PhD Scientific Days 2020

Theoretical and Translational III. Lectures

Intracellular Signaling Pathways of Bradykinin-induced Detrusor Contraction in Murine and Human Urinary Bladder

Előadó neve

Dr. Borsodi, Kinga

Előadó munkahelye

Institute of Translational Medicine, Semmelweis University

Előadó telefonszáma

06205740715

Előadó e-mail címe

kingaborsodi@gmail.com

Az előadás címe

Intracellular Signaling Pathways of Bradykinin-induced Detrusor Contraction in Murine and Human Urinary Bladder

Szerző(k) neve és munkahelye

Kinga Borsodi1, Helga Balla1, Péter József Molnár1, Éva Ruisanchez1, Stefan Offermans2, Zoltán Benyó1
1 Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
2 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

INTRODUCTION: Overactive Bladder (OAB) affects more than a hundred million people’s quality of life. Currently, antimuscarinic drugs are the first-line medical therapy for the management of OAB. However, their application is limited due to the severe side-effects. Bradykinin (BK) is a peptide mediator that evokes contraction in several smooth muscle tissues and its potential role in OAB has been proposed in the literature. We investigated the role of BK in the regulation of mouse and human detrusor contraction as well as the signaling pathways involved.
AIMS: Our aim was to identify novel, more specific potential therapeutic targets for the treatment of OAB.
METHODS: Experiments on murine bladders were performed on adult, male, wild-type (WT) and Gαq/11 or Gα12/13 knockout (KO) mice. Human detrusor tissues were gained from urinary bladders surgically removed during radical cystectomy, from a macroscopically tumor-free area, approved by a uropathologist . Urothelium-free smooth muscle strips were mounted on a myograph system, the force and time course of their contractile responses were registered under isometric conditions. Changes in the muscle tone were normalized on the contractions induced by124 mM K+.
RESULTS: BK evoked dose-dependent contractions in both murine and human detrusor muscle. The muscarinic acetylcholine receptor antagonist atropine had no influence on BK-induced contractions. The B2 receptor antagonist HOE-140 significantly reduced the effect of BK in bladder strips of both species and its simultaneous application with the B1 antagonist R715 abolished the detrusor contractions. The contractile responses to BK were significantly lower in the Gαq/11 and Gα12/13 KO murine detrusor strips. The selective inhibitor (Y27632) of ROCK enzyme also diminished the effect of BK in WT mice and in Gαq/11 KO bladder strips it blocked the contractions completely.
CONCLUSION: Our results demonstrate that BK evokes contraction directly on the bladder smooth muscle, independently of cholinergic signaling pathways in both human and murine detrusor. The effect of BK is mediated predominantly by B2 receptors in both species. In mice the Gq/11-coupled and the G12/13-Rho-ROCK pathways mediate simultaneously the effect of BK on the detrusor. The B2 receptor as well as the ROCK enzyme offer potentially more selective therapeutic targets for the management of OAB.

Additional Information

Grant support: K-125174 and NVKP_16-1-2016-0042 from the Hungarian National Research, Development and Innovation Office and ÚNKP-19-2-I-SE-48

Supervisor: Zoltán Benyó
E-mail address: benyo.zoltan@med.semmelweis-univ.hu

Bemutatás módja

Szóbeli

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

4811

Start

10:25

End

10:40

Authors (legacy)

Kinga Borsodi1, Helga Balla1, Péter József Molnár1, Éva Ruisanchez1, Stefan Offermans2, Zoltán Benyó1
1 Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
2 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany