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

Gehrmann, Josef, Michael Meister, Colin T. Maguire, Donna C. Martins, Peter E. Hammer, Eva J. Neer, Charles I. Berul, and Ulrike Mende. Impaired parasympathetic heart rate control in mice with a reduction of functional G protein -subunits. Am J Physiol Heart Circ Physiol 282: H445–H456, 2002; 10.1152/ajpheart. 00565.2001.—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 G 2-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 timeand 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.