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Effects of an EP2 and EP3 Receptor Dual Agonist, ONO ‐8055, on a Radical Hysterectomy‐Induced Underactive Bladder Model in Monkeys
Author(s) -
MATSUYA Hidekazu,
SEKIDO Noritoshi,
KIDA Jun,
MASHIMO Hiroko,
WAKAMATSU Daisuke,
OKADA Hiroki
Publication year - 2018
Publication title -
luts: lower urinary tract symptoms
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.451
H-Index - 15
eISSN - 1757-5672
pISSN - 1757-5664
DOI - 10.1111/luts.12166
Subject(s) - agonist , receptor , carbachol , overactive bladder , hysterectomy , urology , stimulation , chemistry , medicine , endocrinology , anesthesia , surgery , pathology , alternative medicine
Objectives The objective was to develop an underactive bladder ( UAB ) model in primates and to evaluate the potential of prostanoid EP2 and EP3 receptor dual agonist ONO ‐8055 to become a therapeutic agent for UAB . Methods A surgical procedure resembling radical hysterectomy was performed on female cynomolgus monkeys. Subsequently, in vitro muscle strip studies were performed using bladder muscle strips from normal monkeys and monkeys that underwent surgery. In addition, uroflowmetric data were obtained at specified days after the surgery. To evaluate the effects of ONO ‐8055 and distigmine ( DIS ) on voiding function in the UAB monkey model, uroflowmetry was performed approximately 1 week after the surgery, before and after the cumulative intravenous administration of the compounds at 2 h intervals. Results In the bladder muscle strip studies, the responses to potassium chloride at 2 months, and carbachol and electrical field stimulation from 2 weeks decreased significantly. Voided volume ( VV ), maximum flow rate ( Q max), and average flow rate ( Q ave) decreased after surgery, while voiding time ( VT ) increased. In this model, ONO ‐8055 and DIS significantly increased VV and Q max. DIS prolonged VT , while ONO ‐8055 had no effect. The results also showed that ONO ‐8055 increased Q ave. Conclusions We developed a neurogenic UAB model in primates. As ONO ‐8055 improved voiding function in this model to at least the same degree as DIS , this EP2 and EP3 receptor dual agonist has the potential to be a candidate for neurogenic UAB pharmacotherapy.