N-Acetylcysteine Prevents Hypertension via Regulation of the ADMA-DDAH Pathway in Young Spontaneously Hypertensive Rats

Nai-Chia Fan,You-Lin Tain,Chih-Min Tsai,Li-Tung Huang,Chien-Ning Hsu

doi:10.1155/2013/696317

Abstract

Asymmetric dimethylarginine (ADMA) reduces nitric oxide (NO), thus causing hypertension. ADMA is metabolized by dimethylarginine dimethylaminohydrolase (DDAH), which can be inhibited by oxidative stress. N-Acetylcysteine (NAC), an antioxidant, can facilitate glutathione (GSH) synthesis. We aimed to determine whether NAC can prevent hypertension by regulating the ADMA-DDAH pathway in spontaneously hypertensive rats (SHR). Rats aged 4 weeks were assigned into 3 groups (n = 8/group): control Wistar Kyoto rats (WKY), SHR, and SHR receiving 2% NAC in drinking water. All rats were sacrificed at 12 weeks of age. SHR had higher blood pressure than WKY, whereas NAC-treated animals did not. SHR had elevated plasma ADMA levels, which was prevented by NAC therapy. SHR had lower renal DDAH activity than WKY, whereas NAC-treated animals did not. Renal superoxide production was higher in SHR than in WKY, whereas NAC therapy prevented it. NAC therapy was also associated with higher GSH-to-oxidized GSH ratio in SHR kidneys. Moreover, NAC reduced oxidative stress damage in SHR. The observed antihypertensive effects of NAC in young SHR might be due to restoration of DDAH activity to reduce ADMA, leading to attenuation of oxidative stress. Our findings highlight the impact of NAC on the development of hypertension by regulating ADMA-DDAH pathway.

Highlights

The imbalance between reactive oxygen species (ROS) and nitric oxide (NO) has been implicated in the pathogenesis of hypertension [1, 2]
The major findings of this study are as follows: (1) NAC treatment attenuates hypertension development in young spontaneously hypertensive rats (SHR); (2) NAC administration results in a reduction in plasma Asymmetric dimethylarginine (ADMA) levels, a decrease in superoxide production, and an increase in dimethylarginine dimethylaminohydrolase (DDAH) activity and the GSH/GSSG ratio in the kidneys of SHR; and (3) NAC and GSH both increase renal DDAH activity in vitro
SHR develop hypertension at 12 weeks of age. This is associated with an elevated ADMA level and a decreased arginine-to-ADMA ratio in the plasma, a decreased urinary NOx level, and increased superoxide production in the kidneys

Summary

Introduction

The imbalance between reactive oxygen species (ROS) and nitric oxide (NO) has been implicated in the pathogenesis of hypertension [1, 2]. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS) can reduce NO synthesis while inducing superoxide production, playing an important role in the ROS/NO imbalance. ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase isoforms-1 and -2 (DDAH-1 and -2) in the kidneys and liver [3]. ROS induces ADMA accumulation by inhibiting DDAH, which can be prevented by antioxidants [4, 5]. The antioxidant activity of GSH depends mainly on 2 rate-limiting processes: the supply of cysteine and the activity of γ-glutamylcysteine synthetase [6]. N-Acetylcysteine (NAC) facilitates intracellular GSH synthesis by increasing the supply of cysteine, the precursor of GSH. Depletion of GSH increases oxidative stress and blood pressure in normotensive rats

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