期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 162, 期 5, 页码 1156-1170出版社
WILEY
DOI: 10.1111/j.1476-5381.2010.01115.x
关键词
caveolae; carbachol; ATP; purine receptor; CGRP; CART; NPK; synaptophysin; caveolin; cavin; lower urinary tract dysfunction; MuSK
资金
- Swedish Research Council [K2009-65X-4955-01-3, 522-2008-4216, K2009-55X 21111-01-4]
- ALF
- Crafoord Foundation
- Royal Physiographic Society
- Lars Hierta's Foundation
- Greta and Johan Kock's Foundation
- Novo Nordisk Foundation
- Gyllenstiernska Krapperup
- Fredrik and Ingrid Thuring Foundation
- Magnus Bergwall Foundation
- Albert Pahlsson Foundation
- The Swedish Society of Medicine
- Faculty of Medicine at Lund University
BACKGROUND AND PURPOSE Caveolin-1-deficiency is associated with substantial urogenital alterations. Here, a mechanical, histological and biochemical characterization of female detrusors from wild-type and caveolin-1-deficient (KO) mice was made to increase the understanding of detrusor changes caused by lack of caveolae. EXPERIMENTAL APPROACH Length-tension relationships were generated, and we recorded responses to electrical field stimulation, the muscarinic receptor agonist carbachol and the purinoceptor agonist ATP. Tyrosine nitration and the contents of caveolin-1, cavin-1, muscarinic M-3 receptors, phospholipase C-beta 1, muscle-specific kinase (MuSK) and L-type Ca2+ channels were determined by immunoblotting. Innervation was assessed by immunohistochemistry. KEY RESULTS Bladder to body weight ratio was not changed, nor was there any change in the optimum circumference for force development. Depolarization- and ATP-induced stress was reduced, as was carbachol-induced stress between 0.1 and 3 mu M, but the supramaximal relative (% K+) response to carbachol was increased, as was M-3 expression. The scopolamine-sensitive component of the electrical field stimulation response was impaired, and yet bladder nerves contained little caveolin-1. The density of cholinergic nerves was unchanged, whereas CART- and CGRP-positive nerves were reduced. Immunoblotting revealed loss of MuSK. CONCLUSIONS AND IMPLICATIONS Ablation of caveolae in the female detrusor leads to generalized impairment of contractility, ruling out prostate hypertrophy as a contributing factor. Cholinergic neuroeffector transmission is impaired without conspicuous changes in the density of cholinergic nerves or morphology of their terminals, but correlating with reduced expression of MuSK.
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