LAUSR

Objectives: There are only sparse data on dual (or single) RAS blockade effect on angiotensin peptides. We aimed to investigate the effects of single/combined RAS blockade on angiotensin peptides in spontaneously hypertensive rats (SHR). Methods: 8 groups of SHR were investigated for 4 weeks: aliskiren (Ali), lisinopril (Lis), olmesartan (Olm) or their dual combinations along with SHR and Wistar-Kyoto (WKY) rats. Instant and equilibrated RAS peptide levels in plasma and equilibrated levels in the kidney and left ventricle (LV) were determined along with blood pressure (BP), LV weight and myocardial echocardiography. Results: Compared to WKY, the SHR had increased BP, LV hypertrophy, reduced renin activity and higher circulatory ACE activity. While Ang II was reduced in the LV, it was increased in the kidneys of SHR. Ali achieved only modest BP reduction, while the reduction by Olm, Lis and Olm + Ali were more pronounced. The combinations Olm + Lis and Lis + Ali achieved highest BP reductions. Hypertrophy correlated with BP. While Ali suppressed the RAS, Olm and Lis led to increased Ang I production, which in case of Olm resulted in increased Ang II levels. Both Lis and Olm increased Ang 1–7 equilibrium levels. A discrepancy between instant and equilibrium levels of Ang II and Ang 1-7 suggested their sequestration/degradation in the periphery. Further, levels of both peptides were increased in the kidneys, which was reduced by Olm. All combination treatments reduced the circulatory levels of Ang 1–7 compared to Lis or Olm monotherapy. Conclusion: The circulatory RAS strongly influences the peripheral RAS levels. Dual RAS blockade compromises the potentially protective Ang 1-7 increase. These results provide rationale for the novel therapeutic strategies, combinations and personalized treatment schemes. (VEGA 1/127/17)