ABSTRACT
BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity treatment. Studies in healthy subjects suggested that sibutramine might have opposing effects on peripheral and central sympathetic activity; an increase in blood pressure has been claimed. Direct measurements of muscle sympathetic nerve activity (MSNA) in sibutramine-treated patients have not been conducted. METHODS AND RESULTS: Twenty nondiabetic obese men and women completed the study (mean body mass index, 35 +/- 3 kg/m2; mean age, 42 +/- 8 years). They were treated for 5 days with 15 mg sibutramine per day or matching placebo in a randomized, double-blind, crossover fashion. At the end of each intervention, heart rate, blood pressure, and MSNA were recorded. Patients underwent cold pressor testing and phenylephrine and nitroprusside infusions. RESULTS: The mean blood pressure (systolic/diastolic) was 118 +/- 13 mm Hg/70 +/- 9 mm Hg with placebo and 120 +/- 13 mm Hg/69 +/- 8 mm Hg with sibutramine (P = .29). The mean resting MSNA was 28 +/- 14 bursts/min with placebo and 12 +/- 10 bursts/min with sibutramine (P < .0001). Sibutramine attenuated the rise in blood pressure (25 +/- 9 mm Hg/9 +/- 9 mm Hg versus 31 +/- 12 mm Hg/14 +/- 9 mm Hg, P < .01) and MSNA (0.3 +/- 0.5 arbitrary units/min versus 1.0 +/- 1.1 arbitrary units/min, P = .01) in response to cold pressor testing. Baroreflex heart rate control was similar with sibutramine and with placebo. The sympathetic baroreflex was shifted such that at a given blood pressure, MSNA was substantially decreased (top, 44 +/- 1.23 bursts/min versus 58 +/- 2.99 bursts/min [P < .001]; center point, 65 +/- 0.32 mm Hg versus 67 +/- 0.81 mm Hg [P < .05]). CONCLUSIONS: Sibutramine treatment profoundly and selectively reduces sympathetic nerve traffic at rest and attenuates the responsiveness to sympathetic stimuli. Our data support the idea that sibutramine's peripheral sympathomimetic effect is counteracted by a central sympatholytic mechanism.
Subject(s)
Cyclobutanes/pharmacology , Neurotransmitter Uptake Inhibitors/pharmacology , Obesity/drug therapy , Vasomotor System/drug effects , Adult , Baroreflex/drug effects , Blood Pressure/drug effects , Cross-Over Studies , Cyclobutanes/therapeutic use , Double-Blind Method , Female , Heart Rate/drug effects , Humans , Male , Neurotransmitter Uptake Inhibitors/therapeutic useABSTRACT
At a given degree of adiposity, metabolic and cardiovascular risk varies markedly between individuals. Animal studies suggest that differentially expressed systemic activation of monocytes contributes to the obesity-associated risk variability. We tested the hypothesis that systemic monocyte activation is associated with changes in adipose tissue and skeletal muscle metabolism. In 17 obese hypertensive patients, we assessed CD11b expression on circulating monocytes, gene expression in adipose tissue biopsies, and obtained blood samples and adipose tissue and skeletal muscle microdialysis samples in the fasted state and during a glucose load. Patients were stratified into groups with higher and lower CD11b expression on monocytes. Expression of the macrophage marker CD68 was increased markedly in adipose tissue of subjects with higher CD11b expression. Although no differences in systemic insulin sensitivity were found between both groups, patients with higher peripheral CD11b expression showed a markedly augmented increase in dialysate glucose in adipose tissue during oral glucose tolerance testing and increased adipose tissue lipolysis as well. Our data demonstrate that human monocyte activation is associated with tissue-specific changes in glucose and lipid metabolism. These findings may be explained in part by monocyte/macrophage infiltration of adipose tissue, which appears to interfere with insulin responsiveness.
