Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2499
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 4 1560-1563
Copyright © 2007 by The Endocrine Society
Sympathetic Vasomotor Tone Determines Blood Pressure Response to Long-Term Sibutramine Treatment
Karsten Heusser,
Stefan Engeli,
Jens Tank,
Andre Diedrich,
Susanne Wiesner,
Juergen Janke,
Friedrich C. Luft and
Jens Jordan
Franz-Volhard Clinical Research Center (K.H., S.E., J.T., S.W., J.Ja., F.C.L., J.Jo.), Medical Faculty of the Charité and HELIOS Klinikum, 13125 Berlin, Germany; and Autonomic Dysfunction Service (A.D.), Vanderbilt University, Nashville, Tennessee 37232-2195
Address all correspondence and requests for reprints to: Jens Jordan, M.D., Franz-Volhard Clinical Research Center, Haus 129, Charité-Campus Buch, Wiltbergstr. 50, 13125 Berlin, Germany. E-mail: jens.jordan{at}charite.de.
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Abstract
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Context: The serotonin and norepinephrine transporter inhibitor sibutramine is a widely used antiobesity drug. In acute studies, the peripheral sympathomimetic effect of sibutramine was counteracted by a central sympatholytic action.
Objective: The objective was to test the hypothesis that blood pressure responses to long-term sibutramine therapy may be related to sympathetic nerve traffic before treatment in a prospective open-label study in an academic clinical research center.
Patients: This study comprised 20 obese subjects (body mass index, 30–40 kg/m2; age, 30–57 yr) receiving 5 d of placebo treatment followed by open-label 15 mg/d sibutramine and hypocaloric diet over 12 wk.
Main Outcome Measures: Body weight, blood pressure, heart rate, muscle sympathetic nerve activity (MSNA) (microneurography), plasma catecholamines, and adipose tissue gene expression were measured.
Results: Open-label sibutramine treatment decreased body weight 4.1 kg (P < 0.01) and MSNA 17 bursts per minute (P = 0.001), and increased diastolic blood pressure 3 mm Hg (P < 0.05) and heart rate 8 bpm (P < 0.01). The change in blood pressure with sibutramine treatment was inversely correlated with initial MSNA (r2 = 0.34; P < 0.01). Chronic sibutramine treatment increased adrenoreceptor gene expression and plasma catecholamines.
Conclusions: The blood pressure response to sibutramine treatment is related to initial MSNA so that subjects with higher MSNA exhibit a smaller increase or even a decrease in blood pressure. The phenomenon might be explained by a sustained reduction in central sympathetic activity with sibutramine treatment.
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Introduction
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THE SEROTONIN AND norepinephrine transporter (NET) inhibitor sibutramine is a widely used antiobesity drug that mediates increased satiety (1, 2). A mildly elevated energy expenditure may also contribute to weight loss. Theoretically, NET inhibition with sibutramine could induce or worsen arterial hypertension. Yet in a recent analysis of two placebo-controlled trials, sibutramine did not elicit a major pressor response (3). The observation may be explained by the complex effect of sibutramine on the sympathetic nervous system. NET inhibition in peripheral tissues tends to increase norepinephrine overflow (4). However, NET blockade in the brain attenuates sympathetic outflow through activation of 
-2 adrenoreceptors (5). Indeed, sibutramine ingestion over a few days attenuates the pressor response to sympathetic stimuli in normal-weight subjects (6) and decreases centrally generated sympathetic activity more than 50% in obese subjects (7). The central nervous sympatholytic effect may attenuate sibutramine’s peripheral stimulatory actions. The mechanism may be particularly relevant in patients with raised sympathetic activity. We tested the hypothesis that the blood pressure response to chronic sibutramine is related to sympathetic activity before treatment. Moreover, we measured plasma catecholamines and adrenoreceptor gene expression in adipose tissue before and during sibutramine treatment.
