PROTECTIVE EFFECT OF AN ORAL ENDOTHELIN CONVERTING ENZYME INHIBITOR ON RAT DETRUSOR FUNCTION AFTER OUTLET OBSTRUCTION

Abstract

Endothelin (ET)-1, one of the most potent vasoconstrictors known, is converted from its less potent precursor big ET by the endothelin converting enzyme (ECE). In vitro studies suggest that ET has an important role in smooth muscle growth after bladder outlet obstruction (BOO). We investigated the effect of an orally administered ECE inhibitor by cystometry in conscious rats with and without BOO. BOO was produced in female rats by a standardized method and the animals were divided into 2 groups. One group received the ECE inhibitor WO-03028719 and the remaining animals received vehicle daily by oral gavage. Five sham operated animals served as controls and were treated with WO-03028719. Two weeks after surgery cystometry was performed. BOO led to a significant increase in bladder weight in vehicle treated animals and a nonsignificant increase in the treatment group. Micturition interval and volume increased in each obstructed group. Micturition pressure was significantly decreased in the vehicle group but unchanged in the BOO treatment group. Residual urine occurred in 4 of 11 BOO vehicle animals but not in the sham operated or BOO treatment group. Spontaneous nonvoiding bladder contractions occurred in 37% of BOO treatment animals but in 82% of the BOO vehicle group. Voiding contractions were markedly prolonged in the BOO vehicle group, while they were normal in the BOO treatment group. ECE inhibition did not prevent an increase in bladder weight after BOO but it appeared to have a beneficial effect on detrusor function and decrease detrusor overactivity in conscious rats.