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Vol. 282, Issue 2, H445-H456, February 2002

Impaired parasympathetic heart rate control in mice with a reduction of functional G protein -subunits

Josef Gehrmann^1,*, Michael Meister^2,*, Colin T. Maguire¹, Donna C. Martins², Peter E. Hammer¹, Eva J. Neer^2,, Charles I. Berul^1,*, and Ulrike Mende^2,*

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 (K_ACh). K_ACh 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

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^* J. Gehrmann and M. Meister as well as C. I. Berul and U. Mende contributed equally to the study.

Deceased 20 February 2000.

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