title: Modeling Disease Progression: Angiotensin II Indirectly Inhibits Nitric Oxide Production via ADMA Accumulation in Spontaneously Hypertensive Rats.
abstract: 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 (n= 8) and two treatment groups (n= 8 for each group): standard treatment group (receiving ramipril 2 mg/kg*day) and intensive treatment group (receiving ramipril 10 mg/kg*day). 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.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University Nanjing, China.
authors.forename: Haidong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University Nanjing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University Nanjing, China.
authors.forename: Haochen
authors.initials: H
authors.lastname: Liu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University Nanjing, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University Nanjing, China.
authors.forename: Guimei
authors.initials: G
authors.lastname: Ran
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University Nanjing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University Nanjing, China.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Liu
keywords: angiotensin II; asymmetric dimethylarginine; disease progression modeling; hypertension; intensive blood-pressure control; nitric oxide; spontaneously hypertensive rat