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Isoprostanes evoke contraction of the murine and human detrusor muscle via activation of the thromboxane prostanoid TP receptor and Rho kinase.

Authors :
Molnár PJ
Dér B
Borsodi K
Balla H
Borbás Z
Molnár K
Ruisanchez É
Kenessey I
Horváth A
Keszthelyi A
Majoros A
Nyirády P
Offermanns S
Benyó Z
Source :
American journal of physiology. Renal physiology [Am J Physiol Renal Physiol] 2021 Apr 01; Vol. 320 (4), pp. F537-F547. Date of Electronic Publication: 2021 Jan 25.
Publication Year :
2021

Abstract

Local or systemic inflammation can severely impair urinary bladder functions and contribute to the development of voiding disorders in millions of people worldwide. Isoprostanes are inflammatory lipid mediators that are upregulated in the blood and urine by oxidative stress and may potentially induce detrusor overactivity. The aim of the present study was to investigate the effects and signal transduction of isoprostanes in human and murine urinary bladders in order to provide potential pharmacological targets in detrusor overactivity. Contraction force was measured with a myograph in murine and human urinary bladder smooth muscle (UBSM) ex vivo. Isoprostane 8-iso-PGE <subscript>2</subscript> and 8-iso-PGF <subscript>2α</subscript> evoked dose-dependent contraction in the murine UBSM, which was abolished in mice deficient in the thromboxane prostanoid (TP) receptor. The responses remained unaltered after removal of the mucosa or incubation with tetrodotoxin. Smooth muscle-specific deletion of Gα <subscript>12/13</subscript> protein or inhibition of Rho kinase by Y-27632 decreased the contractions. In Gα <subscript>q/11</subscript> -knockout mice, responses were reduced and in the presence of Y-27632 abolished completely. In human UBSM, the TP agonist U-46619 evoked dose-dependent contractions. Neither atropine nor the purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid decreased the effect, indicating that TP receptors directly mediate detrusor muscle contraction. 8-iso-PGE <subscript>2</subscript> and 8-iso-PGF <subscript>2α</subscript> evoked dose-dependent contraction in the human UBSM, and these responses were abolished by the TP antagonist SQ-29548 and were decreased by Y-27632. Our results indicate that isoprostanes evoke contraction in murine and human urinary bladders, an effect mediated by the TP receptor. The G <subscript>12/13</subscript> -Rho-Rho kinase pathway plays a significant role in mediating the contraction and therefore may be a potential therapeutic target in detrusor overactivity. NEW & NOTEWORTHY Voiding disorders affect millions of people worldwide. Inflammation can impair urinary bladder functions and contribute to the development of detrusor overactivity. The effects and signal transduction of inflammatory lipid mediator isoprostanes were studied in human and murine urinary bladders ex vivo. We found that isoprostanes evoke contraction, an effect mediated by thromboxane prostanoid receptors. The G <subscript>12/13</subscript> -Rho-Rho kinase signaling pathway plays a significant role in mediating the contraction and therefore may be a potential therapeutic target.

Details

Language :
English
ISSN :
1522-1466
Volume :
320
Issue :
4
Database :
MEDLINE
Journal :
American journal of physiology. Renal physiology
Publication Type :
Academic Journal
Accession number :
33491563
Full Text :
https://doi.org/10.1152/ajprenal.00400.2020