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Characterization of a new muscarinic antagonist PNU-171990 in guinea pig, cat and human smooth muscle
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
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Article in journal (Refereed) Submitted
Identifiers
URN: urn:nbn:se:uu:diva-89760OAI: oai:DiVA.org:uu-89760DiVA: diva2:161495
Available from: 2002-04-05 Created: 2002-04-05Bibliographically approved
In thesis
1. Functional Models in the Search for Pharmacological Treatment of Urinary Incontinence: The Role of Adrenergic, Cholinergic, and Serotonergic Receptors
Open this publication in new window or tab >>Functional Models in the Search for Pharmacological Treatment of Urinary Incontinence: The Role of Adrenergic, Cholinergic, and Serotonergic Receptors
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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<0.05). (R)-BM-5 induced bladder contraction and saliva secretion in cats. The selective serotonin 5-HT2A and 5-HT3 receptor antagonists, ketanserin and tropisetron, both inhibited the effect of chemically induced bladder contraction in the anaesthetized cat.

In conclusion, an urethral-selective α1A-adrenoceptor agonist may be a good treatment of stress incontinence. A bladder-selective competitive muscarinic antagonist is considered a good pharmacotherapy for overactive bladder. In addition, the 5-HT2A and 5-HT3 receptor antagonist may improve lower urinary tract symptoms.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 52 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1137
Keyword
Neurosciences, Neurovetenskap
National Category
Neurology
Research subject
Medical Pharmacology
Identifiers
urn:nbn:se:uu:diva-1927 (URN)91-554-5278-7 (ISBN)
Public defence
2002-05-15, sal C2:301, Uppsala biomedicinska centrum, Uppsala, 13:15
Opponent
Available from: 2002-04-05 Created: 2002-04-05Bibliographically approved

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