Submitted on March 23, 2007
Accepted on May 22, 2007
Muscarinic Potassium Channels Augment Dynamic and Static Heart Rate Responses to Vagal Stimulation
Masaki Mizuno1*, Atsunori Kamiya1, Toru Kawada1, Tadayoshi Miyamoto1, Shuji Shimizu1, and Masaru Sugimachi1
1 Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
* To whom correspondence should be addressed. E-mail: m-mizuno{at}ri.ncvc.go.jp.
Vagal control of heart rate (HR) is mediated by direct and indirect actions of acetylcholine (ACh). Direct action of ACh activates the muscarinic potassium (KACh) channels, whereas indirect action inhibits adenylyl cyclase. The role of the KACh channels in the overall picture of vagal HR control remains to be elucidated. We examined the role of the KACh channels in the transfer characteristics of the HR response to vagal stimulation. In nine anesthetized rabbits with sinoaortic denervation and vagotomy, the vagal nerve was stimulated using a binary white-noise signal (0-10 Hz) to examine the dynamic characteristic, and was stimulated in a stepwise manner (5, 10, 15, and 20 Hz every minute) to examine the static characteristic. The dynamic transfer function from vagal stimulation to HR approximated a first-order, low-pass filter with a lag time. Tertiapin, a selective KACh channel blocker (30 nmol kg-1 iv) significantly decreased the dynamic gain from 5.0 ± 1.2 (mean ± SD) to 2.0 ± 0.6 beats min-1 Hz-1 (P<0.01) and the corner frequency from 0.25 ± 0.03 to 0.06 ± 0.01 Hz (P<0.01) without changing the lag time (0.37 ± 0.04 vs. 0.39 ± 0.05 sec). Moreover, tertiapin significantly attenuated the vagal stimulation-induced HR decrease by 46 ± 21, 58 ± 18, 65 ± 15 and 68 ± 11 % at stimulus frequencies of 5, 10, 15 and 20 Hz, respectively. We conclude that KACh channels contribute to a rapid HR change and to a larger decrease in the steady-state HR in response to more potent tonic vagal stimulation.
