Hiroshi Imamura, Yasuyuki Furukawa (*), Miho Kasama, Yuji Hoyano, Takanori
Yonezawa and Shigetoshi Chiba
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto
390, Japan
(*) To whom correspondence should be addressed.
Abstract: Vagal activation influences various cardiac functions
as well as occurrence of arrhythmias. Inhibition of a rapid type of delayed
rectifier K+ current (IKr) has been reported to be effective for the treatment
of both ventricular and supraventricular arrhythmias. However, it is unknown
how IKr inhibition modulates the cardiac responses to vagal activation in
situ. We analyzed the effects of IKr inhibitors, dofetilide and E-4031,
and a class I antiarrhythmic agent, disopyramide, on electrical cardiac
responses to vagus stimulation in anesthetized dogs. Dofetilide (0.003 -
0.3 micromol/kg, i.v.), E-4031 (0.01 - 1 micromol/kg, i.v.) and disopyramide
(2.9 - 29 micromol/kg, i.v.) prolonged sinus cycle length (SCL), right atrial
effective refractory period (AERP) and ventricular effective refractory
period (VERP) dose-dependently. During cervical vagus stimulation-induced
prolongation of SCL, atrio-His (AH) interval and VERP and shortening of
AERP, dofetilide and E-4031 inhibited the prolongation of SCL but potentiated
the shortening of AERP. Dofetilide and E -4031 did not affect prolongations
of AH interval and VERP. On the other hand, disopyramide inhibited all electrical
cardiac responses to vagus stimulation. These results suggest that IKr inhibition
differentially modulate cardiac responses to vagus activation probably due
to a different role of IKr in each cardiac function in the heart in situ.
Keywords: Dofetilide, E-4031, Disopyramide, Parasympathetic nervous system,
Refractory period