Imatinib Mesylate (Gleevec) Induces Human Corpus Cavernosum Relaxation by Inhibiting Receptor Tyrosine Kinases (RTKs): Identification of New RTK Targets - 02/09/13
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.
Conclusion |
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.
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| Financial Disclosures: W.J.G.H: American Medical Systems, Consultant or Advisor; Andromedical, Consultant or Advisor; Auxilium, Meeting Participant or Lecturer, Consultant or Advisor, Investigator; Allergan, Consultant or Advisor, Scientific Study or Trial; Coloplast, Consultant or Advisor, Investigator; Cook, Consultant or Advisor, Lecturer; Endo, Consultant or Advisor, Investigator, Lecturer; Johnson & Johnson, Consultant or Advisor, Meeting Participant or Lecturer, Investigator; Lilly USA, Consultant or Advisor, Lecturer; NIH, Board Member, Officer, Trustee; Slate Pharmaceutical, Lecturer, Advisor, and Investigator; Theralogix, Board Member, Officer, Trustee; VIVUS, Advisor/Consultant, Investigator, Lecturer. The remaining authors declare that they have no relevant financial interests. |
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| Funding Support: This study was supported by The High Council of Higher Education (Turkey). Imatinib mesylate was provided by Novartis Pharmaceuticals AG (Basel, Switzerland). |
Vol 82 - N° 3
P. 745.e11-745.e16 - septembre 2013 Retour au numéro
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