Abstract 11212: Mirabegron Relaxes Arteries From Human Visceral Adipose Tissue Through Antagonism of Alpha 1 -Adrenoceptors

Abstract

Introduction: As adequate perfusion has turned out to be a key determinant of adipose tissue (AT) remodeling, interest has grown regarding possible pharmacological interventions to promote this process and hence prevent the metabolic abnormalities associated with obesity and aging. Clinical trials have shown that mirabegron improves insulin sensitivity and glucose homeostasis in obese humans via stimulation of β 3 -adrenoceptors. Ligands of these receptors have also emerged as endothelium-dependent vasodilators in disparate human vascular beds. Hypothesis: We hypothesized, therefore, that mirabegron might exert vasodilator effect in human AT arteries and tried to characterize the underlying mechanism(s). Methods: Small arteries (116-734 μm) isolated from visceral AT were studied ex vivo in a wire myograph. After vessels had been contracted, changes in vascular tone in response to mirabegron were determined under different experimental conditions. Results: Mirabegron elicited vasorelaxation in vessels contracted with endothelin-1 (P<0001), but not in those contracted with U46619 or high-K + (both P>0.05). Notably, mirabegron markedly blunted the contractile effect of the α 1 -adrenergic receptor agonist phenylephrine (P<0.001). Also, vessels with removed endothelium contracted with phenylephrine had preserved vasorelaxing response to mirabegron. The anti-contractile action of mirabegron on phenylephrine-induced vasoconstriction was not influenced by the presence of the selective β 3 -adrenoceptor blocker L-748,337 (P<0.05); lack of involvement of β 3 -adrenoceptors was further supported by absent vascular staining for them at immunohistochemistry. Similar to the observed effect of mirabegron, preincubation with the α 1 -adrenoceptor antagonist doxazosin abolished the contractile response to phenylephrine. Conclusions: Mirabegron induces endothelium-independent vasorelaxation in arteries from visceral adipose tissue, likely through antagonism of α 1 -adrenoceptors. This action suggests that mirabegron might effectively improve visceral AT perfusion, thereby favoring a healthy AT remodeling and preventing, in turn, some of the unwanted cardiometabolic consequences of obesity and aging.