Department of Urology, Ankara Numune Education and Research Hospital, Ankara, Turkey.
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 [KATP] and Large-conductance Ca(2+)-activated K(+) channels [BKCa2+] 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 (BKCa2+ 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 BKCa2+ 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.
Written by:
Ozgur-Akdemir A, Demirturk K, Karabakan M, Volkan-Oztekin C, Abdulkadir NA, Cetinkaya M, Gur S, Hellstrom WJ. Are you the author?
Reference: Urology. 2011 Aug 26. Epub ahead of print.
doi: 10.1016/j.urology.2011.06.033
PubMed Abstract
PMID: 21872909
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