Effects of imatinib mesylate (Glivec®) as a c‐kit tyrosine kinase inhibitor in the guinea‐pig urinary bladder

Kubota, Yasue; Biers, Suzanne; Kohri, Kenjiro; Brading, Alison F.

doi:10.1002/nau.20085

Cited by 61 publications

(70 citation statements)

References 15 publications

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“…54,55 ICCs are c-kit positive in the guinea-pig bladder 51 and are also highly immunoreactive for cGMP. 50,52 Kubota et al 56 assessed the possible role of these c-kit positive cells in the bladder, and investigated the effects of the c-kit tyrosine kinase inhibitor, imatinib mesylate (Glivec 1 ), on spontaneous excitation and ion channel activity in detrusor smooth muscle using intracellular microelectrodes, isometric muscle tension recordings, and patch-clamp techniques. Glivec converted AP bursts into continuous firing without affecting their shape, but at high concentrations of the drug, spontaneous APs were abolished.…”

Section: Interstitial Cellsmentioning

confidence: 99%

“…Glivec decreased the amplitude of spontaneous contractions in a concentration-dependent manner. Kubota et al 56,57 suggested that c-kit-positive cells may play a role in modulating spontaneous electrical and mechanical activities in the bladder, both normally and after outflow obstruction. This is in agreement with the suggestion that they may be involved in signal transmission within the detrusor, coordinating the different contractile units.…”

Section: Interstitial Cellsmentioning

confidence: 99%

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Detrusor myocyte activity and afferent signaling

Andersson

2009

Neurourology and Urodynamics

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Aims: To discuss (1) mechanisms involved in the generation and control of myocyte contractions and consequent afferent nerve activity and (2) these mechanisms as targets for drugs aimed for treatment of overactive bladder (OAB) symptoms and detrusor overactivity (DO). Methods: Literature review of myocyte activation, bladder afferent nerves, mediators in the bladder, and translational aspects of the findings. Results: During bladder filling, there is normally no parasympathetic outflow from the spinal cord. Despite this, the bladder develops tone during filling and also exhibits non-synchronized local contractions and relaxations that are caused by a basal myogenic mechanical activity that may be reinforced by release of, for example, acetylcholine from non-neuronal and/or neuronal sources or local mediators, such as prostaglandins and endothelins. It is suggested that these spontaneous contractions are able to generate activity in afferent nerves (''afferent noise'') that may contribute to DO and OAB. Conclusions: Spontaneous bladder myocyte contractions and factors that are able to modulate them, as well as the consequent afferent nerve activity, may be targets for drugs meant for treatment of OAB/DO. Neurourol.

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Section: Interstitial Cellsmentioning

confidence: 99%

Section: Interstitial Cellsmentioning

confidence: 99%

Detrusor myocyte activity and afferent signaling

Andersson

2009

Neurourology and Urodynamics

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“…10) As both development and maintenance of ICC require Kit, 11) an inhibitor of Kit signaling could be used as a specific blocker for the function of ICC. Recently, imatinib mesylate has been shown to suppress contractile activity in various phasic smooth muscles, including the human uterus and small intestine, 12) guinea-pig bladder, 13) guinea-pig gall bladder 14) and guinea pig stomach. 15) However, none of the studies has demonstrated that the effects of imatinib mesylate, on pacemaker potentials in ICC.…”

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confidence: 99%

Effects of Imatinib Mesylate in Interstitial Cells of Cajal from Murine Small Intestine

