The Role of TRPV1 and The Mechanisms Underlying Stress Induced Bladder Underactivity
Gerald Mingin, MD1, Thomas Heppner, PhD2, Nathan Tykocki, PhD2, David W. Sobel, MD2.
1University of Vermont / Vermont Children's Hospital, Burlington, VT, USA, 2University of Vermont, Burlington, VT, USA.
BACKGROUND: Previously we reported that TRPV1 channels (a member of the transient receptor potential channel vanilloid family) are responsible for increased afferent activity leading to overactive bladder (increased urinary frequency and decreased bladder capacity) in mice exposed to social stress. With increasing stress intensity, however, we observed a significant increase in bladder capacity and intermicturition interval indicative of incomplete emptying. We hypothesized that TRPV1 channels play a key role in mediating the effects of increased social stress on bladder function (incomplete emptying) via bladder wall remodeling leading to a decrease in contractility.
METHODS: Six week old C57BL/6 and TRPV1-KO mice were exposed to a retired breeder (aggressor mouse) for 23 hours via a clear plastic barrier with holes allowing for olfactory stimulation. The process is repeated each day with a different aggressor mouse, for 2 weeks. Bladders were harvested for ex vivo pressure studies to evaluate changes in afferent activity with and without the bath addition of the TRPV1 antagonist capsazepine (1-10 ÁM). In addition, bladders were used for histology and Western blotting looking for changes in collagen, α-actin and the smooth muscle contractile protein h-caldesmon.
RESULTS: Mice subjected to increased social stress showed no increase in afferent activity, nor was there inhibition of afferent activity with capsazepine. More importantly, there was no increase in afferent activity and a significant decrease in bladder volume in the TRPV1-KO mice exposed to increased stress compared to wild-type stressed mice. We observed a significant increase in the collagen content of the stressed bladders compared to controls, as well as a decrease in the contractile protein h-CAD. These findings suggest that TRPV1 plays a role in bladder wall remodeling and underactivity caused by increased social stress intensity.
CONCLUSIONS: We demonstrate that, contrary to social stress-induced overactive bladder, TRPV1 does not increase afferent nerve activity but rather facilitates bladder wall remodeling. This results in increased capacity and decreased contractility in the setting of increased-intensity social stress. The mechanisms underlying this process include both a change in bladder wall structure and smooth muscle contractile protein expression. Future work will determine how TRPV1 facilitates the above in bladder underactivity.
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