title: Inhibition of adrenergic human prostate smooth muscle contraction by the inhibitors of c-Jun N-terminal kinase, SP600125 and BI-78D3.
abstract: BACKGROUND AND PURPOSE α(1) -Adrenoceptor-induced contraction of prostate smooth muscle is mediated by calcium- and Rho kinase-dependent mechanisms. In addition, other mechanisms, such as activation of c-jun N-terminal kinase (JNK) may be involved. Here, we investigated whether JNK participates in α(1)-adrenoceptor-induced contraction of human prostate smooth muscle. EXPERIMENTAL APPROACH Prostate tissue was obtained from patients undergoing radical prostatectomy. Effects of the JNK inhibitors SP600125 (50 µM) and BI-78D3 (30 µM) on contractions induced by phenylephrine, noradrenaline and electric field stimulation (EFS) were studied in myographic measurements. JNK activation by noradrenaline (30 µM) and phenylephrine (10 µM), and the effects of JNK inhibitors of c-Jun phosphorylation were assessed by Western blot analyses with phospho-specific antibodies. Expression of JNK was studied by immunohistochemistry and fluorescence double staining. KEY RESULTS The JNK inhibitors SP600125 and BI-78D3 reduced phenylephrine- and noradrenaline-induced contractions of human prostate strips. In addition, SP600125 reduced EFS-induced contraction of prostate strips. Stimulation of prostate tissue with noradrenaline or phenylephrine in vitro resulted in activation of JNK. Incubation of prostate tissue with SP600125 or BI-78D3 reduced the phosphorylation state of c-Jun. Immunohistochemical staining demonstrated the expression of JNK in smooth muscle cells of human prostate tissue. Fluorescence staining showed that α(1A)-adrenoceptors and JNK are expressed in the same cells. CONCLUSIONS AND IMPLICATIONS Activation of JNK is involved in α(1)-adrenoceptor-induced prostate smooth muscle contraction. Models of α(1)-adrenoceptor-mediated prostate smooth muscle contraction should include this JNK-dependent mechanism.
authors.affiliation: Department of Urology, University of Munich, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Strittmatter
authors.forename: S
authors.initials: S
authors.lastname: Walther
authors.forename: C
authors.initials: C
authors.lastname: Gratzke
authors.forename: J
authors.initials: J
authors.lastname: Göttinger
authors.forename: C
authors.initials: C
authors.lastname: Beckmann
authors.forename: A
authors.initials: A
authors.lastname: Roosen
authors.forename: B
authors.initials: B
authors.lastname: Schlenker
authors.forename: P
authors.initials: P
authors.lastname: Hedlund
authors.forename: K E
authors.initials: KE
authors.lastname: Andersson
authors.forename: C G
authors.initials: CG
authors.lastname: Stief
authors.forename: M
authors.initials: M
authors.lastname: Hennenberg
mesh_terms: D000368:Aged; D000873:Anthracenes / Q000494:pharmacology*; D004146:Dioxanes / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D011467:Prostate / Q000187:drug effects* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C576038:4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2,4-dihydro-5-((5-nitro-2-thiazolyl)thio)-3H-1,2,4-triazol-3-one; D000873:Anthracenes; D004146:Dioxanes; D047428:Protein Kinase Inhibitors; D018340:Receptors, Adrenergic, alpha-1; D013844:Thiazoles; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases