title: Anti-hypertensive treatment preserves appetite suppression while preventing cardiovascular adverse effects of tesofensine in rats.
abstract: 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.
  
  
  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 (b1 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 AT1 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: NeuroSearch A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.
authors.forename: Bo Hjorth
authors.initials: BH
authors.lastname: Bentzen
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Lars
authors.initials: L
authors.lastname: Hyveled-Nielsen
authors.forename: Claus
authors.initials: C
authors.lastname: Sundgreen
authors.forename: Jørgen Buus
authors.initials: JB
authors.lastname: Lassen
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001066:Appetite / Q000187:drug effects*; D001067:Appetite Depressants / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D002149:Energy Intake / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use; D009765:Obesity / Q000517:prevention & control*; D017207:Rats, Sprague-Dawley; D013566:Sympathomimetics / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019440:Anti-Obesity Agents; D000959:Antihypertensive Agents; D001067:Appetite Depressants; D001562:Benzimidazoles; D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D013566:Sympathomimetics; C518479:Tesofensine; D008790:Metoprolol; D000077333:Telmisartan