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Stress incontinence and overactive bladder are disorders with a common symptom, urinary incontinence, which is a serious medical and social handicap. Several neurotransmitters regulate the function of the lower urinary tract, including noradrenaline, acetylcholine, and serotonin.The present study is part of the search for pharmacological incontinence drugs. The aims of this thesis were to improve the existing pharmacological treatments of urinary incontinence and to look for alternative treatments: i) an α1-adrenergic agonist that preferentially affects urethral over blood pressure was tested in vivo; ii) a modified cystometry model was developed for screening of muscarinic antagonists, by construction of a complete dose-response curve in each individual animal; iii) a new muscarinic antagonist, PNU-171990, was pharmacologically characterized in vitro and in vivo; iv) functional differences of the isomers of the muscarinic agonist BM-5 were characterized in the urinary bladder and ileum, in vitro and in vivo; v) the role of serotonin 5-HT2A, 5-HT3 and 5-HT4 receptors were characterized on urinary bladder contractions in vivo.In the search for urethra selective compounds, the α1-adrenoceptors agonists phenylephrine and phenylpropanolamine selectively enhanced blood pressure as compared to the urethral pressure in rabbit. This is in contrast to the effect of oxymetazoline and NS-49. Muscarinic antagonists produced a dose-dependent inhibition of the volume-induced micturition pressure in the rat. PNU-171990, a non-selective muscarinic antagonist, revealed selectivity for urinary bladder pressure over salivation (P

Objective The aim of this study was to investigate the distribution of alpha1- and alpha2-adrenoceptors in the urethra and urinary bladder of the female pig, cat, guinea-pig and rat. Materials and methods The binding distributions of an alpha1-adrenoceptor ligand (3H-prazosin) and an alpha2-adrenoceptor ligand (3H-rauwolscine) were determined using in vitro autoradiography. Autoradiograms were analysed by combining computer-based image analysis and light microscopy. Results In the pig, guinea-pig and rat urethra 3H-prazosin binding was highest in the muscle layer. In the cat urethra 3H-prazosin binding could not be analysed due to a negative chemography artefact. In the pig, cat and guinea-pig urethra 3H-rauwolscine binding was highest in the urothelium, followed by the sub-mucosa, with low levels in muscle. Little 3H-rauwolscine binding was observed in the rat urethra. In the urinary bladder of all species 3H-prazosin binding was low. In the rat bladder, binding was higher in the trigone than in the dome. In the pig, cat and guinea-pig bladder 3H-rauwolscine binding was highest in the mucosa. with little binding in muscle or lamina propria. In the rat bladder, there was little binding and no regional differences. Conclusions Alpha1-adrenoceptors were predominantly located in urethral smooth muscle, indicating their contractile importance in maintaining continence. Alpha2-Adrenoceptors were present in the urethral submucosa and bladder mucosa, but not in muscle, suggesting a role in regulation of blood flow, urethral lubrication and tumescence, but not in contraction.