Supersensitivity to acetylcholine of the detrusor muscle has been noted in bladders with BOO-induced DO21 and idiopathic or neurogenic DO.50 Such supersensitivity may be due to patchy denervation7,21 and may also enhance SCs. Crizotinib solubility dmso Another myogenic change may be alterations in the expression of ICC in bladders with SCI or BOO. The number of c-Kit-positive ICCs was increased in bladders with neuropathic DO mainly due to SCI compared to the bladders of patients with stress urinary incontinence.51 The c-Kit tyrosine kinase inhibitor,

imatinib mesylate, inhibited SCs more potently in bladder strips from SCI patients than in those from controls.51 These findings suggest that increased ICC expression is associated with the enhanced SCs associated with SCI. The guinea pig bladder with Wnt drug BOO showed an increased number of ICCs compared with controls.52,53 The increased ICC expression might be associated with the enhanced SCs in bladders with SCI or BOO, as the ICCs in the bladder are considered to be pacemakers of SCs like their counterparts in the gut. In addition to myogenic changes, local mediators may enhance SCs. Areas of patchy denervation in the detrusor are found in bladders with DO.21 In such

areas, acetylcholine of low concentration might leak from the damaged nerves and enhance SCs directly via muscarinic receptors on SMCs.7 Supersensitivity to acetylcholine found in bladders with BOO-induced DO or neurogenic DO21,50 might enhance the

effect of acetylcholine on SCs. Other than SMCs, ICCs in the detrusor might enhance SCs as these cells in the detrusor have muscarinic receptors.34 BOO can generate other local mediators, such as prostaglandins, endothelins and angiotensin 2.7 These factors might also Erastin in vitro enhance the spontaneous activity of the detrusor. The muscarinic antagonist, atropine, decreased the frequency of SCs in bladder strips denuded of the mucosa from rats with BOO by approximately 10%, but it did not change the amplitude.54 This decrease in the frequency of SCs was small but significant, and was probably caused by the inhibition of the effect of acetylcholine that was present as a local mediator in the detrusor, although it is unknown whether such a small decrease in the frequency of SCs is enough to influence afferent nerve firing. The cyclooxygenase inhibitor indomethacin attenuated SCs in the detrusor.40 Cyclooxygenase in the detrusor is positive for ICCs39,40; therefore, these cells might influence spontaneous contractile activity of the detrusor via diffusible prostaglandin, and prostaglandins released from ICCs may enhance SCs as a local mediator. Urotheliogenic modulation of SCs may participate in the generation of altered SCs of the bladder. Kanai et al. developed an elegant experiment setting using the bladder sheet of the rat.