β2-adrenoceptor agonist-evoked reactive oxygen species generation in mouse atria: implication in delayed inotropic effect

Ulia G Odnoshivkina; Vaycheslav I Sytchev; Leniz F Nurullin; Arthur R Giniatullin; Andrei L Zefirov; Alexey M Petrov

doi:10.1016/j.ejphar.2015.08.020

β2-adrenoceptor agonist-evoked reactive oxygen species generation in mouse atria: implication in delayed inotropic effect

Eur J Pharmacol. 2015 Oct 15:765:140-53. doi: 10.1016/j.ejphar.2015.08.020. Epub 2015 Aug 20.

Authors

Ulia G Odnoshivkina¹, Vaycheslav I Sytchev¹, Leniz F Nurullin², Arthur R Giniatullin¹, Andrei L Zefirov¹, Alexey M Petrov³

Affiliations

¹ Department of Normal Physiology, Kazan State Medical University, Butlerova st., 49, Kazan 420012, Russia.
² Kazan Institute of Biochemistry and Biophysics, Kazan Scientific Center of Russian Academy of Sciences, Laboratory of Biophysics of Synaptic Processes, Lobatchevsky str. 2/31, P.O. 30, Kazan 420111, Russia.
³ Department of Normal Physiology, Kazan State Medical University, Butlerova st., 49, Kazan 420012, Russia. Electronic address: fysio@rambler.ru.

PMID: 26297975
DOI: 10.1016/j.ejphar.2015.08.020

Abstract

Fenoterol, a β2-adrenoceptor agonist, has anti-apoptotic action in cardiomyocytes and induces a specific pattern of downstream signaling. We have previously reported that exposure to fenoterol (5 μM) results in a delayed positive inotropic effect which is related to changes in both Ca2+ transient and NO. Here, the changes in reactive oxygen species (ROS) production in response to the fenoterol administration and the involvement of ROS in effect of this agonist on contractility were investigated in mouse isolated atria. Stimulation of β2-adrenoceptor increases a level of extracellular ROS, while intracellular ROS level rises only after removal of fenoterol from the bath. NADPH-oxidase inhibitor (apocynin) prevents the increase in ROS production and the Nox2 isoform is immunofluorescently colocalized with β2-adrenoceptor at the atrial myocytes. Treatments with antioxidants (N-acetyl-L-cysteine, NADPH inhibitors, exogenous catalases) significantly inhibit the fenoterol induced increase in the contraction amplitude, probably by attenuating Ca2+ transient and up-regulating NO production. ROS generated in a β2-adrenoceptor-dependent manner can potentiate the activity of some Ca2+ channels. Indeed, inhibition of ryanodine receptors, TRPV-or L-type Ca2+- channels shows a similar efficacy in reduction of positive inotropic effect of both fenoterol and H2O2. In addition, detection of mitochondrial ROS indicates that fenoterol triggers a slow increase in ROS which is prevented by rotenone, but rotenone has no impact on the inotropic effect of fenoterol. We suggest that stimulation of β2-adrenoceptor with fenoterol causes the activation of NADPH-oxidase and after the agonist removal extracellularly generated ROS penetrates into the cell, increasing the atrial contractions probably via Ca2+ channels.

Keywords: Apocynin (PubChem CID: CID: 2214); Atria; Contractility; Fenoterol; Fenoterol (PubChem CID: 5702161); Hydrogen peroxide (PubChem CID: 784); ICI-118.551 (PubChem CID: 5484725); N-Acetyl-l-cysteine (PubChem CID: 12035); NADPH oxidase; Nitric oxide (PubChem CID: 145068); Reactive oxygen species; β(2)-adrenoceptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adrenergic beta-2 Receptor Agonists / pharmacology*
Animals
Atrial Function, Left / drug effects
Atrial Function, Left / physiology*
Cardiotonic Agents / pharmacology*
Male
Mice
Myocardial Contraction / drug effects*
Myocardial Contraction / physiology
Organ Culture Techniques
Reactive Oxygen Species / metabolism*
Receptors, Adrenergic, beta-2 / metabolism*

Substances

Adrenergic beta-2 Receptor Agonists
Cardiotonic Agents
Reactive Oxygen Species
Receptors, Adrenergic, beta-2