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Non-adrenergic non-cholinergic contraction in bladder smooth muscle: implications in Type II diabetic bladder dysfunction
Dissertation   Open access

Non-adrenergic non-cholinergic contraction in bladder smooth muscle: implications in Type II diabetic bladder dysfunction

Derek M. Kendig
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2012
DOI:
https://doi.org/10.17918/00010031
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Abstract

Pharmacology Physiology
Non-adrenergic non-cholinergic (NANC) contractions of bladder smooth muscle are increased in bladder dysfunction including diabetic bladder dysfunction. While many studies on diabetic bladder dysfunction have been performed in animal models of Type I diabetes very few have been performed in animal models of Type II diabetes. Type II diabetes is the most prevalent form of diabetes in the human population. In the ZDF rat model of Type II diabetes we determined the contractility and sensitivity of bladder smooth muscle in response to mediators of depolarization-induced contraction, muscarinic-receptor mediated contraction, NANC-induced contraction, and neurogenic contraction. Studies were performed at 16, 27, and 40 weeks of age to monitor the progression of diabetic bladder dysfunction. The bladder walls of diabetic rats were hypertrophied compared to bladder walls of lean rats; although the hypertrophy was not specific to the smooth muscle layer. Contractility and sensitivity to carbachol and ATP were increased at 27 weeks in bladder smooth muscle strips from diabetic rats, suggesting a compensated state of diabetic bladder dysfunction. At 40 weeks contractility and sensitivity to all forms of contractile stimuli were decreased in bladder strips from diabetic rats, suggesting a decompensated state of bladder smooth muscle function. Purinergic signaling was increased in response to exogenous ATP in bladders from diabetic animals; however, the purinergic component of neurogenic contraction was instead decreased. The purinergic component of neurogenic contraction was reduced by P2X receptor desensitization but was unchanged by P2X receptor inhibition in diabetic rats. This suggests different expression and/or functionality of P2X receptors in the bladders from diabetic rats. Residual and tetrodotoxin-resistant components of neurogenic contraction were increased in bladder strips from diabetic animals. This suggests there are increases in both the non-cholinergic non-purinergic component of neurogenic contraction and direct muscle stimulation. The ZDF rat model of Type II diabetes progressed from a hypercontractile to a hypocontractile state of bladder smooth muscle function. However, whole bladder organ function never reached the decompensated state, suggesting compensation by mechanisms in addition to smooth muscle. The difference in the purinergic component of bladder contraction is a possible therapeutic target for treating diabetic bladder dysfunction.

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