Wang Haidong, Jiang Hao, Liu Haochen, Zhang Xue, Ran Guimei, He Hua, Liu Xiaoquan
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University Nanjing, China.
Front Physiol. 2016 Nov 17;7:555. doi: 10.3389/fphys.2016.00555. eCollection 2016.
Nitric oxide (NO) production impairment is involved in the onset and development of hypertension. Although NO production impairment in spontaneously hypertensive rat (SHR) has been reported in a variety of researches, the time course of this progressive procedure, as well as its relationship with asymmetric dimethylarginine (ADMA) and angiotensin II (Ang II), has not been quantified. The aim of this research is to establish a mechanism-based disease progression model to assess Ang II and ADMA's inhibition of NO production in SHR's disease progression with/without ramipril's intervention. SHR were randomly divided into three groups: one disease group ( = 8) and two treatment groups ( = 8 for each group): standard treatment group (receiving ramipril 2 mg/kgday) and intensive treatment group (receiving ramipril 10 mg/kgday). ADMA, Ang II, NO, and SBP were determined weekly. Intensive treatment with ramipril was found to have no further attenuation of plasma NO and ADMA than standard treatment beyond its significantly stronger antihypertensive effects. Four linked turnover models were developed to characterize the profiles of ADMA, Ang II, NO, and SBP during hypertensive disease progression with/without ramipril intervention. Our model described Ang II and ADMA's contribution to NO production impairment and their responses to ramipril treatment throughout the disease progression in SHR. Model simulations suggested that Ang II affected NO production mainly through inhibiting ADMA elimination rather than affecting nitric oxide synthase (NOS) directly.
一氧化氮（NO）生成受损参与高血压的发生和发展。尽管在各种研究中已报道自发性高血压大鼠（SHR）存在NO生成受损，但这一渐进过程的时间进程及其与不对称二甲基精氨酸（ADMA）和血管紧张素II（Ang II）的关系尚未量化。本研究的目的是建立一个基于机制的疾病进展模型，以评估在有/无雷米普利干预的情况下，Ang II和ADMA对SHR疾病进展中NO生成的抑制作用。将SHR随机分为三组：一个疾病组（n = 8）和两个治疗组（每组n = 8）：标准治疗组（接受雷米普利2 mg/kg·天）和强化治疗组（接受雷米普利10 mg/kg·天）。每周测定ADMA、Ang II、NO和收缩压（SBP）。结果发现，与标准治疗相比，雷米普利强化治疗除了具有更强的降压作用外，对血浆NO和ADMA没有进一步的降低作用。建立了四个相互关联的周转模型来描述在有/无雷米普利干预的高血压疾病进展过程中ADMA、Ang II、NO和SBP的变化情况。我们的模型描述了Ang II和ADMA对NO生成受损的作用及其在SHR整个疾病进展过程中对雷米普利治疗的反应。模型模拟表明，Ang II影响NO生成主要是通过抑制ADMA的清除，而不是直接影响一氧化氮合酶（NOS）。
