N-Acetylcysteine attenuates the development of hypertension in the SHRSP

Laura Fields, Delyth Graham, Martin McBride, Anna Dominiczak. University of Glasgow, Glasgow, United Kingdom.

Background: Glutathione plays a critical role in protecting cells from oxidative stress by scavenging and neutralising reactive oxidative species (ROS). Potential disruption to the glutathione pathway has previously been identified in the stroke-prone spontaneously hypertensive rat (SHRSP). The aim of this study was to investigate whether enhancing the glutathione system, with N-Acetylcysteine (NAC) would improve cardiovascular function in the SHRSP.

Methods: SHRSP, WKY and SP.WKYGla2c* congenic rats were treated +/- NAC (4g/kg/per day) for 12 weeks. Systolic blood pressure was measured weekly by tail cuff plethysmography and cardiac hypertrophy was measured by echocardiography. At sacrifice, mRNA and protein were extracted from kidneys for TaqMan expression and western blot analysis of glutathione pathway genes and proteins.

Results: NAC treatment significantly reduced systolic blood pressure in SHRSP (NAC treated: 167.25 ± 17.19 v control: 197.30 ± 8.41 mmHg; P<0.005) but had no effect on SP.WKYGla2c* (NAC treated: 164.73 ± 5.75 v control: 169.21 ± 6.77 mmHg) or WKY rats (NAC treated: 160 ± 5.17 v control 153.45 ± 5.79 mmHg). NAC treatment did not affect cardiac and left ventricular mass index. NAC treatment significantly increased Gstm1 expression levels by approximately 4 fold in SP.WKYGla2c* (p<0.001) and WKY (p<0.0001) rats. Western blot analysis confirmed these findings. Ggt1 mRNA expression was not significantly affected by NAC treatment. In contrast GGT1 protein expression levels appeared to be increased in NAC treated WKY rats. No change was observed in SHRSP or SP.WKYGla2c* GGT1 protein levels.

Conclusion: NAC treatment in young SHRSP significantly improved systolic blood pressure and increased renal gene expression and protein levels of glutathione synthesis pathway components. These results confirm the importance of the glutathione pathway in the development of hypertension in the SHRSP.