Kobayashi N, Mori Y, Nakano S, Tsubokou Y, Shirataki H, Matsuoka H
Department of Hypertension and Cardiorenal Medicine, Institute for Medical Science, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
J Hypertens. 2001 Apr;19(4):795-801. doi: 10.1097/00004872-200104000-00017.
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.
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.
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.
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.
在人类和实验性高血压模型中，内皮依赖性血管舒张功能减弱，这种现象可能主要归因于一氧化氮（NO）释放减少或活性降低。然而，很少有研究评估β-肾上腺素能受体拮抗剂是否会增加左心室中内皮型一氧化氮合酶（eNOS）的表达。我们研究了长期使用具有弱β2-激动剂作用的特异性β1-拮抗剂塞利洛尔治疗对左心室eNOS表达的影响，并评估其与醋酸脱氧皮质酮（DOCA）-盐高血压大鼠左心室心肌重塑的关系。
对右肾切除术后的DOCA-盐大鼠（n = 18）每周注射DOCA（30 mg/kg）并给予1%盐水作为饮用水。在诱导DOCA-盐高血压5周后，给予塞利洛尔（DOCA-CEL，n = 9，每天10 mg/kg，亚降压剂量）或溶剂（DOCA-V，n = 9），年龄匹配的假手术大鼠（ShC，n = 9）作为对照组。
DOCA-V组和DOCA-CEL组的血压水平相似，且显著高于ShC组。与ShC组相比，DOCA-V组左心室中的eNOS mRNA和蛋白水平以及NOS活性显著降低，与DOCA-V组相比，DOCA-CEL组显著升高。DOCA-V组的壁腔比、血管周围纤维化、心肌纤维化和I型胶原mRNA显著增加，而塞利洛尔可使所有这些参数得到显著改善。
亚降压剂量的塞利洛尔可显著改善DOCA-盐高血压大鼠的心肌重塑，这可能是由于左心室中eNOS表达增加所致。
