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Celiprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in
N Kobayashi1, Y Mori, S Nakano
1Department of Hypertension and Cardiorenal Medicine, Institute for Medical Science, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. a-fukuda@dokkyomed.ac.jp
Insights
Celiprolol treatment increased nitric oxide synthase expression in the hearts of hypertensive rats. This improved cardiac remodeling, suggesting a potential therapeutic benefit for hypertension.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Molecular Biology
Background:
- Endothelium-dependent vasodilation is often impaired in hypertension, potentially due to reduced nitric oxide (NO).
- The effect of beta-adrenoceptor antagonists on endothelial NO synthase (eNOS) expression in the heart is not well understood.
- Investigating celiprolol's impact on eNOS and cardiac remodeling in hypertension is crucial.
Purpose of the Study:
- To investigate the long-term effects of celiprolol on eNOS expression in the left ventricle of DOCA-salt hypertensive rats.
- To evaluate the relationship between celiprolol-induced changes in eNOS and myocardial remodeling.
- To determine if celiprolol, at a subdepressor dose, can ameliorate cardiac structural changes in hypertension.
Main Methods:
- DOCA-salt hypertension was induced in rats via DOCA injections and saline consumption post-nephrectomy.
- Rats received either celiprolol (10 mg/kg/day) or vehicle for 5 weeks.
- Sham-operated rats served as controls; measurements included eNOS mRNA, protein, NOS activity, and cardiac remodeling markers.
Main Results:
- Hypertensive rats treated with celiprolol showed significantly increased left ventricular eNOS mRNA, protein levels, and NOS activity compared to vehicle-treated rats.
- Celiprolol treatment significantly improved cardiac remodeling, including reduced wall-to-lumen ratio, perivascular fibrosis, myocardial fibrosis, and type I collagen mRNA.
- Blood pressure levels were similar between celiprolol and vehicle groups, indicating effects beyond simple blood pressure reduction.
Conclusions:
- Subdepressor doses of celiprolol significantly ameliorated myocardial remodeling in DOCA-salt hypertensive rats.
- The beneficial effects of celiprolol on cardiac remodeling may be attributed to increased eNOS expression in the left ventricle.
- Celiprolol demonstrates potential as a therapeutic agent for managing hypertensive cardiac complications through mechanisms involving NO pathways.
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.