Angiotensin II Type 1 Receptor Blockers Inhibit KAT II Activity in the Brain\u2014Its Possible Clinical Applications

Izabela Zakrocka,Krzysztof Jóźwiak,Waldemar A Turski,Tomasz Kocki,Artur Wnorowski,Katarzyna M Targowska-Duda

doi:10.1007/s12640-017-9781-2

Izabela Zakrocka, Krzysztof Jóźwiak + Show 4 more

Open Access

https://doi.org/10.1007/s12640-017-9781-2

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Journal: Neurotoxicity research	Publication Date: Jul 21, 2017
Citations: 30	License type: open-access

Affiliation: Medical University of Lublin

Abstract

Angiotensin II receptor blockers (ARBs) are one of the most frequently recommended antihypertensive drugs. Apart from their activity towards the circulatory system, ARBs also penetrate the blood-brain barrier and display neuroprotective effects. Kynurenic acid (KYNA) is an endogenous metabolite of tryptophan produced by kynurenine aminotransferase II (KAT II) in the brain. Antagonism towards all ionotropic glutamate (GLU) receptors is the main mechanism of KYNA action. An elevated brain level of KYNA is linked with memory impairment and psychotic symptoms. The aim of this study was to examine the influence of three ARBs: irbesartan, losartan, and telmisartan on KYNA production and KAT II activity in rat brain. The effect of ARBs on KYNA production was analyzed in rat brain cortical slices and on isolated KAT II enzyme. Irbesartan, losartan, and telmisartan decreased KYNA production and KAT II activity in a dose-dependent manner in rat brain cortex in vitro. Molecular docking suggested that the examined ARBs could bind to an active site of KAT II. In conclusion, ARBs decrease KYNA production in rat brain by direct inhibition of KAT II enzymatic activity. This novel mechanism of ARBs action may be advantageous in the treatment of cognitive impairment or the management of schizophrenia.

Highlights

Arterial hypertension remains the most common cardiovascular disorder affecting nearly half of the population (ESH/ESC Task Force for the Management of Arterial Hypertension 2013)
The present study shows that all examined AT-II type 1 receptors (AT1R) blockers (ARBs), irbesartan, losartan, and telmisartan, reduce Kynurenic acid (KYNA) production in brain cortical slices in vitro
All analyzed ARBs decrease the activity of kynurenine aminotransferase II (KAT II) in brain cortical homogenates in vitro

Summary

Introduction

Arterial hypertension remains the most common cardiovascular disorder affecting nearly half of the population (ESH/ESC Task Force for the Management of Arterial Hypertension 2013). Renin-angiotensin system (RAS) inhibitors are the most preferred hypotensive agents. Active components of RAS are synthesized from angiotensinogen present primarily in glial cells (Intebi et al 1990). The main receptors responsible for angiotensin II (AT-II) action are AT-II type 1 receptors (AT1R) which dominate in astroglial cells (Sumners et al 1994). Activation of central AT1R by AT-II is linked with the pathogenesis of hypertension (Toney and Porter 1993). E.g., tonin, may produce AT-II from angiotensin I or angiotensinogen (Kondo et al 1980), AT1R blockers (ARBs) seem to provide better control over RAS activity than angiotensin converting enzyme (ACE) inhibitors

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