Reduction of endothelin-1 binding and inhibition of endothelin-1-mediated detrusor contraction by naftidrofuryl

Abstract

Endothelin-1 (ET-1) causes urinary bladder smooth muscle contraction and the endothelin receptors A and B (ET(A) and ET(B)) are both known to be present in the rabbit urinary bladder. Alterations in ET-1 signalling have been implicated in the pathophysiology of urinary tract disorders secondary to bladder outlet obstruction and also in diabetic cystopathy. Naftidrofuryl (Naf) (marketed under the trade name Praxilene) improves walking distance in patients with peripheral vascular disease, an effect which may be partially attributed to ET-1 antagonism. The purpose of this study is to assess whether Naf will reduce ET-1 binding in the rabbit detrusor muscle and to assess whether there is inhibition of ET-1-mediated detrusor contraction. Detrusor smooth muscle strips were mounted in organ baths and cumulative response curves were measured for ET-1-mediated contractions in the presence and absence of 10(-6) M Naf (therapeutic concentration). In addition, ET-1 was added to the detrusor strips in the presence of the ET(A) antagonist, BQ123, and the ET(B) antagonist, BQ788, to identify the receptor subtype functionally involved. Overall inhibition of [(125)I]ET-1 binding by Naf was assessed using autoradiography. Identification of receptor-subtype binding reduction was assessed using the radioligands [(125)I]PD151242 and [(125)I]BQ3020. Naf inhibited ET-1-mediated detrusor contractions significantly (P<0.04), e.g. at 10(-10) M ET-1, contraction was completely abolished by Naf. Autoradiography indicated that Naf competitively inhibited [(125)I]ET-1 binding in a dose-dependent manner (IC(50)=3x10(-7) M). All radioligand binding was reduced indicating binding of Naf to both ET(A) and ET(B) receptors. Naf reduces binding of ET-1 to rabbit detrusor ET(A) and ET(B) receptors and inhibits ET-1-induced detrusor contractions mediated by ET(A) receptors. Naf may have therapeutic potential in the treatment of bladder disorders secondary to bladder outlet obstruction and diabetes mellitus.