One of the key identifying pharmacological characteristics of the 3-adrenoceptor is its weak afinity for conventional -adrenoceptor antagonists

One of the key identifying pharmacological characteristics of the 3-adrenoceptor is its weak afinity for conventional -adrenoceptor antagonists. simultaneous injection of nisoxetine and fluoxetine at doses (30?mg?kg?1) that had no effect on VO2 when injected individually. It is concluded that activation of thermogenesis by sibutramine requires central reuptake inhibition of both serotonin and noradrenaline, resulting in improved efferent sympathetic activation of BAT thermogenesis 3-adrenoceptor, and that this contributes to the compound’s activity as an anti-obesity agent. using rat mind tissue display that sibutramine is a poor inhibitor of NA and 5-HT reuptake, whereas Metabolites 1 and 2 are approximately equipotent as the selective NA reuptake inhibitor desipramine and as the selective 5-HT reuptake inhibitor fluoxetine (Cheetham the jugular cannula. Serial blood samples (50?l) were taken through the Y-33075 same cannula at 1, 3, 5, 10, 20, 40 and 60?min after the 2DG injection. Samples were immediately deproteinized, centrifuged and the supernatant used for the dedication of blood glucose with a glucose oxidase kit (Boehringer, Germany) and plasma radioactivity (Beckman Ready Value scintillation cocktail and a Beckman LS6000 counter) and rats were killed 60?min after the administration of the 2DG, and the following cells were dissected, freeze-clamped and stored in liquid N2 prior to extraction and dedication of radioactive 2DG-6-phosphate: gastrocnemius, soleus, tibialis anterior, extensor digitorum longus, adductor longus, diaphragm, heart, brain, periovarian white colored adipose cells and interscapular brown adipose cells (BAT). Cells GU was determined by dividing the radioactivity (d.p.m.) of 2DG-6-phosphate in the tissues from the determined 60-min integral of the percentage of blood 2DG/blood glucose (d.p.m.?ng?1), and the results were expressed while ng Y-33075 glucose min?1?mg?1 damp weight of cells. Medicines Sibutramine hydrochloride monohydrate (BTS 54 524; Knoll Pharmaceuticals) was given orally (gavage) by dissolving in sterile water at a concentration designed to provide the appropriate doses in 1?ml?kg?1 body weight. In the GU experiment, sibutramine was given by intraperitoneal injection after dissolving in sterile saline. Additional drugs were dissolved in sterile saline and given by intraperitoneal or subcutaneous injection (see individual experiments). The other drugs used were: Y-33075 sibutramine Metabolite 1 (BTS 54354; improved sympathetic activity, this will activate all adrenoceptor subtypes ( and ), whereas the activity of BRL 35135 will be restricted primarily to 3-adrenoceptor. Open in a separate window Number 10 Assessment of the effects of sibutramine and BRL 35135 on BAT glucose utilization. Calculations based on data for sibutramine (SIB) in Table 2, and from Liu & Stock (1995) for BRL 35135 (BRL). The GU experiment indicated that sibutramine, like BRL 35135, was a highly effective agonist of BAT thermogenesis, and prompted an experiment to determine if the effects of sibutramine on VO2 were mediated by 3-adrenoceptor. BAT thermogenesis is mainly due to sympathetic activation of 3-adrenoceptor, and clarifies the potent thermogenic activity of selective 3-adrenoceptor agonists such as BRL 35135 (observe Stock, 1993). One of the important identifying pharmacological characteristics of the 3-adrenoceptor is definitely its poor afinity for standard -adrenoceptor antagonists. The low pA2 of standard selective and non-selective antagonists for the 3-adrenoceptor means it is possible to use doses of medicines such as atenolol, SEDC ICI 118551, propranolol and nadolol that selectively inhibit 1-adrenoceptor and 2-adrenoceptor reactions while leaving 3-adrenoceptor reactions intact (e.g. Carlisle & Stock, 1992; Liu pharmacology of sibutramine and its metabolites (Buckett conversion of sibutramine to M1, and the conversion of that to M2 cannot account for the slow onset of the thermogenic response to sibutramine. The fact that it takes 60C90?min to see the maximum effect of any of these compounds might suggest that penetration of the blood-brain barrier may be the Y-33075 limiting element, but a more likely explanation is that it is the slow rise in synaptic concentrations of 5-HT and noradrenaline.