title: Imatinib mesylate (Gleevec) as protein-tyrosine kinase inhibitor elicits smooth muscle relaxation in isolated human prostatic tissue.
abstract: OBJECTIVE
  To evaluate the mechanism of action of imatinib mesylate (Gleevec), a protein tyrosine kinase inhibitor on the human prostate with benign prostatic hyperplasia.
  
  
  METHODS
  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).
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Urology, Ankara Numune Education and Research Hospital, Ankara, Turkey.
authors.forename: Alp
authors.initials: A
authors.lastname: Ozgur-Akdemir
authors.forename: Kursat
authors.initials: K
authors.lastname: Demirturk
authors.forename: Mehmet
authors.initials: M
authors.lastname: Karabakan
authors.forename: Cetin
authors.initials: C
authors.lastname: Volkan-Oztekin
authors.forename: Nour A
authors.initials: NA
authors.lastname: Abdulkadir
authors.forename: Mesut
authors.initials: M
authors.lastname: Cetinkaya
authors.forename: Serap
authors.initials: S
authors.lastname: Gur
authors.forename: Wayne J G
authors.initials: WJ
authors.lastname: Hellstrom
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000368:Aged; D001549:Benzamides; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011467:Prostate / Q000187:drug effects* / Q000201:enzymology*; D011469:Prostatic Diseases / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D000068877:Imatinib Mesylate; C047638:alfuzosin; D011505:Protein-Tyrosine Kinases; D019331:NG-Nitroarginine Methyl Ester