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

详细信息	查看全文 | 推荐本文 |

• 作者：Xuan Zhou^b ; ^c ; Dewei Shang^d ; Tianlan Zhang^b ; Liang Li^c ; Tianyan Zhou^a ; ^c ; ^{tianyanzhou@vip.sina.com} ; Wei Lu^a ; ^c ; ^{luwei_pk@bjmu.edu.cn}
• 关键词：ACE ; angiotensin-converting enzyme ; ACE2 ; angiotensin-converting enzyme 2 ; ACEI ; angiotensin-converting enzyme inhibitor ; Ang II ; angiotensin II ; Ang-(1-7) ; angiotensin-(1-7) ; AT1R ; angiotensin II type 1 receptor ; FOCE ; first order conditional estimation
• 刊名：Pharmacological Research
• 出版年：2012
• 期刊代码：54_10436618
• 类别：pha
• 出版时间：August, 2012
• 卷：66
• 期：2
• 页码：177-184
• 文件大小：1081 K

摘要

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 (5 mg kg^鈭? day^鈭?). 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).