Comparison of alpha 1-adrenoceptor agonists in canine urethral pressure profilometry and abdominal leak point pressure models

Purpose: We describe and compare the usefulness of 3 minimally invasive dog urethral function models to demonstrate the efficacy potential of alpha1 a gonists for stress urinary incontinence. From this overall composite datase t the efficacy profiles of the alpha 1A selective agonist A-61603 and the a ctive metabolite of midodrine ST-1059 were specifically compared. Materials and Methods: Isoflurane anesthetized multiparous female beagle do gs were used in all studies. Intraurethral pressure was measured using a 7F r balloon catheter. Profilometry was performed using an 8Fr Millar transduc er catheter. Bladder pressure required to produce leakage in response to ex ternal abdominal ballottements of increasing intensity was measured using a 5Fr transurethral catheter. Agonist responses were measured before and aft er increasing cumulative intravenous doses of each compound in each test. Results: Agonist induced increases in maximal urethral closure and leak poi nt pressure strongly correlated in linear fashion (R-2 = 0.94), as did meas urements of agonist induced increases in proximal intraurethral pressure us ing the microtransducer or balloon catheter technique (R-2 = 0.87). A dose of 0.01 to 1 nmol./kg. A-61603 and 10 to 1,000 nmol./kg. ST-1059 intravenou sly each caused dose dependent increases in maximum urethral closure, leak point and intraurethral pressure. Conclusions: While the dose range for which al agonists affect urethral pre ssure was adequately predicted by any of the 3 methods used, the leak point pressure assay described has the advantage of being a dynamic test that di rectly evaluates efficacy to protect against leakage caused by increases in abdominal pressure. This leak point pressure test appears be useful for th e preclinical evaluation of compounds used to treat stress urinary incontin ence.