Gender comparison of muscarinic receptor expression and function in rat and human urinary bladder: differential regulation of M2 and M3 ... View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2003-03-28

AUTHORS

Christian Kories, Claudia Czyborra, Charlotte Fetscher, Tim Schneider, Susanne Krege, Martin C. Michel

ABSTRACT

Since symptoms of bladder dysfunction occur more frequently in women than in men and since muscarinic receptors are the physiologically most important system to mediate bladder contraction, we have compared the number, subtype distribution and function of muscarinic receptors in bladders from male and female rats. Muscarinic receptor function was also assessed in bladder strips from male and female human bladder. Male and female rats expressed a similar number of muscarinic receptors (144±5 vs. 140±6 fmol/mg protein in saturation radioligand binding). While competition binding curves for the moderately M2-selective methoctramine were not consistently better fitted by a two-site model, most competition curves for the M3-selective darifenacin were biphasic and yielded 29±10% and 31±7% high affinity sites (corresponding to M3 receptors) in male and females, respectively. Immunoreactivity of α-subunits of the G-proteins Gq/11, Gi1/2, Gi3 and Gs did not significantly differ between both genders. The muscarinic receptor agonist carbachol similarly stimulated inositol phosphate accumulation in bladder slices from male and female rats with calculated maximum responses of 69±17 and 77±18% over basal and pEC50 values of 4.90±0.45 and 4.40±0.46, respectively. While darifenacin inhibited carbachol-stimulated inositol phosphate formation approximately 100-fold more potently than methoctramine, each antagonist was similarly potent in both genders. Carbachol concentration-dependently contracted bladder strips with a pEC50 of 5.66±0.05 and 5.72±0.06 and maximum effects of 4.3±0.1 and 4.2±0.2 mN/mg wet weight in male and female rats, respectively. The contractile effect of carbachol was concentration-dependently antagonised by the non-selective atropine (1–30 nM), the M1-selective pirenzepine (1–30 M), the M2-selective methoctramine (1–10 µM) and the M3-selective darifenacin (10–100 nM), with the latter exhibiting a partly unsurmountable antagonism. The overall potency of all four antagonists suggested that contraction was mediated predominantly if not exclusively by M3 receptors with no appreciable differences between both male and female rats. Similarly, the maximum effects (4.4±0.6 vs. 4.4±2.4 mN/mg) and pEC50 (6.07±0.05 vs. 6.32±0.14) of carbachol did not differ between genders in bladder samples from 25 consecutive patients. We conclude that number und function of muscarinic receptors and the relative roles of their M2 and M3 subtypes do not differ between urinary bladders of male and female rats; at least with regard to overall muscarinic responsiveness this situation appears to be similar in humans. More... »

PAGES

524-531

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00210-003-0713-8

DOI

http://dx.doi.org/10.1007/s00210-003-0713-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1031464615

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/12669188


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75 female human bladder
76 female rats
77 females
78 formation
79 function
80 gender
81 gender comparisons
82 high-affinity site
83 human bladder
84 human urinary bladder
85 humans
86 immunoreactivity
87 important systems
88 inositol
89 m2
90 males
91 maximum effect
92 maximum response
93 men
94 methoctramine
95 model
96 most competition
97 muscarinic receptor agonist carbachol
98 muscarinic receptor expression
99 muscarinic receptor function
100 muscarinic receptors
101 muscarinic responsiveness
102 number
103 overall potency
104 pEC50
105 pEC50 values
106 patients
107 pirenzepine
108 potency
109 rats
110 receptor agonist carbachol
111 receptor expression
112 receptor function
113 receptors
114 regard
115 regulation
116 relative roles
117 response
118 responsiveness
119 role
120 samples
121 similar number
122 sites
123 situation
124 slices
125 strips
126 subtype distribution
127 subtypes
128 symptoms
129 system
130 two-site model
131 unsurmountable antagonism
132 urinary bladder
133 values
134 weight
135 wet weight
136 women
137 α-subunit
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