The receptor antagonist picotamide inhibits adrenergic and thromboxane-induced contraction of hyperplastic human prostate smooth muscle.
Inhibition of prostate smooth muscle contraction is an important strategy for medical treatment of lower urinary tract symptoms (LUTS). Besides α1-adrenoceptors, prostate smooth muscle contraction is induced by activation of thromboxane (TXA2) receptors (TXA2-R). Here, we examined the effects of the TXA2-R antagonist picotamide on contraction of human prostate tissue. Prostate tissues were obtained from radical prostatectomy. The effects of picotamide (300 μM), L-665,240 (3 μM), and seratrodast (3 μM) on U46619-, electric field stimulation- (EFS-), phenylephrine-, and norepinephrine-induced contractions were studied in organ baths. Expression of TXA2-R and TXA2 synthase (TXS) was examined by fluorescence stainings. Picotamide, seratrodast, and L-655,240 inhibited concentration-dependent contractions induced by the TXA2 analog U46619. Picotamide, but not seratrodast or L-655,240, inhibited frequency-dependent contractions induced by EFS. Picotamide inhibited concentration-dependent contractions induced by norepinephrine or by the selective α1-adrenoceptor agonist phenylephrine. In prostate strips, where only submaximal contraction by a low dose of phenylephrine was induced, application of U46619 raised tone to maximum phenylephrine-induced tension. Immunoreactivity for TXA2-R and TXS was observed in the stroma and in epithelial cells of glands. Colocalization of both immunoreactivites was observed with the smooth muscle markers calponin and α-smooth muscle actin, with the epithelial marker pan-cytokeratin, and with prostate-specific antigen in the stroma and glands. The receptor antagonist picotamide inhibits α1-adrenergic, TXA2-mediated, and EFS-induced contractions in the human prostate. To the best of our knowledge, this is the first antagonist able to inhibit two different contraction systems in the prostate.
Urologische Klinik & Poliklinik, Marchioninistr. 15, 81377 München. Christian.Gratzke@med.uni-muenchen.de.
Martin
M
Hennenberg
Marijan
M
Miljak
Daniel
D
Herrmann
Frank
F
Strittmatter
Sebastian
S
Walther
Beata
B
Rutz
Yasemin
Y
Hocaoglu
Thomas
T
Kunit
Andrea
A
Schreiber
Karl-Erik
KE
Andersson
Christian G
CG
Stief
Christian
C
Gratzke
D000322:Adrenergic Agonists / Q000494:pharmacology*; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013930:Thromboxane-A Synthase / Q000378:metabolism; D013931:Thromboxanes / Q000494:pharmacology*
D000322:Adrenergic Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D010795:Phthalic Acids; D011448:Prostaglandin Antagonists; D018340:Receptors, Adrenergic, alpha-1; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013931:Thromboxanes; C011581:picotamide; D013930:Thromboxane-A Synthase
benign prostate hyperplasia; lower urinary tract symptoms; picotamide; smooth muscle contraction; α1-adrenoceptor