Zatebradine Attenuates Cyclic Amp‐related Positive Chronotropic but Not Inotropic Responses in Isolated, Perfused Right Atria of the Dog

Abstract

1. Inhibition of I(f) or ICa by zatebradine has been reported in mammalian SA nodal cells. We thus investigated whether zatebradine differentially attenuates the positive chronotropic and inotropic responses to norepinephrine, isoproterenol, NKH 477 (an adenylyl cyclase activator), 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 (a calcium channel agonist) in the isolated, blood-perfused dog atrium. 2. When zatebradine (0.03-1 mumol) 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 tachycardia (by approximately 80% from the control) more effectively than the spontaneous sinus rate (by approximately 30% from the control). 3. Zatebradine similarly attenuated the positive chronotropic but not inotropic responses to isoproterenol, NKH 477 and IBMX. Fifty per cent inhibition doses of zatebradine (0.10-0.18 mumol) for the chronotropic responses to each substance were not significantly different. 4. On the other hand, zatebradine attenuated neither positive chronotropic nor inotropic responses to Bay k 8644. 5. We therefore suggest that zatebradine selectively attenuates the positive chronotropic but not inotropic responses to cyclic AMP-related substances due to inhibition of I(f) but not ICa in the dog heart.

Acute Effects of Zatebradine on Cardiac Conduction and Repolarization

“…In both anesthetized rabbit and canine models, zatebradine induced a reduction in heart rate and stroke volume without a significant negative inotropic effect (9,10). In anesthetized cats, zatebradine abolished STsegment elevation in the epicardial electrogram induced by repeated coronary occlusions (11).…”

Negative Chronotropic and Inotropic Effects of U-92032, a Novel T-Type Ca2+ Channel Blocker, on the Isolated, Blood-Perfused Dog Atrium

“…Zatebradine, an If blocker different from IK and Ica-L blockers, directly and selectively decreased the sinus rate without decreases in the atrial contractile force and attenuated the increase in the sinus rate induced by adrenergic interventions (11,12). Thus, because of non selective depression by U-92032 of the chronotropic and inotropic effects, U-92032 may not be useful as a brady cardic agent in the heart.…”