Kim

Chae

Kwon

et al. 2010

Biological & Pharmaceutical Bulletin

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The interstitial cells of Cajal (ICCs) are pacemakers in the gastrointestinal tract. The possibility of whether imatinib mesylate, a Kit receptor tyrosine kinase inhibitor, modulates pacemaker activities in the ICC was examined using the whole cell patch clamp technique. Imatinib decreased the amplitude of pacemaker potentials in a dose-dependent manner in current-clamp mode. Because the effects of imatinib on pacemaker potentials were the same as those of pinacidil, we examined the effect of glibenclamide on ICC exposed to imatinib. The effects of imatinib on pacemaker potentials were blocked by glibenclamide. To see whether the production of prostaglandins (PGs) is involved in the inhibitory effect of imatinib on pacemaker potentials, we tested the effects of naproxen (a non-selective cyclooxygenase inhibitor) and AH6809 (a prostaglandin EP1 and EP2 receptor antagonist). Naproxen and AH6809 blocked the inhibitory effects of imatinib on ICC. Butaprost (an EP2 receptor agonist) showed the actions on pacemaker potentials in the same manner as imatinib. However, SC 19220 (an EP1 receptor antagonist) has no effects. To investigate the involvement of cAMP and protein kinase A (PKA) in the effects of imatinib on ICC, SQ 22536 (an inhibitor of adenylate cyclase) and mPKAI (an inhibitor of myristoylated PKA) were used. Both SQ-22536 and mPKAI blocked the imatinib-mediated inhibition of pacemaker potentials. However, the protein kinase C (PKC) inhibitors did not block the imatinib-mediated inhibition of pacemaker potentials. These results indicate that imatinib inhibits the pacemaker potentials of ICC by activating ATP-sensitive K ؉ ؉ channels and PKA-dependent, PKC-independent manner.

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“…Therefore, although the location of boundary interstitial cells seems to be ideal to drive the bulk of smooth muscles, they clearly are not electrical pacemaker cells. However, experiments in which Glivec, a kit receptor antagonist, has been applied, show reduction in the activity of both isolated whole bladders [34][35][36] and the contractile and electrical activity of strips of detrusor, suggesting that interstitial cells may be in some way involved in the integration of activity. Interstitial cells are also found in the submucosa, close to the urothelium and the suburothelial sensory nerves, [37][38][39] where they may play a similar role in integrating activity.…”

Section: Sexual and Lut Function Af Brading Et Almentioning

confidence: 99%

“…Moreover, imatinib mesylate (Glivec), an inhibitor of Kit receptor tyrosine kinase, was more potent in inhibiting evoked and spontaneous contractions in overactive bladder than in normal bladder, and also improved parameters of cystometry. [34][35][36] ICC are thought to be involved in neuromuscular transmission, including inhibitory transmission mediated by NO; 45,46 therefore, they may also play an important role in the nerve-mediated modulation of detrusor smooth muscle excitability. Following stimulation with sodium nitroprusside, interstitial Sexual and LUT function AF Brading et al cells throughout the bladder demonstrated an intense induction of cGMP immunoreactivity, but detrusor muscle cells remained uniformly negative.…”

Section: Possible Role Of Interstitial Cells In Lutsmentioning

confidence: 99%

A survey of commonalities relevant to function and dysfunction in pelvic and sexual organs

2007

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Micturition, defecation and sexual function are all programmed through spinal reflexes that are under descending control from higher centres. Interaction between these reflexes can clearly be perceived, and evidence is accumulating the dysfunction in one reflex is often associated with dysfunction in another. In this article, we describe some of the basic properties and neural control of the smooth muscles mediating the reflexes, reviewing the common features that underlie these reflex functions, and what changes may be responsible for dysfunction. We propose that autonomic control within the pelvis predisposes pelvic and sexual organs to crosstalk, with the consequence that diseases and conditions of the pelvis are subject to convergence on a functional level. It should be expected that disturbance of the function of one system will inevitably impact adjacent systems.

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Effects of imatinib mesylate (Glivec®) as a c‐kit tyrosine kinase inhibitor in the guinea‐pig urinary bladder

Abstract: The results suggest that ICC-like cells may be responsible for generating bursts of action potentials and contractions in detrusor smooth muscle. Drugs inhibiting the c-kit receptor may prove useful for treating the overactive bladder.

Cited by 61 publications

References 15 publications

Detrusor myocyte activity and afferent signaling

Detrusor myocyte activity and afferent signaling

Effects of Imatinib Mesylate in Interstitial Cells of Cajal from Murine Small Intestine

A survey of commonalities relevant to function and dysfunction in pelvic and sexual organs

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