ZATEBRADINE ATTENUATES CYCLIC AMP-RELATED POSITIVE CHRONOTROPIC BUT NOT INOTROPIC RESPONSES IN ISOLATED, PERFUSED RIGHT ATRIA OF THE DOG

1. Inhibition of I-f or I-Ca by zatebradine has been reported in mamma lian SA nodal cells. We thus investigated whether zatebradine differen tially attenuates the positive chronotropic and inotropic responses to norepinephrine, isoproterenol, NKH 477 (an adenylyl cyclase activator ), 3-isobutyl-1-methyl-xanthine (IBMX) and Bay k 8644 (a calcium chann el agonist) in the isolated, blood-perfused dog atrium. 2. When zatebr adine (0.03-1 mu mol) decreased sinus rate from 104 +/- 4.5 to 73 +/- 4.9 beats/min dose-dependently, it selectively attenuated the positive chronotropic but not inotropic responses to norepinephrine in a dose- related manner. Zatebradine decreased the norepinephrine-induced tachy cardia (by approximately 80% from the control) more effectively than t he spontaneous sinus rate (by approximately 30% from the control). 3. Zatebradine similarly attenuated the positive chronotropic but not ino tropic responses to isoproterenol, NKH 477 and IBMX, Fifty per cent in hibition doses of zatebradine (0.10-0.18 pmol) for the chronotropic re sponses to each substance were not significantly different. 4. On the other hand, zatebradine attenuated neither positive chronotropic nor i notropic responses to Bay k 8644. 5. We therefore suggest that zatebra dine selectively attenuates the positive chronotropic but not inotropi c responses to cyclic AMP-related substances due to inhibition of It b ut not Ic, in the dog heart.