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

Hennenberg, Martin; Tamalunas, Alexander; Wang, Yiming; Keller, Patrick; Schott, Melanie; Strittmatter, Frank; Herlemann, Annika; Yu, Qiuming; Rutz, Beata; Ciotkowska, Anna; Stief, Christian G.; Gratzke, Christian

doi:10.1016/j.ejphar.2017.03.022

Cited by 12 publications

(22 citation statements)

References 62 publications

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“…It could be speculated that EHT1864 improves storage symptoms with higher efficacy than anticholinergics, as EHT1864 did not only inhibit cholinergic and neurogenic detrusor contractions, but also U46619-induced contractions. Thromboxane A 2 may act as a paracrine mediator of smooth muscle contraction in the urinary bladder and other organs, including the prostate (Strittmatter et al, 2011;Rahnama'i et al, 2012;Hennenberg et al, 2013;Hennenberg et al, 2017). In OAB, thromboxane A 2 and other prostanoinds may account for spontaneous detrusor contractions (Collins et al, 2009;Rahnama'i et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766

Wang

et al. 2020

Front. Pharmacol.

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Introduction: Lower urinary tract symptoms (LUTS) due to overactive bladder (OAB) are caused by spontaneous detrusor contractions. Medical treatment with muscarinic receptor antagonists or b 3-adrenoceptor agonists aims to inhibit detrusor contractions, but overall results are unsatisfactory. Consequently, improved understanding of bladder smooth muscle contraction and identification of novel compounds for its inhibition are needed to develop alternative options. A role of the GTPase Rac1 for smooth muscle contraction has been reported from the prostate, but is unknown in the human detrusor. Here, we examined effects of the Rac inhibitors NSC23766, which may also antagonize muscarinic receptors, and EHT1864 on contraction of human detrusor tissues. Methods: Female and male human detrusor tissues were obtained from radical cystectomy. Effects of NSC23766 (100 µM) and EHT1864 (100 µM) on detrusor contractions were studied in an organ bath. Results: Electric field stimulation induced frequency-dependent contractions of detrusor tissues, which were inhibited by NSC23766 and EHT1864. Carbachol induced concentration-dependent contractions. Concentration response curves for carbachol were shifted to the right by NSC23766, reflected by increased EC 50 values, but unchanged E max values. EHT1864 reduced carbachol-induced contractions, resulting in reduced E max values for carbachol. The thromboxane analog U46619 induced concentration-dependent contractions, which remained unchanged by NSC23766, but were reduced by EHT1864. Conclusions: NSC23766 and EHT1864 inhibit female and male human detrusor contractions. NSC23766, but not EHT1864 competitively antagonizes muscarinic receptors. In addition to neurogenic and cholinergic contractions, EHT1864 inhibits thromboxane A 2-induced detrusor contractions. The latter may be promising, as the

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Section: Discussionmentioning

confidence: 99%

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766

Wang

et al. 2020

Front. Pharmacol.

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“…α-SMA and β-actin are proteins that are cytoskeletal constituents of smooth muscle. The prostate is an organ that has abundant smooth muscle, which is responsible for dynamic obstruction in BPH 23 . Thus, these molecules are present in various cells of normal prostate tissues.…”

Section: Discussionmentioning

confidence: 99%

Complement activation by autoantigen recognition in the growth process of benign prostatic hyperplasia

Hata

Machida

Matsuoka

et al. 2019

Sci Rep

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The pathophysiology of benign prostatic hyperplasia (BPH) remained unclear. Here, we concentrated on the complement activation in the growth of BPH using a rat model. BPH tissues were harvested from rats after rat urogenital sinus implantation. The local expression and deposition levels of C1q, C3, mannose-binding lectin (MBL), factor B (FB), and C5b-9 in the rat and human BPH tissues were analyzed by real-time RT-PCR, western blotting and immunohistochemistry (IHC). Serum IgG levels in the rat BPH model were analyzed by ELISA, and IHC was used to assess tissue localization. Proteins binding serum IgG autoantibody in the BPH rats were isolated by immunoprecipitation. C1q, C3, MBL, FB and C5b-9 were highly localized in rat BPH tissues compared to normal tissues. In contrast, C3, FB and C5b-9, but not C1q and MBL, were abundantly detected in human BPH tissues compared to normal tissues. Diffuse localization of IgG in rat BPH tissues was found. Heat shock protein 90, annexin, α-smooth muscle actin, and β-actin were identified as targets for IgG autoantibodies in the BPH model. Our results strongly suggested the role for complement activation in the growth process of BPH, likely triggered by classical pathway activation with autoantibodies.

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“…Thus, besides platelet aggregation, picotamide inhibited vascular, prostate, and trigone smooth muscle contractions in vitro. [11][12][13] In addition to an expectable, competitive inhibition of thromboxane A 2 receptor-induced contractions, inhibition of α 1 -adrenoceptorand serotonin-induced contractions with non-competitve features was observed in rabbit aortic rings. 13 In rat aortic rings, picotamide inhibited acetylcholine-induced contractions.…”

Section: Introductionmentioning

confidence: 95%

“…14 Similarly, effects on contractions on other agonists than thromboxane A 2 have been reported from lower urinary tract smooth muscle. 11,12 Application of picotamide to human tissues suggested inhibition of α 1 -adrenergic, neurogenic and endothelin-induced smooth contractions in the prostate, and of cholinergic, α 1 -adrenergic and neurogenic smooth muscle contractions in the bladder trigone, besides inhibition of thromboxane A 2 -induced contractions. 11,12 Together, properties and actions of picotamide are obviously still incompletely understood, despite its applications in clinical studies and as an antiplatelet drug.…”

Section: Introductionmentioning

confidence: 99%

Picotamide inhibits a wide spectrum of agonist‐induced smooth muscle contractions in porcine renal interlobar and coronary arteries

Huang

Wang

et al. 2021

Pharmacology Res & Perspec

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

Cited by 12 publications

References 62 publications

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766

Complement activation by autoantigen recognition in the growth process of benign prostatic hyperplasia

Picotamide inhibits a wide spectrum of agonist‐induced smooth muscle contractions in porcine renal interlobar and coronary arteries

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