Anti-Hypertensive Treatment Preserves Appetite Suppression While Preventing Cardiovascular Adverse Effects of Tesofensine in Rats

Objective: Tesofensine is a novel triple monoamine reuptake inhibitor which is in development for the treatment of obesity. Preclinical and clinical data suggest that appetite suppression is an important mechanism by which tesofensine exerts its robust weight reducing effect. Notably, the strong hypophagic response to tesofensine treatment is demonstrated to be linked to central stimulation of noradrenergic and dopaminergic neurotransmission. The sympathomimetic mode of action of tesofensine may also associate with the elevated heart rate and blood pressure observed in clinical settings, and we therefore sought experimentally to address this issue. Design and Methods: The anorexigenic and cardiovascular effects of tesofensine were studied simultaneously in telemetrized conscious rats in a combined real-time food intake and cardiovascular telemetry monitoring system. Results: Acute administration of tesofensine caused a dose-dependent hypophagic effect as well as increased heart rate and blood pressure. Interestingly, combined treatment with metoprolol (b(1) adrenoceptor blocker, 10-20 mg/kg, p.o.) fully prevented the cardiovascular sympathetic effects of tesofensine while leaving the robust inhibitory efficacy on food intake unaffected. Similarly, the angiotensin AT(1) receptor antagonist telmisartan (1.0-3.0 mg/kg, p.o.) did not interfere with the anti-obesity effects of tesofensine, however, telmisartan only partially reversed the increase in systolic blood pressure and had no effect on the elevated heart rate induced by tesofensine. Conclusion: These data suggests that tesofensine causes elevations in heart rate and blood pressure by increasing sympathetic activity, and that different adrenoceptor subtypes may be responsible for the anti-obesity and cardiovascular effects of tesofensine.