ELECTROCARDIOGRAPHIC EFFECTS OF ZATOSETRON AND ONDANSETRON, 2 5HT3 RECEPTOR ANTAGONISTS, IN ANESTHETIZED DOGS

The pharmacology of 5-hydroxytryptamine3 (5HT3)-antagonists is an area under active investigation, and several agents of this class are currently under development for multiple therapeutic indications. Recently, two 5HT, receptor antagonists of a tropane derived series, ICS 205 930 and zatosetron, have been shown to alter electrocardiographic properties of heart muscle. A prototypical, but structurally distinct (imidazole) 5HT3-antagonist, ondansetron, was examined for its comparative cardiovascular activity in anesthetized dogs at intravenous doses of 0.66-5.25 mg/kg. Similar to zatosetron, a significant, dose-dependent prolongation of the duration of the action potential of the electrocardiogram (Q-T(c) interval) occurred following ondansetron exposure, with a maximum increase of 28%. Other cardiovascular parameters (heart rate, mean arterial pressure, pulmonary pressure, cardiac output, peripheral vascular resistance, stroke volume and work index) were essentially unchanged by ondansetron treatment. At equivalent 5HT3 blocking doses, both ondansetron and zatosetron prolonged the Q-T(c) interval in anesthetized dogs similarly. However, for both compounds, the doses required to increase Q-T(c) interval were higher than the doses required to demonstrate 5HT3 receptor blockade. The fact that ondansetron, an imidazole, exhibited electrophysiological effects on cardiac muscle like the 5HT3 receptor antagonists derived from tropane suggests that the electrocardiographic effects are related to some property shared by 5HT3 receptor antagonists rather than a property of the tropane structure.