Abstract 253: The Direct Renin Inhibitor Aliskiren Prevents Endothelial Dysfunction in Spontaneously Hypertensive Rat Aortas

Abstract

Introduction: Hypertension is a significant medical problem. Aliskiren is a novel anti-hypertensive agent that inhibits renin directly. We tested the hypothesis that aliskiren prevents endothelial dysfunction in spontaneously hypertensive rats (SHRs). Methods: SHRs and age-matched Wistar Kyoto (WKY) rats were randomly divided and subjected to oral administration of aliskiren (10 mg/kg/day) or vehicle for 8 weeks. Blood pressure was monitored bi-weekly by a tail-cuff method. After an initial equilibration period, each ring was contracted by elevated KCl (60 mmol/L) to ensure a level of contractility suitable for subsequent experimentation. To examine endothelium-dependent relaxations in phenylephrine-contracted rings, two consecutive concentration-response curves to acetylcholine (ACh; 3 nmol/L -30 μmol/L) were constructed. In some phenylephrine-contracted rings without intact endothelium, sodium nitroprusside (SNP; 3 nmol/L – 10μmol/L) were applied cumulatively to the bathing solution to test the sensitivity of vascular smooth muscle cells (VSMCs) to NO. Results: Aliskiren reduced systolic blood pressure (SBP) to 155.6 ± 1.87 mmHg as compared to 165.3 ± 3.2 mmHg in vehicle-treated SHRs (n = 7), while chronic aliskiren administration did not affect SBP in WKY rats. SHR aortas with endothelium relaxed less in response to different concentrations of ACh than age-matched WKY rat aortas and ACh failed to cause relaxations of aortic rings without endothelium. By contrast, endothelium-independent relaxations caused by sodium nitroprusside (SNP) were comparable in aortas from SHR and WKY rats. Chronic aliskiren administration improved endothelium-dependent dilatations of aortas from SHRs compared to vehicle-treated SHRs, but this was unaffected in WKY rats. Endothelium-independent relaxations to SNP were not significantly different in aortas from the four treatment groups. Conclusions: Aliksiren reduces blood pressure and improves endothelium-dependent dilatations of SHRs. Figure 1. Effects of 8-week treatment of aliskiren on acetylcholine (ACh)-induced endothelium-dependent dilatations in SHR (A) and WKY (B) aortas. Results are mean ± SEM of 7 experiments. *p<0.05.