Effects of imatinib mesylate (Glivec) as a c-kit tyrosine kinase inhibitor in the guinea-pig urinary bladder.
OBJECTIVE
In the gastrointestinal tract, slow wave activity in smooth muscle is generated by the interstitial cells of Cajal (ICC). Detrusor smooth muscle strips of most species show spontaneous contractions which are triggered by action potential bursts, however, the pacemaker mechanisms for the detrusor are still unknown. Recently, ICC-like cells have been found in guinea-pig bladder, using antibodies to the c-kit receptor. We have investigated the effects of Glivec, a c-kit tyrosine kinase inhibitor, on spontaneous action potentials in guinea-pig detrusor and intravesical pressure of isolated guinea-pig bladders.


METHODS
Changes in the membrane potential were measured in guinea-pig detrusor smooth muscle using conventional microelectrode techniques. Pressure changes in the bladder were recorded using whole organ bath techniques.


RESULTS
Smooth muscle cells in detrusor muscle bundles exhibited spontaneous action potentials, and spontaneous pressure rises occurred in isolated bladders. Glivec (10 microM) converted action potential bursts into continuous firing with no effects on the shape of individual action potentials. Glivec (>50 microM) reduced the amplitude of spontaneous pressure rises in the whole bladder in a dose dependent manner and abolished spontaneous action potentials in detrusor smooth muscle cells.


CONCLUSIONS
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.
Kubota
Yasue
Y
University Department of Pharmacology, Oxford, United Kingdom.|Department of Urology, Nagoya City University Medical School, Nagoya, Japan.
Biers
Suzanne M
SM
University Department of Pharmacology, Oxford, United Kingdom.
Kohri
Kenjiro
K
Department of Urology, Nagoya City University Medical School, Nagoya, Japan.
Brading
Alison F
AF
University Department of Pharmacology, Oxford, United Kingdom.
D000818:Animals; D001549:Benzamides; D006168:Guinea Pigs; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D008297:Male; 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*
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit