Antiarrhythmic and Hemodynamic Effects of Tropisetron in Anesthetized Rabbits

Tropisetron (ICS 205-930) is a novel drug that blocks serotonin (5-HT3) receptors and, at higher concentrations, potassium channels. Programmed electrical stimulation (PES) and tracer microspheres were used to investigate antiarrhythmic, systemic, and regional hemodynamic effects in anesthetized rabbits. Tropisetron (0.3, 1, and 3 mg/kg intravenously, i.v.) dose-dependently increased the effective refractory period (ERP) to a first and similarly to a second extrastimulus. The arrhythmias elicited by PES with one and two extrastimuli were suppressed dose dependently. The same doses and a higher dose (6 mg/kg i.v.) were tested for systemic, especially cardiodepressant, and regional hemodynamic activity in a second series of experiments. Doses < or = 3 mg/kg were almost devoid of systemic hemodynamic activity and did not alter the ECG. At the highest dose used (6 mg/kg), cardiodepression caused a decrease in blood pressure (BP), cardiac output (CO), and heart rate (HR) and an increase in central venous pressure (CVP). A selective increase in gastric blood flow was observed, starting at the lowest dose used. The highest cardiodepressant dose reversed this increase and decreased regional myocardial blood flow, especially to the subendocardial layer of the left ventricle, probably by lowering myocardial oxygen consumption. Antiarrhythmic effects thus start at 0.3 mg/kg, and doses < or = 3 mg/kg i.v. did not elicit hemodynamic side effects.