Angiotensin AT2 Receptor Agonist Prevents Salt‐Sensitive Hypertension in Obese Zucker Rats

Abstract

High sodium intake is a risk factor for the pathogenesis of hypertension, especially in obesity. The present study was designed to investigate whether angiotensin type‐2 receptor (AT2R) activation with selective agonist C21 prevents high‐sodium diet (HSD)‐induced hypertension in obese animals. Male obese rats were treated with AT2R agonist C21 (1mg/kg/day, oral) while maintained on either normal‐sodium diet (NSD, 0.4%) or HSD (4%) for 2‐weeks. Radio‐telemetric recording showed a time dependent increase in systolic blood pressure in HSD‐fed obese rats, being maximal increase (~27 mmHg) at day 12 of the HSD regimen. C21 treatment completely prevented the increase in blood pressure in HSD‐fed rats. Compared to NSD controls, HSD‐fed obese rats had greater natriuresis/diuresis, which were further increased by C21 treatment. HSD‐fed rats expressed higher level of cortical Ang II, which was reduced to 50% by C21 treatment. HSD feeding and/or C21 treatment had no effects on cortical renin activity and the expression of ACE and chymase, both AngII producing enzymes. However, Ang(1‐7) concentration and ACE2 activity in the cortex were reduced by HSD feeding, but C21 treatment rescued both the parameters. Also, C21 treatment reduced the cortical expression of AT1R in HSD‐fed rats, but had no effect of AT2R expression. We conclude that chronic treatment with the AT2R agonist C21 prevents salt‐sensitive hypertension in obese animals and a reduction in the renal AngII/AT1R levels may play a potential role in this phenomenon.Acknowledgement: This study was supported by NIH R01grant DK61578 to TH.