Imatinib Mesylate (Gleevec) as Protein-tyrosine Kinase Inhibitor Elicits Smooth Muscle Relaxation in Isolated Human Prostatic Tissue

Abstract

To evaluate the mechanism of action of imatinib mesylate (Gleevec), a protein tyrosine kinase inhibitor on the human prostate with benign prostatic hyperplasia. Prostate samples were obtained from 16 patients with benign prostatic hyperplasia (mean age 68.3 ± 1.9 years), who had undergone transurethral prostatectomy. In tissue bath studies, cumulative concentration-response curves were constructed for imatinib after precontraction with 120 mM KCl. Imatinib-induced relaxation was quantitated in tissues treated with l-N(G)-Nitroarginine Methyl Ester (l-NAME) (an inhibitor of nitric oxide synthase) or 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (a soluble guanylyl cyclase inhibitor). Two K+ channel blockers (adenosine triphosphate [K(ATP)] and Large-conductance Ca(2+)-activated K(+) channels [BK(Ca2+)] channels) were also evaluated as antagonists of imatinib-induced relaxation and repeated in the presence of the α-adrenergic receptor blocker alfuzosin. An electrical field stimulation (1-20 Hz, 5 ms, 5 seconds, 60 V)-induced contractile response was performed on strips incubated with imatinib (10(-3) M). KCl-induced contractions in human prostatic tissue were significantly inhibited by imatinib (maximal response 84.9 ± 4.5%) and were attenuated by l-NAME (42%, P < .001) and ODQ (43%, P < .001). This relaxant effect was also suppressed by glibenclamide (adenosine triphosphate-sensitive K+ channel blocker, 41%, P < .001) and tetraethylammonium (BK(Ca2+) channel blocker, 24%, P < .05). Imatinib induced prostatic smooth muscle relaxation in vitro. This effect was suppressed by l-NAME and ODQ, showing a dependence on the nitric oxide-cyclic guanosine monophosphate pathway and modulated by the K(ATP) and BK(Ca2+) K+ channels. Our findings suggest that imatinib can augment relaxation of human prostatic tissues by way of a novel ligand-protein tyrosine kinase signaling pathway.