Investigation of the effect of the c-kit inhibitor Glivec on isolated guinea-pig detrusor preparations

Kubota, Yasue; Kajioka, Shunichi; Biers, Suzanne; Yokota, Etsuko; Kohri, Kenjiro; Brading, Alison F.

doi:10.1016/j.autneu.2004.08.004

Cited by 37 publications

(45 citation statements)

References 22 publications

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“…Recently, it has been used in four studies observing the effect of acute inhibition of the c-kit receptor on the contractility of smooth muscle strips with the anticipation that inhibition of c-kit and therefore ICC would decrease the frequency and overall contractility of the muscle studied. The first three studies on murine small intestine [15] , Guinea pig bladder [16] and rabbit myometrium [7] all had very similar findings despite the differing species and tissue types. The amplitude of contractions decreased only at very high concentrations of the drug.…”

Section: Discussionmentioning

confidence: 51%

Effect of Prolonged c-Kit Receptor Inhibition by Imatinib Mesylate on the Uterine Contractility of Pregnant Rabbits

Hutchings¹,

Gevaert²,

Deprest³

et al. 2007

Gynecol Obstet Invest

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Background: The c-kit receptor expressed by interstitial cells in the gastrointestinal tract is crucial to their pacemaking function. The function of similar c-kit-expressing myometrial cells is unknown. Methods: Imatinib mesylate, a specific c-kit receptor antagonist, was administered to pregnant New Zealand white rabbits (term = 31 days, n = 35) from day 27 gestation by intramuscular injection twice daily at high (50 µg/kg) or medium (10 µg/kg) dose and compared with a control group injected with vehicle only. In a second phase, two further groups received imatinib at medium or low (1 µg/kg) dose for a longer duration starting from day 18 until delivery. Three does from the latter groups as well as controls underwent myometrial biopsy under general anesthesia after spontaneous vaginal birth. Contractility was recorded by isometric tensiometry. The outcome measures were delay of parturition and in vitro contractility characteristics. Results: High-dose imatinib induced early delivery when compared with the control group (28.6 vs. 30.7 days, p < 0.001). The other groups delivered at term. No effect on in vitro contractility was apparent in any of the groups. Conclusions: c-kit receptor inhibition in pregnant rabbits does not delay significantly the length of gestation or change myometrial contractility in vitro.

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Section: Discussionmentioning

confidence: 51%

Effect of Prolonged c-Kit Receptor Inhibition by Imatinib Mesylate on the Uterine Contractility of Pregnant Rabbits

Hutchings¹,

Gevaert²,

Deprest³

et al. 2007

Gynecol Obstet Invest

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“…Recent studies suggest a role for such agents in nonmalignant conditions with aberrant tissue growth. In support of this, Gleevec was found to attenuate spontaneous action potentials and contractions of smooth muscle strips from guinea pig detrusor [10]. Collectively, these observations suggest a potential role for kinase inhibitors for treatment of aberrant growth and contractility of bladder muscle.…”

Section: Targeting Kinase Signaling For Therapeutic Gainmentioning

confidence: 77%

Recent Insights into the Cell Biology of Bladder Smooth Muscle

Adam¹

2005

Nephron Exp Nephrol

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Much of current biomedical research is focused on the development of ‘targeted therapies’ based on detailed knowledge about the signals that mediate aberrant cellular behavior in a given disease. Although this concept has been used most widely in cancer treatment, the same strategy applies to nonmalignant conditions such as pathologic tissue expansion in the genitourinary tract. A rigorous understanding of the key molecular events and pathways that underlie normal and pathologic activity of the bladder would allow us to identify potential targets for rational drug design. In this review, I will summarize our current understanding of cell signaling in bladder smooth muscle and highlight potential targets for drug-based treatment of tissue remodeling in the lower urinary tract.

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“…These cells also provide pathways for the conduction of electrical signals through the tissue. Inhibition of these cells in vitro using imatinib mesylate, a C-Kit tyrosine kinase inhibitor, abolishes contractions in smooth muscle derived from the gut of mice [9] and reduces contractility in smooth muscle from the bladder [10] . C-kit positive cells have been positively identifi ed in human myometrium but electrophysiological and immunuohistochemical fi ndings of the two investigating groups were confl icting and the function of these cells was not investigated [11,12] .…”

Section: Introductionmentioning

confidence: 99%

The Effect of Imatinib Mesylate on the Contractility of Isolated Rabbit Myometrial Strips

Hutchings¹,

Deprest²,

Nilius³

et al. 2006

Gynecol Obstet Invest

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Background: C-kit receptor expressing interstitial cells generate and coordinate the electrical signals that control peristalsis in the gut. However, the function of interstitial cells in the myometrium is not known. Methods: (1) Sections of rabbit myometrium were subjected to immunohistochemical staining for the c-kit receptor. (2) Spontaneously contracting myometrial strips from New Zealand White rabbits near term were mounted in an organ bath and attached to a tension-recording device. The effect of increased concentrations of the c-kit receptor antagonist imatinib mesylate on these contractions was observed. The main outcome measures were the change in frequency, amplitude and duration of contraction. Results: (1) Multipolar cells expressing c-kit were identified in the fibromuscular septum confirming the presence of interstitial cells in rabbit myometrium. (2) Imatinib decreased the amplitude of contractions by approximately 20% at 100 µM. No effect was seen at lower concentrations. No effect of imatinib on frequency or duration of contractions was observed at any of the concentrations studied. Conclusions: In isolated rabbit myometrium, acute inhibition of the c-kit receptor by imatinib mesylate affects only the amplitude of spontaneous contractions at concentrations, the equivalent of ×10–100 the normal therapeutic concentration.

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Investigation of the effect of the c-kit inhibitor Glivec on isolated guinea-pig detrusor preparations

Cited by 37 publications

References 22 publications

Effect of Prolonged c-Kit Receptor Inhibition by Imatinib Mesylate on the Uterine Contractility of Pregnant Rabbits

Effect of Prolonged c-Kit Receptor Inhibition by Imatinib Mesylate on the Uterine Contractility of Pregnant Rabbits

Recent Insights into the Cell Biology of Bladder Smooth Muscle

The Effect of Imatinib Mesylate on the Contractility of Isolated Rabbit Myometrial Strips

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