title: Modeling of angiotensin II-angiotensin-(1-7) counterbalance in disease progression in spontaneously hypertensive rats treated with/without perindopril.
abstract: Angiotensin II (Ang II) and angiotensin-(1-7) (Ang-(1-7)) are biologically active effectors in the renin-angiotensin system (RAS) and have been demonstrated to have potential function in predicting cardiovascular diseases. We developed mechanism-based mathematical models to characterize the up/down-regulation of Ang II/Ang-(1-7), and the effects of perindopril on hypertension progression in spontaneously hypertensive rats (SHR). SHR were randomly assigned to the control group (n=6) and treatment group (n=6). Rats in the treatment group received oral perindopril (5mgkg(-1)day(-1)). Systolic blood pressure (SBP) was measured by the tail-cuff method. Serum Ang II and Ang-(1-7) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Three linked turnover models were developed to describe Ang II, Ang-(1-7) and SBP profiles. All parameters were estimated using nonlinear mixed-effects modeling. The results showed that Ang II, Ang-(1-7) and SBP gradually increased in the control group. These counterbalance mechanisms were reflected in the models with two feedback cycles. It was assumed that the Ang-(1-7) production rate constant (K(in_Ang17)) was stimulated by Ang II, and the Ang II output rate constant (K(out_Ang2)) reflecting Ang II degradation was stimulated by Ang-(1-7). The decrease in Ang II and increase in Ang-(1-7) were observed in rats treated with perindopril. The models described the counterbalance relationship of Ang II and Ang-(1-7) well, and provided insights into ACE inhibition using perindopril. The models could be extended to incorporate other biomarkers and the effects of various ACE inhibitors (ACEIs).
authors.affiliation: Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.forename: Dewei
authors.initials: D
authors.lastname: Shang
authors.forename: Tianlan
authors.initials: T
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Tianyan
authors.initials: T
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D000803:Angiotensin I / Q000502:physiology*; D000804:Angiotensin II / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008954:Models, Biological; D010446:Peptide Fragments / Q000502:physiology*; D020913:Perindopril / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D010446:Peptide Fragments; D000804:Angiotensin II; D000803:Angiotensin I; C118790:angiotensin I (1-7); D020913:Perindopril