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Patients and Methods
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We recruited 20 obese patients from our obesity clinic and through a press release (seven men, 13 women; age, 42 ± 2 yr; body mass index, 35 ± 0.7 kg/m2). Patients with secondary causes of obesity, diabetes mellitus, and other serious comorbid conditions were excluded. Written informed consent was obtained before study entry. The institutional review board approved all studies.
Patients underwent an initial cardiovascular evaluation including measurements of sympathetic activity and an adipose tissue biopsy after 5 d of treatment with placebo. Respiration and electrocardiogram were measured continuously (Cardioscreen; Medis GmbH, Ilmenau, Germany). Arterial blood pressure was determined as the mean of three supine measurements with an automated oscillometric brachial cuff (Dinamap; Critikon, Newport, UK). Muscle sympathetic nerve activity (MSNA) was recorded from the right peroneal nerve with a unipolar tungsten electrode as described previously (8, 9).
After the cardiovascular evaluation, we treated all patients for 3 months with 15 mg/d sibutramine in an open-label fashion. Patients received dietary advice from a dietitian before and monthly during the study (600 kcal/d caloric deficit). We determined supine blood pressure and heart rate during each visit. Patients with an increase in blood pressure 15 mm Hg or more or heart rate 15 bpm or more on two consecutive study visits were excluded from the study.
We determined venous plasma catecholamine concentrations and MSNA in the supine position before sibutramine treatment and again at the end of the treatment period. Before sibutramine treatment (placebo), after 5 d of sibutramine treatment, and after 12 wk of sibutramine treatment, we obtained abdominal sc adipose tissue samples (0.5–1.0 g) by needle biopsy from the periumbilical region as described previously (10). Adrenoreceptor mRNA expression was assessed by real-time PCR with 18S rRNA as endogenous control ("housekeeping gene") (10).
Statistics
All data are expressed as mean ± SEM. In case of exclusion from the study, the last observations were carried forward. Intraindividual differences were compared by the paired t-test or by one-way ANOVA followed by Dunnett’s posttest. Pearson’s correlation was used to assess the linear relationship between variables. P < 0.05 indicated statistical significance.
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Results
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Before sibutramine treatment, supine blood pressure was 123 ± 4/69 ± 2 mm Hg. Supine heart rate was 69 ± 2 bpm. MSNA was 28 ± 3 bursts per minute. During sibutramine treatment, seven patients had to be excluded because blood pressure and/or heart rate exceeded the specified margin. With sibutramine, body weight decreased 4.1 ± 0.8 kg. Blood pressure changed 5 ± 3/3 ± 1 mm Hg (P < 0.05 for diastolic blood pressure), and heart rate increased 8 ± 2 bpm (P < 0.01). The change in supine blood pressure with sibutramine treatment was negatively correlated with MSNA before treatment (Fig. 1
). Supine plasma norepinephrine was 197 ± 24 pg/ml before sibutramine treatment and 332 ± 27 pg/ml after 12 wk of sibutramine treatment (P < 0.001; n = 10). Supine plasma epinephrine was 9.3 ± 1.4 pg/ml before sibutramine treatment and 18.8 ± 1.7 pg/ml after 12 wk of sibutramine treatment (P < 0.001; n = 10). In nine of the 13 completers, we obtained MSNA recordings on the last day of chronic sibutramine treatment (baseline, 26 ± 4 bursts/min; sibutramine, 9 ± 2 bursts/min; P = 0.001).
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FIG. 1. Change in supine blood pressure over 3 months of open-label sibutramine treatment related to initial sympathetic activity. Filled circles, completers; open circles, last observations carried forward.
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Acute and chronic sibutramine treatment led to a similar up-regulation of -2A and ß-1 adrenoreceptor mRNA (P < 0.05; Fig. 2). ß-2 adrenoreceptor expression was increased with acute (P < 0.05), but not with chronic sibutramine treatment. ß-3 adrenoreceptor expression was not affected.
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FIG. 2. Gene expression data in adipose tissue biopsies before sibutramine treatment, after 5 d of sibutramine treatment, and after completion of chronic sibutramine treatment. We determined the mRNA expression of ß-1, 2, and 3, and -2 adrenoreceptors. *, P < 0.05 compared with baseline.
