Abstract
Endothelial dysfunction in hypertension is related to nitric oxide (NO)‐deficiency. We studied the efficacy of transcriptional enhancement of endothelial nitric oxide synthase (eNOS) expression by AVE3085 in spontaneously hypertensive rats (SHR) regarding the improvement of endothelial function. Isometric force study was performed with protein expression of eNOS and phosphorylated eNOS (p‐eNOS) determined in rat aortas that were treated with or without AVE3085 for 2‐hr (acute group), or from the rats fed with AVE3085 or vehicle for 4 weeks (chronic group). WKY rats were also studied under both acute and chronic treatment. In SHR, 4‐week treatment of AVE3085 markedly increased the acetylcholine (ACh)‐induced relaxation (50.1±3.4% vs. 19.7±7.0%) with the augmentation as well observed in the acute group (50.2±4.5% vs. 26.9±4.4%) (P<0.05). 4‐week AVE3085 dramatically reduced blood pressure in SHR (170.0±4.0 vs. 151.8±1.8 mmHg, P<0.001). Either removal of endothelium or L‐NAME incubation of the aorta enhanced phenylephrine‐induced contraction in AVE3085‐treated SHR (P<0.05) but not in SHR without treatment. eNOS and p‐eNOS protein expression were significantly higher in the SHR treated with AVE3085. In contrast, AVE3085 had no effect on ACh‐induced relaxation and eNOS/p‐eNOS expression in WKY rats. Enhancement of eNOS expression by AVE3085 may ameliorate endothelial dysfunction in hypertension.
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