Imatinib inhibits spontaneous rhythmic contractions of human uterus and intestine

Abstract: 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 μM. 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. [Copyright &y& Elsevier]