The receptor antagonist picotamide inhibits adrenergic and thromboxane-induced contraction of hyperplastic human prostate smooth muscle

Abstract

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.

Inhibition of human prostate smooth muscle contraction by the LIM kinase inhibitors, SR7826 and LIMKi3

“…In 30–35% of patients, decreases in IPSS will be restricted to 25% or less, so that α 1 ‐blockers are inadequately effective in up to 69% of patients (Chapple et al ., ; Fullhase et al ., ; Matsukawa et al ., ; Lee et al ., ). These restrictions may be attributed to non‐adrenergic mediators, which contribute to prostate smooth muscle tone in parallel with α 1 ‐adrenoceptors, but which are not affected by α 1 ‐blockers (Strittmatter et al ., ; Hennenberg et al ., ; ). Therefore, it would make sense that future therapies address adrenergic and non‐adrenergic contractions simultaneously, to obtain higher efficacy in medical LUTS treatment.…”

“…Calculations of group sizes for organ bath experiments were carried out using GLIMMPSE (version 2.2.7, http://glimmpse.samplesizeshop.org), an open‐source online tool for calculating power and sample size, on the basis of own previous experimental data (Hennenberg et al ., ; Kreidler et al ., ; Wang et al ., ; ). Calculations were performed separately for each agonist or EFS.…”

Hydrochlorothiazide Potentiates Contractile Activity of Mouse Cavernosal Smooth Muscle

“…The possible pharmacologic interaction between HTZ and amiloride in the contractile response to phenylephrine also was evaluated by incubating CC strips with HTZ (100 μmol/L) in the presence or absence of amiloride (100 μmol/L). To evaluate cholinergic-mediated relaxation, cumulative concentration-response curves were obtained by adding acetylcholine (ACh; 0.001–10 μmol/L) to CC strip pre-contracted with U46619 (9,11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α; 100 nmol/L) 31 in the absence (control) or presence of HTZ (100 μmol/L). All concentration-response data were evaluated for fit to a logistics function and non-linear regression analysis was used to determine the parameters maximal response and log half-maximal effective concentration (EC 50 ) using GraphPad Prism (GraphPad Software, San Francisco, CA, USA).…”

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

“…The prostanoid TXA 2 plays a central role in haemostasis and is widely implicated in a range of cardiovascular, renal, pulmonary and prostate diseases (1)(2)(3)5). In humans, TXA 2 signals 2 From references (9, 60, 61).…”

“…It also induces the constriction of various other types of smooth muscle (SM), including pulmonary, renal and prostate SM, and promotes vascular remodelling in response to endothelial injury contributing to neointimal hyperplasia and restenosis post-stenting (2)(3)(4). Accordingly, imbalances in the levels of TXA 2 or of its synthase (TXS) or of its receptor, the T prostanoid receptor (or, in short, the TP), are widely implicated in several cardiovascular, pulmonary, renal and prostate pathologies (1)(2)(3)5). In humans and in other primates, the TP exists as two structurally related isoforms referred to as TPα and TPβ, which are identical for their N-terminal 328 amino acid residues but which differ exclusively in their intracellular C-terminal domains (6).…”