-induced bradycardia as well as the increases in time- and frequency-domain indexes of heart rate variability and baroreflex sensitivity that were
observed in wild types. In addition, sinus node recovery time
and inducibility of atrial arrhythmias were reduced in transgenic mice.
Our data demonstrate in vivo that G plays a crucial role for
parasympathetic heart rate control, sinus node automaticity, and atrial
arrhythmia vulnerability.
atrial arrhythmia; heart rate regulation; in vivo electrophysiology; sinus node pacemaker activity; transgenic mice
Deceased 20 February 2000.
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