PhD Scientific Days 2020

Theoretical and Translational III. Lectures

Signal Transduction Pathways of Detrusor Smooth Muscle Contraction Evoked by Prostanoids and Isoprostanes in Murine and Human Urinary Bladder

Előadó neve

Dr. Molnár, Péter József

Előadó munkahelye

1 Institute of Translational Medicine, Semmelweis University, Budapest, Hungary; 2 Department of Urology, Semmelweis University, Budapest, Hungary

Előadó telefonszáma

+36306406874

Előadó e-mail címe

molnarpeterjozsef@gmail.com

Az előadás címe

Signal Transduction Pathways of Detrusor Smooth Muscle Contraction Evoked by Prostanoids and Isoprostanes in Murine and Human Urinary Bladder

Szerző(k) neve és munkahelye

Péter József Molnár1,2, Bálint Dér1, Kinga Borsodi1, Helga Balla1, Éva Ruisanchez1, Stefan Offermanns3, Péter Nyirády2, Zoltán Benyó1

1 Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
2 Department of Urology, Semmelweis University, Budapest, Hungary
3 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

Szekció

Theoretical and Translational III. Lectures

Language of the presentation

English

Section, first choice

Theoretical and Translational Medicine

Section, second choice

Clinical Medicine

Összefoglaló szövege

Overactive bladder (OAB) is a clinical condition with a prevalence of 16% and affects the patients’ quality of life significantly. The current pharmacological treatment is limited due to the adverse effects of anticholingergics. The arachidonic acid derivate prostaglandins (PGs) and the isoprotanes (isoPs), the latter produced non-enzymatically during oxidative stress, might act directly on the detrusor smooth muscle leading to detrusor overactivity.
Our aim was to examine the effects and the signal transduction pathways of PGs and isoPs in murine and human urinary bladder smooth muscle (UBSM), and potentially provide theoretical basis for the development of more specific medication of OAB with less adverse effects.
Urinary bladder tissues were obtained from mice with various genetic background and from human patients underwent radical cystectomy. UBSM strips were prepared without urothelium under microscope. Contraction force was measured by myograph under isometric conditions and normalized to reference contractions evoked by 124 mM K+.
PGE2 and PGF2α, as well as 8-epi-PGE2 and 8-iso-PGF2α evoked contraction in the murine UBSM strips. The effect of the PGs was decreased, and the effect of the isoPs was abolished in the strips of thromboxane receptor (TP) KO mice. The TP agonist U-46619 evoked dose-dependent contraction in both murine and human UBSM samples. The responses were abolished in the presence of TP receptor antagonist SQ29548, but were not altered in the presence of cholinergic antagonist atropine or the purinergic P2X-antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), indicating that the TP agonist has a direct effect on the detrusor muscle. The contraction responses were decreased in the strips of Gα12/13-KO mice. Correspondingly, the responses evoked by the PGs and isoPs were reduced by the Rho-kinase (ROCK) inhibitor Y-27632. In the strips of Gα/11-KO mice, the responses were also decreased, and in the presence of Y-27632 abolished completely.
The examined PGs and isoPs evoke contraction acting directly on the detrusor muscle. These responses are mediated mainly by the TP receptor and are linked to the Gαq/11 and to the Gα12/13-Rho-ROCK intracellular signaling pathways in the murine urinary bladder. The Rho-ROCK signaling pathway may provide a novel, more specific target in the treatment of OAB.

Additional Information

Grant Support: K-112964, K-125174 and NVKP_16-1-2016-0042 from the Hungarian National Research, Development and Innovation Office, EFOP-3.6.3-VEKOP-16-2017-00009 and ÚNKP-19-3-I-SE-107.

Bemutatás módja

Szóbeli

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

3640

Start

10:10

End

10:25

Authors (legacy)

Péter József Molnár1,2, Bálint Dér1, Kinga Borsodi1, Helga Balla1, Éva Ruisanchez1, Stefan Offermanns3, Péter Nyirády2, Zoltán Benyó1

1 Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
2 Department of Urology, Semmelweis University, Budapest, Hungary
3 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.