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