Abstract 087: Intrarenal Ghrelin Receptor Inhibition Attenuates Angiotensin II-Dependent Hypertension In Normal Rats
Recent studies have shown that the intrarenal ghrelin receptor (GHSR) mediates distal nephron-dependent sodium (Na+) reabsorption in rats. Renal GHSR expression is increased in response to chronic high fat diet (HFD) and chronic intrarenal GHSR antagonism prevents HFD-induced hypertension. However, the role of the antinatriuretic renal GHSR in the development of other forms of hypertension is unknown. Normal female Sprague-Dawley rats (N=27) underwent uninephrectomy and telemetric blood pressure probe implantation. Following a 72h recovery, a subcutaneous osmotic minipump was inserted in the rat for the chronic systemic delivery of angiotensin II (Ang II; 200 ng/kg/min) or 5% dextrose in water (D5W) and received either bolus infusions of GHSR siRNA (15 μg x 3 over 5 days) or a second osmotic minipump for chronic intrarenal delivery of D5W (0.25 μL/h x 5 days) or GHSR antagonist [D-Lys-3]-GHRP-6 (D-LYS, 0.9 mg over 5 days). Four groups were studied: Group 1 (N=10); systemic D5W + intrarenal D5W; Group 2 (N=8): systemic Ang II + intrarenal D5W; Group 3 (N=4): systemic Ang II + GHSR siRNA (day 1, 3, 5); Group 4 (N=5): systemic Ang II + intrarenal D-LYS. While there was no change in mean systolic blood pressure (SBP) in the control group, systemic Ang II infusion significantly increased SBP from 126±5 to 192±2 mm Hg over 5 days (ANOVA F=47.9; P<0.0001). Intrarenal GHSR siRNA infusion markedly inhibited the pressor effect of systemic Ang II (136±2 mm Hg day 5; ANOVA; F=26.2; P<0.0001) and resulted in 65% knock down of collecting duct GHSR protein expression (P<0.05). Intrarenal GHSR antagonism with D-LYS also significantly reduced Ang II-induced hypertension, (151±13 mm Hg day 5; ANOVA F=10.7; P<0.001), albeit to a lesser extent. Collectively, these data demonstrate that chronic inhibition of intrarenal GHSR activity significantly reduces Ang II-induced hypertension in normal rats. Thus, renal GHSRs represent a novel therapeutic target for the prevention of hypertension.
Author Disclosures: B.A. Kemp: None. N.L. Howell: None. J.J. Gildea: None. S.H. Padia: None.
- © 2014 by American Heart Association, Inc.