title: Imatinib mesylate (Gleevec) induces human corpus cavernosum relaxation by inhibiting receptor tyrosine kinases (RTKs): identification of new RTK targets.
abstract: OBJECTIVE
  To evaluate the effect of the tyrosine kinase inhibitor imatinib mesylate (Gleevec) on human corpus cavernosum (HCC) smooth muscle tone.
  
  
  METHODS
  HCC were obtained from 18 erectile dysfunction (ED) patients undergoing penile prosthesis surgery. The effects of imatinib in HCC strips were investigated in the presence of various inhibitors. The human phosphoreceptor protein tyrosine kinase (PTK) array (Proteome Profiler Array) detected changes in receptor phosphorylation before and after imatinib. Immunohistochemistry was used to localize phosphorylated c-kit (CD117/stem cell factor) in HCC smooth muscle cells.
  
  
  RESULTS
  Phenylephrine-induced contraction in HCC was significantly inhibited by imatinib (97.7% ± 2.3%). l-nitro-arginine methyl ester (l-NAME) or guanylyl cyclase inhibitor [1H-1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) alone did not reverse the effect of imatinib, but suppressed this response in combination (18.0% ± 0.6%). The K(+) channel blockers (apamin and tetraethyl ammonium) decreased the imatinib-induced relaxation by 64% and 51%, respectively. PTK microarray analysis of 42 different phospho-receptor tyrosine kinases showed 14 were clearly activated in HCC. Imatinib treatment significantly inhibited phosphorylation of PTKs. A high level of CD117/c-kit-positive immunostaining was detected in untreated HCC smooth muscle, but not in treated HCC.
  
  
  CONCLUSIONS
  Imatinib caused HCC smooth muscle relaxation in vitro mediated by nitric oxide/guanosine monophosphate signaling, involving the large-conductance Ca(2+)-activated K(+)-channels (BK(Ca)) or by inhibiting the upregulated PTK pathway. These results suggest that imatinib may also benefit erectile dysfunction patients who are not responsive to phosphodiesterase-5 inhibitors.
authors.affiliation: Department of Urology, Tulane Health Sciences Center, New Orleans, LA, USA.
authors.forename: Serap
authors.initials: S
authors.lastname: Gur
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Sikka
authors.forename: Asim B
authors.initials: AB
authors.lastname: Abdel-Mageed
authors.forename: Zakaria Y
authors.initials: ZY
authors.lastname: Abd Elmageed
authors.forename: Bashir
authors.initials: B
authors.lastname: Rezk
authors.forename: Edward
authors.initials: E
authors.lastname: Pankey
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kadowitz
authors.forename: Wayne J G
authors.initials: WJ
authors.lastname: Hellstrom
mesh_terms: D000328:Adult; D000368:Aged; D001030:Apamin / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D007172:Erectile Dysfunction / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010413:Penis / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019789:Tetraethylammonium / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D001549:Benzamides; D010069:Oxadiazoles; D010879:Piperazines; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011810:Quinoxalines; D001030:Apamin; D019789:Tetraethylammonium; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D019331:NG-Nitroarginine Methyl Ester