The functional effects of a c-kit tyrosine inhibitor on guinea-pig and human detrusor.
OBJECTIVE
To describe the effect of a specific c-kit receptor inhibitor (imatinib mesylate) on human detrusor strips in vitro and guinea-pig cystometry in vivo, and to show histological data suggesting differences in the distribution of interstitial cells of Cajal (ICC)-like cells in 'normal' and overactive human detrusor, as these cells have been identified as possible mediators of spontaneous activity and excitability in bladder smooth muscle.


METHODS
Specimens of human detrusor were stained immunohistochemically with a c-kit antibody. Human detrusor strips were mounted in a superfused organ-bath apparatus, and smooth muscle contraction was evoked with carbachol and electrical field stimulation in the presence and absence of imatinib mesylate. Also, guinea-pig urodynamic studies were conducted before and after i.v. administration of imatinib mesylate, and changes in bladder variables and spontaneous activity were recorded.


RESULTS
Imatinib mesylate (10(-6)M) inhibited evoked smooth muscle contraction and spontaneous activity in overactive human detrusor, with less effect on normal human tissue. Imatinib mesylate (10(-5)M) improved bladder capacity, compliance, voided volumes, urinary frequency, and reduced contraction thresholds and spontaneous activity during guinea-pig cystometry. c-kit labelling showed significantly more ICC-like cells in overactive human detrusor than in normal specimens.


CONCLUSIONS
c-kit receptor blockers have inhibitory effects on guinea-pig and overactive human detrusor, possibly via c-kit receptors on bladder ICC-like cells. This and the possibility that there are more ICC-like cells in overactive bladder suggest that the c-kit receptor may provide a novel target for treating detrusor overactivity.
Department of Pharmacology, Oxford University and Department of Urology, Churchill Hospital, Oxford, UK. suzannebiers@hotmail.com
Suzanne M
SM
Biers
John M
JM
Reynard
Tracyann
T
Doore
Alison F
AF
Brading
D000818:Animals; D001549:Benzamides; D006168:Guinea Pigs; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit; D011743:Pyrimidines / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology; D014549:Urinary Incontinence / Q000188:drug therapy* / Q000473:pathology; D014563:Urodynamics
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit