Inhibition of agonist-induced smooth muscle contraction by picotamide in the male human lower urinary tract outflow region.
Male lower urinary tract symptoms (LUTS) due to bladder outlet obstruction are characterized by abnormal smooth muscle contractions in the lower urinary tract. Alpha1-adrenoceptor antagonists may induce smooth muscle relaxation in the outflow region and represent the current gold standard of medical treatment. However, results may be unsatisfactory or inadequate. Apart from α1-adrenoceptor agonists, smooth muscle contraction in the outflow region may be induced by thromboxane A2(TXA2), endothelins, or muscarinic receptor agonists. Here, we studied effects of the thromboxane A2receptor (TP receptor) antagonist picotamide on contraction in the human male bladder trigone and prostate. Carbachol, the α1-adrenoceptor agonist phenylephrine, the thromboxane A2analog U46619, and electric field stimulation (EFS) induced concentration- or frequency-dependent contractions of trigone tissues in an organ bath. Picotamide (300µM) inhibited carbachol-, phenylephrine-, U46619-, and EFS-induced contractions. Endothelins 1-3 induced concentration-dependent contractions of prostate tissues, which were inhibited by picotamide. Analyses using real time polymerase chain reaction and antibodies suggested expression of thromboxane A2receptors and synthase in trigone smooth muscle cells. Thromboxane B2(the stable metabolite of thromboxane A2) was detectable by enzyme immune assay in trigone samples, with most values ranging between 50 and 150pg/mg trigone protein. Picotamide inhibits contractions induced by different stimuli in the human lower urinary tract, including cholinergic, adrenergic, thromboxane A2- and endothelin-induced, and neurogenic contractions in different locations of the outflow region. This distinguishes picotamide from current medical treatments for LUTS, and suggests that picotamide may induce urodynamic effects in vivo.
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Martin
M
Hennenberg
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Alexander
A
Tamalunas
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Yiming
Y
Wang
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Patrick
P
Keller
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Melanie
M
Schott
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Frank
F
Strittmatter
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Annika
A
Herlemann
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Qingfeng
Q
Yu
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Beata
B
Rutz
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Anna
A
Ciotkowska
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Christian G
CG
Stief
Department of Urology, Ludwig-Maximilians University, Munich, Germany. Electronic address: christian.gratzke@med.uni-muenchen.de.
Christian
C
Gratzke
D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology*; D010795:Phthalic Acids / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
D058646:Adrenergic alpha-1 Receptor Agonists; D016232:Endothelins; D010795:Phthalic Acids; D018340:Receptors, Adrenergic, alpha-1; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; C011581:picotamide
Benign prostatic hyperplasia (BPH); Carbachol (PubChem CID 2551); Lower urinary tract symptoms (LUTS); Phenylephrine (PubChem CID 5284443); Picotamide; Picotamide (PubChem CID 4814); Prostate smooth muscle contraction; Tetrodotoxin (PubChem CID 6324668); Thromboxane A2; Trigone; U46619 (PubChem CID 16760624)