Comparison of alpha 1-adrenoceptor agonists in canine urethral pressure profilometry and abdominal leak point pressure models.
OBJECTIVE
We describe and compare the usefulness of 3 minimally invasive dog urethral function models to demonstrate the efficacy potential of alpha 1 agonists for stress urinary incontinence. From this overall composite dataset the efficacy profiles of the alpha 1A selective agonist A-61603 and the active metabolite of midodrine ST-1059 were specifically compared.


METHODS
Isoflurane anesthetized multiparous female beagle dogs were used in all studies. Intraurethral pressure was measured using a 7Fr balloon catheter. Profilometry was performed using an 8Fr Millar transducer catheter. Bladder pressure required to produce leakage in response to external abdominal ballottements of increasing intensity was measured using a 5Fr transurethral catheter. Agonist responses were measured before and after increasing cumulative intravenous doses of each compound in each test.


RESULTS
Agonist induced increases in maximal urethral closure and leak point pressure strongly correlated in linear fashion (R(2) = 0.94), as did measurements of agonist induced increases in proximal intraurethral pressure using 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 intravenously each caused dose dependent increases in maximum urethral closure, leak point and intraurethral pressure.


CONCLUSIONS
While the dose range for which alpha 1 agonists affect urethral pressure 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 directly evaluates efficacy to protect against leakage caused by increases in abdominal pressure. This leak point pressure test appears be useful for the preclinical evaluation of compounds used to treat stress urinary incontinence.
Brune
M E
ME
Neurological and Urological Disease Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-6118, USA.
O'Neill
A B
AB
Gauvin
D M
DM
Katwala
S P
SP
Altenbach
R J
RJ
Brioni
J D
JD
Hancock
A A
AA
Sullivan
J P
JP
D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D011312:Pressure; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D014521:Urethra / Q000187:drug effects / Q000502:physiology*; D014546:Urinary Catheterization; D014563:Urodynamics
D058646:Adrenergic alpha-1 Receptor Agonists; D018340:Receptors, Adrenergic, alpha-1