Inhibitory effects of vibegron, a β3-adrenoceptor agonist, on the myogenic contractile and mechanosensitive afferent activities in an obstructed rat bladder

Abstract

To determine the role of β3-adrenoceptor agonists on bladder sensory facilitation related to bladder myogenic contractile activities in bladder hyperactivity, we investigated the effects of vibegron, a β3-adrenoceptor agonist, on the bladder and sensory function by evaluating cystometry and mechanosensitive single-unit afferent activities (SAAs), respectively, in a male rat model of bladder outlet obstruction (BOO).BOO was created by partial ligation of the urethra. Ten days after the surgical procedure, cystometric and SAA measurements were taken under two distinct conditions: a conscious-restrained condition, in which the bladder was constantly filled with saline, and a urethane-anesthetized condition involving an isovolumetric process with saline. For each measurement, vibegron (3 mg/kg) or its vehicle was administered intravenously after the data were reproducibly stable. In addition, the expression of β3-adrenoceptor and substance P (SP), a sensory neuropeptide, in the bladder was further evaluated following immunohistochemical procedures.Number of non-voiding contractions (NVCs) in cystometry was decreased after vibegron-administration, which was a significant change from vehicle group. Number of microcontractions and SAAs of Aδ- and C-fibers were significantly decreased by vibegron-administration. Furthermore, β3-adrenocepor and SP were co-expressed in the suburothelium layer of the bladder.These findings indicated that vibegron showed inhibitory effects on NVCs and microcontractions of the bladder, and SAAs of the Aδ- and C-fibers in BOO rats. The study suggested that vibegron can partly inhibit the mechanosensitive afferent transduction via Aδ- and C-fibers by suppressing bladder myogenic contractile activities in the rat bladder hyperactivity associated with BOO.