Modeling of angiotensin II–angiotensin-(1-7) counterbalance in disease progression in spontaneously hypertensive rats treated with/without perindopril

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−1day−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 (Kin_Ang17) was stimulated by Ang II, and the Ang II output rate constant (Kout_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).