Inhibition of agonist-induced smooth muscle contraction by picotamide in the male human lower urinary tract outflow region

Abstract

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 A₂ receptor (TP receptor) antagonist picotamide on contraction in the human male bladder trigone and prostate. Carbachol, the α₁-adrenoceptor agonist phenylephrine, the thromboxane A₂ analog 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 A₂ receptors 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.

Keywords: 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).