Miho Kasama, Yasuyuki Furukawa (*), Takeshi Oguchi, Yuji Hoyano and Shigetoshi
Chiba
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto
390-8621, Japan
(*) To whom correspondence should be addressed.
Abstract: We investigated the effects of hypothermia (25 C) on
the chronotropic and inotropic effects of zatebradine (a blocker of hyperpolarization-activated
inward current, If), E-4031 (a blocker of the rapid type of the
delayed rectifier K+ current, IKr) and verapamil,
and on the positive cardiac responses to isoproterenol after treatment with
zatebradine and E-4031 in isolated, blood-perfused dog atria. Hypothermia
shifted the dose-response curves to the right for the negative chronotropic
and inotropic effects of verapamil and for the negative chronotropic and
positive inotropic effects of zatebradine, but not for the negative chronotropic
and positive inotropic effects of E-4031. Hypothermia attenuated the positive
chronotropic response to isoproterenol or Bay k 8644 (an L type Ca2+
channel agonist) and was attenuated more than the inotropic one. Zatebradine
selectively inhibited the positive chronotropic response to isoproterenol
at a normal temperature, but in hypothermia, it inhibited neither the chronotropic
nor inotropic responses. E-4031 did not affect the positive responses to
isoproterenol. These results suggest that verapamil and zatebradine but
not E-4031 influence the atrial rate and contractile force much less in
hypothermia than in normothermia and that the If and inward Ca2+
current are sensitive to hypothermia in the heart.
Keywords: Zatebradine, E-4031, Verapamil, Hypothermia, Dog heart