Angiotensin II Receptor–Neprilysin Inhibitor Sacubitril/Valsartan Improves Endothelial Dysfunction in Spontaneously Hypertensive Rats

Figure 1. Time course of systolic blood pressure (SBP; A) and heart rate (HR; B) in the spontaneously hypertensive rats in the control group (SHR‐C), SHRs treated with sacubitril/valsartan, 60 mg/kg per day (SHR‐L), SHRs treated with valsartan, 20 mg/kg per day (SHR‐V), and Wistar‐Kyoto (WKY) rats. Values are mean±SEM (n=8–12 rats per group). *P<0.05 vs SHR‐C, † P<0.05 vs WKY, &ddagger; P<0.05 vs SHR‐V. bpm indicates beats per minute.

Figure 2. A, Representative tracings showing hyperpolarization in response to acetylcholine (ACh; 10−5 mol/L) in the resting state of the membrane in endothelium‐intact mesenteric arteries of spontaneously hypertensive rats in the control group (SHR‐C), SHRs treated with sacubitril/valsartan, 60 mg/kg per day (SHR‐L), SHRs treated with valsartan, 20 mg/kg per day (SHR‐V), and Wistar‐Kyoto (WKY) rats. B, Concentration‐response curves of hyperpolarization in response to ACh on the basis of A. Relationship between the amplitude of ACh (10−5 mol/L)–induced hyperpolarization in endothelium‐intact mesenteric arteries and systolic blood pressure (SBP) in all groups (C) and in treated SHR and WKY rats (D). Indomethacin (10−5 mol/L) and Nω‐nitro‐l‐arginine (10−4 mol/L) were present throughout. Values are mean±SEM (n=4–6 rats per group). NS indicates not significant. *P<0.05 vs SHR‐C, † P<0.05 vs WKY.

Figure 3. Concentration‐response curves of relaxation in response to acetylcholine (ACh) in endothelium‐intact mesenteric arterial rings precontracted with phenylephrine (10−5 mol/L) in the spontaneously hypertensive rats in the control group (SHR‐C), SHRs treated with sacubitril/valsartan, 60 mg/kg per day (SHR‐L), SHRs treated with valsartan, 20 mg/kg per day (SHR‐V), and Wistar‐Kyoto (WKY) rats. A, Without indomethacin and Nω‐nitro‐l‐arginine (L‐NAME). B, Effects of indomethacin (10−5 mol/L). C, Effects of indomethacin (10−5 mol/L) and L‐NAME (10−4 mol/L). Values are mean±SEM (n=6 rats per group). *P<0.05 vs SHR‐C, † P<0.05 vs WKY.

Figure 4. Concentration‐response curves of relaxation in response to acetylcholine (ACh) in endothelium‐intact mesenteric arterial rings precontracted with 77 mmol/L KCl in the presence of indomethacin (10−5 mol/L) in spontaneously hypertensive rats in the control group (SHR‐C), SHRs treated with sacubitril/valsartan, 60 mg/kg per day (SHR‐L), SHRs treated with valsartan, 20 mg/kg per day (SHR‐V), and Wistar‐Kyoto (WKY) rats. Values are mean±SEM (n=6 rats per group).

Figure 5. Concentration‐response curves of relaxation in response to sodium nitroprusside (SNP; A) and levcromakalim (B) in endothelium‐intact mesenteric arterial rings precontracted with phenylephrine (10−5 mol/L) in the presence of indomethacin (10−5 mol/L) and Nω‐nitro‐l‐arginine (L‐NAME; 10−4 mol/L) in the spontaneously hypertensive rats in the control group (SHR‐C), SHRs treated with sacubitril/valsartan, 60 mg/kg per day (SHR‐L), SHRs treated with valsartan, 20 mg/kg per day (SHR‐V), and Wistar‐Kyoto (WKY) rats. Values are mean±SEM (n=6 rats per group). *P<0.05 vs SHR‐C, † P<0.05 vs WKY.