Doxazosin modifies serotonin-mediated rabbit urinary bladder contraction. Potential clinical relevance.
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 alpha1 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.
Khan
M A
MA
Department of Urology, Royal Free and University College, Medical School, University College, London.
Thompson
C S
CS
Dashwood
M R
MR
Mumtaz
F H
FH
Mikhailidis
D P
DP
Morgan
R J
RJ
D000818:Animals; D001345:Autoradiography; D017292:Doxazosin / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*; D013565:Sympatholytics / Q000494:pharmacology*; D014316:Tritium; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology*
D013565:Sympatholytics; D014316:Tritium; D012701:Serotonin; D017292:Doxazosin