Benidipine induces thermogenesis in brown adipose tissue by releasing endogenous noradrenaline: a possible mechanism for the anti-obesity effect of calcium antagonists

Abstract

BACKGROUND: Anti-obesity effects of calcium antagonists such as benidipine and nifedipine have been described in rodent obesity models, but the mode of action of the calcium antagonists as anti-obesity agents has not been established. OBJECTIVE: To examine whether the anti-obesity effects of calcium antagonists (here benidipine) could be ascribed to a direct stimulation of brown adipose tissue (BAT) thermogenesis. METHODS: Examination of the ability of benidipine to induce thermogenesis (increased rate of oxygen consumption) in isolated brown-fat cells from rats, mice and hamsters -and in intact cold-acclimated rats. RESULTS: Benidipine itself, or in combination with any dose of noradrenaline (NA), was totally unable to induce or augment thermogenesis in isolated brown-fat cells of any species tested. However, it markedly induced thermogenesis in intact animals (approx 60% increase over resting metabolic rate). This effect could be fully inhibited by propranolol. CONCLUSION: Benidipine is itself without thermogenic effect. The thermogenic response in-vivo (and thus presumably the anti-obesity effect) is probably secondary to a previously described general side-effect of calcium antagonists: a release of NA from sympathetic nerves, here most likely directly from nerves in the BAT. The antiobesity effect of benedipine is thus probably not due to its calcium channel blocking effect. PERSPECTIVES: It is probable that the anti-obesity effects of calcium antagonists reported in several models of genetically obese rodents (MSG-obese and agouti mice, SHHFaMcc-fa cp and JCR:LA-corpulent rats) are mediated via an indirect stimulation of BAT. To what extent calcium antagonists may induce similar effects in a clinical situation, is currently unknown.

Up-regulation of Muscle Uncoupling Protein 3 Gene Expression by Calcium Channel Blocker, Benidipine Hydrochloride in Rats

“…First, the present findings show that benidipine upregulates UCP1 gene expression in BAT and reduces body weight in rats. These findings are consistent with previous studies [7,15,17], in which the activity of BAT was increased by benidipine. Using guanosine-5' diphosphate showed that benidipine activated BAT function in obese MSG mice [7].…”

“…Karasawa et al reported that benidipine did not significantly affect plasma NE concentrations, although nifedipine and amlodipine significantly increased plasma NE concentrations [19]. Zhao et al using isolated brown fat cells from rats reported that benidipine itself has no thermogenic effect, and that the thermogenic response in-vivo is probably secondary to a release of NE from sympathetic nerves, here most likely directly from nerves in the BAT [17]. On the other hand, BAT is not only a target for pharmacotherapy of obesity and insulin resistance but also an endocrine tissue with leptin secretion and high insulin sensitivity.…”

The Effects of Calcium Channel Blocker Benidipine and Calmodulin Antagonist W7 on GDP-Binding Capacity of Brown Adipose Tissue in Mice

“…As described above, the addition of benidipine into laboratory chow could result in an increase in BAT blood flow and BAT thermogenic activity, as well as the decrease in adiposity of laboratory rodents [18][19][20]. However, benidipine's effect on increasing BAT thermogenesis in intact animals cannot be reproduced in the in vitro study [20].…”

“…The administration dosages of benidipine and W7 used in this study were consistent with previous reports [20,24]. Brown-fat cells were incubated for 4 h at 37°C.…”

“…Benidipine, a calcium antagonist, is not only used to treat hypertension by inhibiting L-type calcium channels in the heart and peripheral vascular system but also has an anti-obesity action. Dietary benidipine administration can increase blood flow and thermogenic activity in brown adipose tissue (BAT) and reduce the adiposity of laboratory rodents [18][19][20]. Furthermore, calmodulin, which is the major cytosolic calcium-binding protein, provides four binding sites for calcium ions and participates in intracellular calcium-dependent signal transduction [21].…”