Autoradiographic localisation and contractile properties of prostatic endothelin receptors in patients with bladder outlet obstruction.

Abstract

Previous studies have used endothelin (ET) receptor agonists and antagonists to localise ET receptor subtypes in prostatic tissue. We have utilised high affinity ET(A) ([(125)I]PD151242) and ET(B) ([(125)I]BQ3020) receptor-specific radioligands to determine the density and distribution of ET receptor subtypes in prostatic tissues obtained from patients with symptomatic benign prostatic hyperplasia (BPH). The contractile properties of the ET receptor subtypes as well as the effect of ET-1 on alpha(1)-adrenergic receptor-mediated prostatic smooth muscle contraction were assessed. Saturation binding and quantitative autoradiographic studies were performed using specific radioligands for ET(A) and ET(B) receptors on prostate sections obtained from patients with bladder outflow obstruction secondary to BPH. In vitro isometric tension studies were carried out to characterise the ET receptor subtypes in prostatic smooth muscle strips from the same group of patients. In addition, the effect of ET-1 on alpha(1)-adrenergic receptor-induced prostatic smooth muscle contraction was also investigated. There were dense ET(A) and ET(B) receptor-binding sites in the prostatic stroma. ET(A) receptor-binding sites were also prominent on the prostatic epithelium. ET-1 and sarafotoxin 6 c (ET(B) receptor agonist) elicited prostatic smooth muscle contraction (-log EC(50) 8.31+/-0.15 and 8.22+/-0.22 M, respectively). Both BQ123 (ET(A) antagonist) and BQ788 (ET(B) antagonist) significantly inhibited ET-1- and S6c-mediated prostatic smooth muscle contractile responses, respectively. ET-1 at sub-threshold concentrations significantly enhanced alpha(1)-adrenergic receptor-mediated prostatic smooth muscle contractile responses. ET(A) receptor-binding sites are prominent in both prostatic stroma and epithelium, whereas ET(B) receptor-binding sites were predominantly seen in the prostatic stroma in symptomatic BPH. Both ET(A) and ET(B) receptors mediate prostatic smooth muscle contraction. ET-1 enhances alpha(1)-adrenergic receptor-mediated contractile responses, suggesting that ET may play a pathophysiological role in bladder outlet obstruction associated with BPH.