Imatinib inhibits spontaneous rhythmic contractions of human uterus and intestine.
The interstitial cells of Cajal (ICC) in the digestive tract and ICC-like cells in extradigestive organs express the c-kit tyrosine-kinase receptor, and have been implicated as pacemakers of smooth muscle spontaneous activity. We used imatinib mesylate (Glivec) to investigate whether c-kit activity of Cajal-like cells in human myometrium is involved in spontaneous rhythmic contractions of human uterine smooth muscle, taking intestinal smooth muscle as a reference tissue. We show that imatinib concentration-dependently inhibited the myogenic contractions of human myometrium in the organ bath, while it significantly affected noradrenaline or K(+)-induced contractions only at concentrations exceeding 50 muM. An inhibitory antibody directed against the extracellular domain of the platelet derived growth factor receptor (PDGFR), another target of imatinib that is expressed by the uterine muscle cells themselves, failed to affect myogenic contractions. These results suggest that Cajal-type cells of human myometrium, as well as ICC of intestinal smooth muscle, participate in myogenic contractile mechanisms, via a novel ligand-independent c-kit/CD117 tyrosine-kinase signaling.
Popescu
Laurentzio M
LM
Department of Cellular and Molecular Medicine, Carol Davila University of Medicine and Pharmacy, PO BOX 35-29, Bucharest 35, Romania. LMP@jcmm.org
Vidulescu
Cristina
C
Curici
Antoanela
A
Caravia
Laura
L
Simionescu
Anca A
AA
Ciontea
Sanda M
SM
Simion
Sorin
S
D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D011743:Pyrimidines / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit