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(Circulation. 2002;106:2459.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Paradoxical Effect of Sibutramine on Autonomic Cardiovascular Regulation

Andreas L. Birkenfeld, MD; Christoph Schroeder, MD; Michael Boschmann, MD; Jens Tank, MD, PhD; Gabi Franke; Friedrich C. Luft, MD; Italo Biaggioni, MD; Arya M. Sharma, MD; Jens Jordan, MD

From the Franz-Volhard Clinical Research Center (A.L.B., C.S., J.T., G.F., F.C.L., A.M.S., J.J.), Medical Faculty of the Charité, Humboldt-University, Berlin, Germany; German Institute of Human Nutrition (M.B.), Potsdam, Germany; and Autonomic Dysfunction Service (I.B.), Vanderbilt University, Nashville, Tenn.

Correspondence to Jens Jordan, MD, Clinical Research Center, Haus 129, Franz-Volhard-Clinic, Humboldt University, Wiltbergstraße 50, 13125 Berlin, Germany. E-mail jordan{at}fvk-berlin.de

Background— Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment. Norepinephrine reuptake inhibition with sibutramine conceivably could exacerbate arterial hypertension and promote cardiovascular disease.

Methods and Results— In 11 healthy subjects (7 men, age 27±2 years, body mass index 23.1±0.7 kg/m²), we compared the effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. In addition, we tested sibutramine in combination with metoprolol. Testing was conducted in a double-blind and crossover fashion. Supine systolic blood pressure was 113±3 mm Hg with placebo, 121±3 mm Hg with sibutramine (P<0.001 versus placebo), and 111±2 mm Hg with the combination of sibutramine and metoprolol. Similarly, sibutramine increased upright blood pressure. Sibutramine substantially increased upright heart rate. This effect was abolished with metoprolol. The blood pressure response to cold pressor and handgrip testing was attenuated with sibutramine compared with placebo. Furthermore, sibutramine decreased low-frequency oscillations of blood pressure and plasma norepinephrine concentrations in the supine position.

Conclusions— The cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous system effects. The inhibitory clonidine-like action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect. Our findings strongly suggest that current concepts regarding the action of sibutramine on the sympathetic nervous system should be reconsidered.

Key Words: obesity • norepinephrine • nervous system, sympathetic • catecholamines

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