Valsartan improves endothelial dysfunction in hypertension: a randomized, double-blind study

Abstract

Endothelial dysfunction can predict cardiac outcomes in hypertension and reversing this abnormality has become an attractive therapeutic objective. We tested the hypothesis that blocking the angiotensin type 1 (AT(1)) receptor with valsartan in comparison with amlodipine would lead to an improvement in forearm resistance artery endothelial dysfunction. In total, 25 hypertensive subjects (mean age 60 years, SD 8) with a mean daytime ambulatory blood pressure (BP) of 154 (10)/97 (6) mmHg were randomized following a 3-week placebo run-in period to a double-blind, crossover trial of 16-week treatment periods with either valsartan or amlodipine, separated by a 3-week washout period. Intra-arterial infusions of acetylcholine (ACh) and N(G)-monomethyl-L-arginine (L-NMMA) were used to assess stimulated and basal endothelium-dependent nitric oxide (NO) release, respectively. Coinfusion of ACh and L-NMMA was employed to investigate the existence of an NO-independent vasodilatory pathway. Valsartan and amlodipine each lowered the clinical BP to the same extent (139 [7]/87 [6] and 139 [11]/89 [4] mmHg, respectively). The vasodilatory response to ACh was significantly increased with valsartan (maximal percentage change in forearm blood flow (max. DeltaFBF%) 301 [47] vs. 185 [34], mean [SEM]; P < 0.05) as compared with placebo, but remained unchanged with amlodipine. Both valsartan and amlodipine similarly increased the vasoconstrictive response to L-NMMA (max. DeltaFBF%-43 [5], -42 [5], respectively, vs. -26 [3] baseline; P < 0.001). The vasodilatory response after coinfusion of ACh and L-NMMA was significantly (P < 0.05) enhanced only with valsartan. Valsartan reserved peripheral endothelial dysfunction through both NO-dependent and -independent pathways, while for the same degree of BP control, amlodipine had only a partial effect on NO bioactivity.

Figure 1

Percentage changes in forearm blood flow (FBF) ratio (infused/noninfused) from baseline preceding each drug infusion for three dose levels of (A) acetycholine, (B) sodium nitroprusside, and (C) L-NMMA and (D) coinfusion of acetylcholine and L-NMMA in normotensive control group (▪) and hypertensive patients (▴), respectively. Values are mean (SEM). *P < 0.05, ^†P < 0.001 for differences between the treatments.

Figure 2

Percentage changes in forearm blood flow (FBF) ratio (infused/noninfused) from baseline preceding each drug infusion for three dose levels of (A) acetycholine, (B) sodium nitroprusside, and (C) L-NMMA and (D) coinfusion of acetylcholine and L-NMMA after placebo (•), valsartan (▪), and amlodipine (▴) treatment periods, respectively. Values are mean (SEM). *P < 0.05, ^†P < 0.001 for differences between the treatments.