Abstract 70: Effect of Mas Receptor Stimulation and loss on Cardiac Pathology in Salt Sensitive Hypertension
Aim: We investigated the role of the Mas receptor in the development of cardiac pathology induced by salt loading.
METHODS: Studies were performed on 8 week old Mas+/+ (n = 30) and Mas-/- (n= 28) rats produced on the genetic background of the SS/MCWi rat using zinc-finger nuclease technology and fed on low salt (LS) or high salt (HS) diets. Mas stimulation was achieved via AVE0991 administered in the drinking water (20nmoles/kg/day). Animals were grouped into Mas+/+ rats on LS, HS, and HS + AVE0991 and Mas-/- rats on LS, HS, (n=10 for all preceding groups) and HS + AVE0991 (n=8). Blood pressure, left ventricular (LV) wall thickness, and LV pressure volume relationships (PVR) were measured daily, weekly and at the end of the 4 week experiment respectively. Hearts were stained to assess LV fibrosis.
Results: Salt loading led to significant increases in MAP in all HS treated animals compared to LS controls (p<0.05). There was no effect of Mas receptor loss (Mas-/-) or stimulation (AVE0991 treatment) on MAP. Compared to LS controls, HS diet led to significant increases in LV thickness in Mas+/+ (2.1mm vs 2.4mm p<0.05) and Mas-/- (2mm vs 2.6mm p<0.05) rats at 4 weeks following salt loading. AVE0991 stimulation of Mas attenuated salt-induced hypertrophy in Mas+/+ (2.4mm vs 2.2mm p<0.05) but not in Mas-/- (2.6mm vs 2.6mm) rats. HS increased ventricular stiffness (end diastolic PVR) to a greater degree in Mas-/- (2.1 fold) compared to Mas+/+ rats (1.5 fold). Treatment of HS rats with AVE0991 blocked salt induced changes in LV stiffness in Mas+/+ (1.5 vs 1.03 fold p<0.05) but had no effect on Mas-/- rats. Increases in systolic contractility in response to dobutamine infusion was robust in Mas+/+ rats on LS (2.3 fold), HS (1.7 fold) and HS + AVE0991 (1.8 fold) and Mas-/- rats on LS (1.9 fold). There was a blunted response to dobutamine in Mas-/- rats on HS (1.25 fold) and HS +AVE0991 (1.23 fold). Percent LV fibrosis was increased in Mas+/+ and Mas-/- rats on HS compared to LS controls (1.1% vs 2% p<0.05 and 1.2% vs 2.8% p<0.05). AVE0991 treatment abolished the fibrotic response in Mas+/+ rats (2% vs 1.4% p<0.05) but not in Mas-/- rats (2.8% vs. 2.9%)
Conclusion: The Mas receptor plays a significant role in the modulation of LV hypertrophy, fibrosis and systolic and diastolic dysfunction following salt loading.
- © 2012 by American Heart Association, Inc.