EVALUATION OF THE EFFECT OF ENDOTHELIN-1 AND CHARACTERIZATION OF THE SELECTIVE ENDOTHELIN-A RECEPTOR ANTAGONIST PD155080 IN THE PROSTATE

Purpose: To evaluate the contractile effect of endothelin-1 (ET-1) on prostatic urethral pressure and to characterize the effect of the sele ctive ETA receptor antagonist PD155080 on ET-1 mediated prostatic uret hral pressure. Materials and Methods: The effect of intravenous ET-1 a dministration on canine urethral pressure was determined in the presen ce and absence of PD 155080. The affinity of PD155080 for endothelin m ediated contraction was determined using antagonist dissociation studi es. Saturation and competition binding studies were performed using [I -125] ET-1 in both human and canine prostate. Results: ET-1 bolus inje ction elicited shallow and prolonged increases the prostatic urethral pressure. Pretreatment with PD155080 totally abolished the urethral co ntractile response to ET-1. Specific [I-125] ET-1 binding was saturabl e and of high affinity. Two ET receptor subtypes (ETA receptor, ETB re ceptor) have been identified in human prostate. The ratio of ETA to ET B receptors was approximately 1.5:1 in both human and canine prostates . Isometric tension studies revealed that PD155080 shifted the ET-1 do se-response curves to the right and exhibited no effect on the ETB rec eptor selective agonist sarafotoxin dose-response curves. Conclusion: ET-1 mediates prostate smooth muscle tone and may play a role in the p athophysiology and treatment of benign prostatic hyperplasia (BPH).