Urinary NGF is produced from the urothelium and bladder muscles. Urinary NGF levels increase in patients with OAB and patients with detrusor overactivity.28,29 Recently, it has been reported that urinary NGF levels are biomarkers in the assessment of OAB.28 Although we did not measure APO866 molecular weight urinary NGF level and did not evaluate the relationship between CGRP and NGF in the present

study, these changes also might be related to detrusor overactivity in WHHL-MI rabbits. Interestingly, old WHHL-MI rabbits showed decreased voiding pressure in cystometric findings and decreased contractile responses to carbachol and EFS in smooth muscle strips. The decrease in S-100-positive neurons advanced in old WHHL-MI rabbits. These results may imply that decreased release of neurotransmitter, such as acetylcholine and ATP, from motor neurons contribute to the decreased bladder contraction. In addition, fibrosis of

the bladder wall also progressed and the amount of detrusor muscle Veliparib mouse reduced in old WHHL-MI rabbits. Fibrosis in the bladder wall might be related to a significant increase in the expression of transforming growth factor beta-1, and fibrosis might play an important role on bladder dysfunction.23 Thus, it may be speculated that decreased function of the peripheral nervous system and accompanied structural changes of the bladder wall finally result in detrusor underactivity in old WHHL-MI rabbits. In this study, old WHHL-MI rabbits showed both detrusor overactivity and detrusor underactivity. This is a similar condition to

detrusor hyperactivity with impaired contraction (DHIC), which is clinically experienced in the elderly. The present Orotic acid data showed one of the developmental mechanisms of bladder dysfunction due to chronic hyperlipidemia, which included both detrusor overactivity and detrusor underactivity (DHIC). The speculated mechanism is summarized in Figure 1. Detrusor overactivity might be caused by the partial denervation of motor neurons, resulting in the increased smooth muscle responsiveness to neurotransmitters (denervation supersensitivity). This may be one of the compensation mechanisms for bladder contraction. Activation of CGRP-positive neurons may also contribute to detrusor overactivity. Progress of denervation may lead to further decrease in neurotransmitter release, resulting in impaired bladder contractility (de-compensation phase). Moreover, decreased bladder smooth muscles may contribute to detrusor underactivity. Thus, WHHL-MI rabbit is a useful animal model for the evaluation of the pathophysiology of OAB and DHIC, and for the exploration of future treatment possibilities. MY is a Consultant for Kissei Pharmaceutical Co. and Speaker Honorarium for Kissei Pharmaceutical Co., Astellas Pharma Inc, Pfizer, Ono Pharmaceutical Co, Kyorin Pharmaceutical Co and Daiichi-Sankyo Co. The other authors report no conflict of interest.