Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1009, USA.
Menopause. 2011 Jun;18(6):698-708. doi: 10.1097/gme.0b013e31820390a2.
The loss of estrogen in mRen2.Lewis rats leads to an exacerbation of diastolic dysfunction. Because specific neuronal nitric oxide synthase (nNOS) inhibition reverses renal damage in the same model, we assessed the effects of inhibiting neuronal nitric oxide on diastolic function, left ventricular remodeling, and the components of the cardiac nitric oxide system in ovariectomized (OVX) and sham-operated mRen2.Lewis rats treated with N5-(1-imino-3-butenyl)-L-ornithine (L-VNIO; 0.5 mg/kg per day for 28 d) or vehicle (saline).
Female mRen2.Lewis rats underwent either bilateral oophorectomy (OVX; n = 15) or sham operation (or surgical procedure) (sham; n = 19) at 4 weeks of age. Beginning at 11 weeks of age, the rats were randomized to receive either L-VNIO or vehicle.
The surgical loss of ovarian hormones, particularly estrogen, led to exacerbated hypertension, impaired myocardial relaxation, diminished diastolic compliance, increased perivascular fibrosis, and increased relative wall thickness. The cardiac tetrahydrobiopterin-to-dihydrobiopterin levels were lower among OVX rats compared with sham-operated rats, and this altered cardiac biopterin profile was associated with enhanced myocardial superoxide production and decreased nitric oxide release. L-VNIO decreased myocardial reactive oxygen species production, increased nitrite concentrations, attenuated cardiac remodeling, and improved diastolic function.
Impaired relaxation, diastolic stiffness, and cardiac remodeling were found among OVX mRen2.Lewis rats. A possible mechanism for this unfavorable cardiac phenotype may have resulted from a deficiency in available tetrahydrobiopterin and subsequent increase in nNOS-derived superoxide and reduction in nitric oxide synthase metabolites within the heart. Selective nNOS inhibition with L-VNIO attenuated cardiac superoxide production and limited remodeling, leading to improved diastolic function in OVX mRen2.Lewis rats.
mRen2.Lewis 大鼠的雌激素丧失会导致舒张功能恶化。由于特定的神经元型一氧化氮合酶（nNOS）抑制可逆转该模型中的肾脏损伤，因此我们评估了抑制神经元型一氧化氮对去卵巢（OVX）和假手术 mRen2.Lewis 大鼠舒张功能、左心室重构以及心脏一氧化氮系统成分的影响，这些大鼠接受 N5-（1-亚氨基-3-丁烯基）-L-鸟氨酸（L-VNIO；每天 0.5mg/kg，共 28 天）或载体（盐水）治疗。
4 周龄时，雌性 mRen2.Lewis 大鼠接受双侧卵巢切除术（OVX；n=15）或假手术（sham；n=19）。11 周龄时，大鼠被随机分为 L-VNIO 或载体治疗组。
卵巢激素（特别是雌激素）的手术丧失导致高血压加重、心肌松弛受损、舒张顺应性降低、血管周围纤维化增加以及相对壁厚度增加。与假手术组相比，OVX 大鼠的心脏四氢生物蝶呤/二氢生物蝶呤水平降低，这种改变的心脏生物蝶呤谱与心肌超氧自由基产生增加和一氧化氮释放减少有关。L-VNIO 降低心肌活性氧的产生，增加亚硝酸盐浓度，减轻心脏重构，改善舒张功能。
OVX mRen2.Lewis 大鼠出现松弛受损、舒张僵硬和心脏重构。这种不利的心脏表型可能是由于心脏中可利用的四氢生物蝶呤缺乏，随后 nNOS 衍生的超氧自由基增加和一氧化氮合酶代谢物减少所致。L-VNIO 选择性抑制 nNOS 可减少心脏超氧自由基的产生并限制重构，从而改善 OVX mRen2.Lewis 大鼠的舒张功能。
