title: Effects of imatinib mesylate on the spontaneous activity generated by the guinea-pig prostate.
abstract: What's known on the subject? and what does the study add?: Several studies have examined the functional role of tyrosine kinase receptors in the generation of spontaneous activity in various segments of the gastrointestinal and urogenital tracts through the application of its inhibitor, imatinib mesylate (Glivec®), but results are fairly inconsistent. This is the first study detailing the effects of imatinib mesylate on the spontaneous activity in the young and ageing prostate gland. As spontaneous electrical activity underlies the spontaneous rhythmic prostatic contractions that occur at rest, elucidating the mechanisms involved in the regulation of the spontaneous electrical activity and the resultant phasic contractions could conceivably lead to the identification of better targets and the development of more specific therapeutic agents to treat prostate conditions.
  
  
  OBJECTIVE
  To investigate the effect of imatinib mesylate, a tyrosine kinase receptor inhibitor, in the generation of spontaneous electrical and contractile activity in the young and ageing guinea-pig prostate.
  
  
  METHODS
  Standard tension and intracellular recording were used to measure spontaneous contractions and slow waves, respectively from the guinea-pig prostate at varying concentrations of imatinib mesylate (1-50 μm).
  
  
  RESULTS
  Imatinib mesylate (1-10 μm), did not significantly affect slow waves recorded in the prostate of both age groups but at 50 μm, the amplitude of slow waves from the ageing guinea-pig prostate was significantly reduced (P < 0.05, n = 5). In contrast, the amplitude of contractions across all concentrations in the young guinea-pig prostate was reduced to between 35% and 41% of control, while the frequency was reduced to 15.7% at 1 μm (n = 7), 49.8% at 5 μm (n = 10), 46.2% at 10 μm (n = 7) and 53.1% at 50 μm (n = 5). Similarly, imatinib mesylate attenuated the amplitude and slowed the frequency of contractions in ageing guinea-pigs to 5.15% and 3.3% at 1 μm (n = 6); 21.1% and 20.8% at 5 μm (n = 8); 58.4% and 8.8% at 10 μm (n = 11); 72.7% and 60% at 50 μm (n = 5).
  
  
  CONCLUSIONS
  A significant reduction in contractions but persistence of slow waves suggests imatinib mesylate may affect the smooth muscle contractile mechanism. Imatinib mesylate also significantly reduced contractions in the prostates of younger guinea pigs more than older ones, which is consistent with the notion that the younger guinea-pig prostate is more reliant on the tyrosine-dependent pacemaker ability of interstitial cells of Cajal-like prostatic interstitial cells.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lam
authors.forename: Anupa
authors.initials: A
authors.lastname: Dey
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lang
authors.forename: Betty
authors.initials: B
authors.lastname: Exintaris
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D006168:Guinea Pigs; D000068877:Imatinib Mesylate; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects* / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate
keywords: BPH; benign prostatic hyperplasia; c-Kit; imatinib mesylate; interstitial cells