Acetylcholine (ACh) released from the stimulated vagus nerve decreases heart rate via modulation of several types of ion channels expressed in cardiac pacemaker cells. Although the muscarinic-gated potassium channel I(KACH) has been implicated in vagally mediated heart rate regulation, questions concerning the extent of its contribution have remained unanswered. To assess the role of I(KACH) in heart rats regulation in vivo, we generated a mouse line deficient in I(KACH) by targeted disruption of the gene coding for GIRK4, one of the channel subunits. We analyzed heart rate and heart rate variability at rest and after pharmacological manipulation in unrestrained conscious mice using electrocardiogram (ECG) telemetry. We found that I(KACH) mediated approximately half of the negative chronotropic effects of vagal stimulation and adenosine on heart rate. In addition, this study indicates that I(KACH) is necessary for the fast fluctuations in heart rate responsible for beat-to-beat control of heart activity, both at rest and after vagal stimulation. Interestingly, noncholinergic systems also appear to modulate heart activity through I(KACH). Thus, I(KACH) is critical for effective heart rate regulation in mice.
Bibliographical noteFunding Information:
We would like to acknowledge Dr. Andrew Spicer, Stephanie Munger, Suresh Savarirayan, Dr. Matthew Kennedy, Dr. J. P. Saul, Dr. Marina Picciotto, Luba Krapivinsky, Anita Jennings, Dr. Gary Mitchell, and Drs. Marc and Janice Pfeffer for their technical assistance, kind advice, or for reviewing the manuscript. This work was supported by a National Institutes of Health grant awarded to D. E. C. and S. J. G. and a National Institutes of Health training grant to K. W. All mouse experiments were conducted according to protocols approved by the Children's Hospital Animal Care and Utilization Committee.