Celiprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in deoxycorticosterone acetate-salt hypertensive rats

OBJECTIVE: Endothelium-dependent vasodilation is attenuated in humans and experimental hypertension models, and this phenomenon may be largely due to decreased release or activity of nitric oxide (NO). However, very few studies have evaluated whether beta-adrenoceptor antagonists increase endothelial NO synthase (eNOS) expression in the left ventricle. We examined the effects of long-term treatment with celiprolol, a specific beta1-antagonist with a weak beta2-agonist action, on eNOS expression in the left ventricle and evaluated its relationship to myocardial remodeling in the left ventricle of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. METHODS: DOCA-salt rats (n = 18) were induced with weekly injections of DOCA (30 mg/kg) and 1% saline in their drinking water after right nephrectomy. Celiprolol (DOCA-CEL, n = 9, 10 mg/kg per day, subdepressor dose) or a vehicle (DOCA-V, n = 9) were given after induction of DOCA-salt hypertension for 5 weeks, and age-matched sham-operated rats (ShC, n = 9) served as a control group. RESULTS: Blood pressure levels in DOCA-V and DOCA-CEL were similar and significantly higher than that in ShC. The eNOS mRNA and protein levels, and NOS activity in the left ventricle significantly decreased in DOCA-V compared with ShC, and significantly increased in DOCA-CEL compared with DOCA-V. DOCA-V showed a significant increase in the wall-to-lumen ratio, perivascular fibrosis, myocardial fibrosis, and type I collagen mRNA, with all these parameters being significantly improved by celiprolol. CONCLUSIONS: Myocardial remodeling of DOCA-salt hypertensive rats was significantly ameliorated by subdepressor doses of celiprolol, which may be due to increased eNOS expression in the left ventricle.