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Effect of muscarinic antagonists on micturition pressure measured by cystometry in normal, conscious rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
2002 (English)In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 59, no 6, 963-968 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To establish an in vivo model to screen new muscarinic antagonists for the treatment of overactive urinary bladder and to calculate the respective ID(50) values.

METHODS: The conscious rat cystometry model was modified to determine a complete dose-response curve in each animal. Spontaneous micturition was induced by infusion of room-temperature saline into rat bladders at a constant rate of 12 mL/hr. Cumulative doses of muscarinic antagonists administered in the femoral vein caused dose-dependent inhibition of the urinary bladder contraction measured as the micturition pressure. In addition, the in vitro pK(B) values for atropine, PNU-200577 (DD01), tolterodine, oxybutynin, and terodiline were determined in carbachol-contracted rat bladder strips.

RESULTS: The rank order of the in vivo ID(50) values were atropine (14 +/- 4 nmol/kg), PNU-200577 (22 +/- 12 nmol/kg), tolterodine (94 +/- 20 nmol/kg), oxybutynin (175 +/- 89 nmol/kg), darifenacin (236 +/- 144 nmol/kg), desethyloxybutynin (313 +/- 209 nmol/kg), propiverine (4561 +/- 2079 nmol/kg), and terodiline (18,339 +/- 5348 nmol/kg). Tolterodine and PNU-200577 caused a parallel shift of the in vitro concentration-response curve to the right and did not alter the maximal contraction. The ID(50) values correlated significantly with the in vitro rat pK(B) and human bladder pA(2) values.

CONCLUSIONS: The present results suggest that the rat cystometry model can be used in in vivo screening for new muscarinic antagonists.

Place, publisher, year, edition, pages
2002. Vol. 59, no 6, 963-968 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-89759DOI: 10.1016/S0090-4295(02)01535-2PubMedID: 12031395OAI: oai:DiVA.org:uu-89759DiVA: diva2:161494
Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2013-06-10Bibliographically 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.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1137
Neurosciences, Neurovetenskap
National Category
Research subject
Medical Pharmacology
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
Available from: 2002-04-05 Created: 2002-04-05Bibliographically approved

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