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Discussion
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We tested the hypothesis that centrally generated sympathetic activity influences the cardiovascular response to long-term sibutramine treatment. MSNA before treatment and the blood pressure response during sibutramine treatment were inversely correlated. Furthermore, we observed changes in plasma catecholamines and adrenoreceptor expression that may give further insight into sibutramine’s mechanism of action and the contribution of NET to long-term sympathetic regulation.
Previous studies showed reduction in sympathetic traffic with systemic NET inhibition by a central nervous mechanism (7, 9, 11). Thus, the net response of blood pressure and heart rate to acute NET inhibition may be the sum of peripheral sympathetic stimulation and central sympathetic inhibition. The balance between both mechanisms differs between organs. In the heart, NET inhibition results in sympathetic stimulation. In the kidney and in the vasculature, sympathetic inhibition prevails (11, 12).
In previous studies, weight reduction of 16 kg (13) and 7 kg (14) through caloric restriction reduced MSNA 35.5 and 15%, respectively. In our study, a much smaller reduction in body weight was associated with 65% reduction in MSNA suggesting that the central sympatholytic action of sibutramine is sustained with chronic treatment. The mechanism is relevant in how individual patients respond to chronic sibutramine treatment. In a patient with low sympathetic activity, sympathetic activity cannot be decreased further. The peripheral NET inhibition dominates and tends to increase blood pressure. In contrast, in a patient with higher sympathetic activity, the central sympatholytic effect may be fully expressed. In that patient, blood pressure may increase to a lesser degree or even decrease.
Venous norepinephrine and epinephrine concentrations were increased with chronic sibutramine treatment. In contrast, supine norepinephrine concentrations were not raised or even decreased with acute NET inhibition (6, 7, 15, 16). Our data suggest that increased plasma catecholamines with chronic sibutramine may be explained by peripheral mechanisms rather than tachyphylaxis to the central sympatholytic action.
The physiological response to a change in norepinephrine turnover is influenced by postsynaptic adrenoreceptor responsiveness. Previously, NET inhibition acutely increased isoproterenol mediated tachycardia and lipolysis (16). Our present study suggests that the phenomenon may be explained by up-regulation of postsynaptic adrenoreceptors. Up-regulation of the cardiac ß-1 adrenoreceptor could, conceivably, contribute to the orthostatic tachycardia in patients on NET inhibitors (6, 17) or patients with genetic NET deficiency (18).
The number of patients treated with selective or nonselective NET inhibitors for psychiatric diseases is much greater than the number of patients receiving sibutramine. Yet few studies addressed the effects of NET inhibitors on metabolism and cardiovascular regulation. The present and previous studies suggest that NET inhibitors elicit a central sympatholytic effect in the brain counteracting, at least in part, a peripheral sympathetic stimulation. Furthermore, NET inhibition alters the expression of postsynaptic adrenoreceptors at least in adipose tissue. The complex interaction of central nervous and peripheral mechanisms may explain the large variability in cardiovascular and metabolic responses to these drugs.
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Acknowledgments
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The authors thank Dr. J. Lenders from the Department of General Internal Medicine and Dr. J. J. Willemsen from the Department of Chemical Endocrinology (University Medical Center St. Radboud, Nijmegen, The Netherlands) for catecholamine determinations.
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Footnotes
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This work was supported in part by research grants from Abbott Laboratories and by the Deutsche Forschungsgemeinschaft. Abbott Laboratories provided study medications.
Author Disclosure: K.H., S.E., J.T., A.D., J.Ja., and F.C.L. have nothing to disclose. S.W. and J.Jo. received lecture fees from Abbott Pharmaceuticals.
First Published Online February 6, 2007
Abbreviations: MSNA, Muscle sympathetic nerve activity; NET, norepinephrine transporter.
Received November 14, 2006.
Accepted January 25, 2007.
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References
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Abstract
Introduction
