AB321. SPR-48 The effects of myrbetriq on detrusor overactivity associated with suprasacral spinal cord injury (SCI) in rats

OBJECTIVE: β3-adrenoceptor agonists (BARA) represent a novel mechanism of action for direct relaxation of urinary bladder smooth muscle. Myrbetriq (MYR) is an FDA approved BARA developed by Astellas Pharma, and has proven to be very useful for treating overactive bladder. Preliminary data from this laboratory demonstrated a remarkable effect of a rat-specific BARA, CL-316,243 (CL), on the hallmark attributes of neurogenic bladder subsequent to spinal cord injury (SCI). This included an increase in true bladder capacity (TBC), a decrease in the number and amplitude of non-voiding contractions (NVC) and an increased filling compliance (C). The current report reflects a formalized preclinical study of both the rat specific BARA, CL, and MYR, in order to provide preclinical support for utilization of MYR in treating SCI patients with neurogenic detrusor overactivity. METHODS: Female rats (4 weeks post-SCI at T9–10, n=43, 10–11/group) were anesthetized with isoflurane and fitted with femoral vein, ureteral diversion and transvesical catheters. The animals were mounted in Ballman restraint cages to which they had been previously acclimated. Conscious cystometry was performed before and after 3 repeated vehicles (Veh 1–3) and 3 escalating 1/2 log doses of either CL or MYR, and their paired repeated vehicle controls (Veh 4–6) at 30-minute intervals. See figure for testing scheme protocol. Data were analyzed using ANOVA with repeated measures. P<0.05 was considered significant. RESULTS: Both CL and MYR significantly increased TBC and NVC count, MYR decreased maximal NVC amplitude, and CL increased C, relative to their respective repeated vehicle controls. CONCLUSIONS: The results of these studies support the use BARA for the treatment of NDO secondary to SCI, as at least one of the drugs tested was able to distinguish themselves from their repeated vehicle control groups as having a positive effect for each of the four measures. FUNDING SOURCE(S): an IIR grant from Astellas