Effects of low temperature on the chronotropic and inotropic responses to zatebradine, E-4031 and verapamil in isolated perfused dog atria

We investigated the effects of hypothermia (25 degrees C) on the chronotrop ic and inotropic effects of zatebradine (a blocker of hyperpolarization-act ivated inward current, I-f), E-4031 (a blocker of the rapid type of the del ayed rectifier K+ current, I-Kr) 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 c urves to the right for the negative chronotropic and inotropic effects of v erapamil and for the negative chronotropic and positive inotropic effects o f zatebradine, but not for the negative chronotropic and positive inotropic effects of E-4031. Hypothermia attenuated the positive chronotropic respon se to isoproterenol or Bay k 8644 (an L type Ca2+ channel agonist) and was attenuated more than the inotropic one. Zatebradine selectively inhibited t he positive chronotropic response to isoproterenol at a normal temperature, but in hypothermia, it inhibited neither the chronotropic nor inotropic re sponses. E-4031 did not affect the positive responses to isoproterenol. The se results suggest that verapamil and zatebradine but not E-4031 influence the atrial rate and contractile force much less in hypothermia than in norm othermia and that the I-f and inward Ca2+ current are sensitive to hypother mia in the heart.