Doxazosin modifies serotonin-mediated rabbit urinary bladder contraction

Abstract

5-Hydroxytryptamine (5-HT) induces rabbit detrusor contractions via 5-HT₃ receptors. Similarly, 5-HT₄ receptors are known to be present in the human bladder. Doxazosin, a non-selective α₁ antagonist, is used for the symptomatic relief of bladder outflow obstruction. Previous work has shown that doxazosin inhibits 5-HT₂-mediated platelet shape change. Hence, the aim of this study was to assess, using organ baths and autoradiography, whether doxazosin has any 5-HT-inhibiting activity in the rabbit detrusor. Detrusor strips from adult New Zealand White rabbits were placed in organ baths; phenoxybenzamine (10⁻⁵ M) was added to block alpha-receptors. After KCl responses were assessed, the tissues were exposed to 10⁻³ M 5-HT. Subsequently, the strips were incubated with doxazosin or ondansetron (10⁻⁵ M; 5-HT₃ antagonist) followed by a further exposure to 5-HT. In some experiments, after the initial 5-HT-induced contractions, the tissues were washed and then re-exposed to 5-HT. These latter experiments acted as controls. Low-resolution autoradiography was performed on detrusor sections to assess the effect of doxazosin on 5-HT binding. These sections were analyzed densitometrically. Doxazosin and ondansetron produced a significant reduction in 5-HT-mediated contractions. Inhibition by doxazosin was in a concentration-dependent manner. Autoradiography demonstrated a significant reduction in [³H]-5-HT binding by doxazosin. Doxazosin significantly inhibits 5-HT-mediated contractions in the rabbit detrusor. This effect appears to be mainly mediated via 5-HT₃ receptor inhibition. Autoradiographic evidence suggests that doxazosin reduces 5-HT binding in the rabbit detrusor. The beneficial effects of doxazosin in bladder outflow obstruction may be due, at least in part, to 5-HT antagonism.