ASP6432, a type 1 lysophosphatidic acid receptor antagonist, reduces urethral function during urine voiding and improves voiding dysfunction

Abstract

Current pharmacotherapies for voiding dysfunctions are in need of improvement. Lysophosphatidic acid (LPA) is a phospholipid that contracts the urethra by activating type 1 LPA receptors (LPA1). However, the role of LPA1 in regulating urethral tonus during urine voiding which primarily affects the voiding function has not been investigated. To elucidate the role of LPA1 in the regulation of urethral tonus during urine voiding, we investigated the effects of ASP6432, a novel LPA1 antagonist, and the α1-adrenoceptor antagonist tamsulosin on urethral perfusion pressure (UPP) at the filling phase (UPPbase) and the minimum UPP at the voiding phase (UPPnadir) in anesthetized rats under isovolumetric conditions. We further evaluated the effects of ASP6432 and tamsulosin on voiding dysfunction characterized by changes in post-void residual urine (PVR) and voiding efficiency (VE) induced by the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) in conscious rats using single cystometry. ASP6432 dose-dependently decreased UPPbase and UPPnadir, while tamsulosin reduced UPPbase but did not change UPPnadir. ASP6432 dose-dependently suppressed the L-NAME-induced increase in PVR and decrease in VE, whereas tamsulosin did not affect either PVR or VE. We demonstrate that ASP6432 reduced UPPnadir and ameliorated L-NAME-induced voiding dysfunction, neither of which were affected by tamsulosin. Our study results suggest that LPA1 has a significant role in regulating urethral tonus during urine voiding, and highlight the potential of ASP6432 for improving voiding dysfunctions associated with various lower urinary tract diseases.