Electrocardiographic effects of zatosetron and ondansetron,two 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 5HT₃ 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.