Combined RAS Modulation: The Effect on Plasma and Tissue Angiotensin Peptide Levels

Combined renin–angiotensin system (RAS) inhibition can enhance blood pressure control but has not improved clinical outcomes, underscoring the importance of complex changes in angiotensin peptide profiles in combined RAS blockade. We investigated hemodynamics and circulating and tissue angiotensin peptide profile in spontaneously hypertensive rats (SHR) treated with lisinopril, olmesartan and aliskiren and their dual combinations. SHR exhibited hypertension and left ventricular hypertrophy along with reduced circulating Ang I, Ang II, and Ang 1–7. Lisinopril produced the most pronounced antihypertensive effects, with additional reduction when combined with olmesartan or aliskiren. In contrast, aliskiren – either alone or in combination – had only modest effects in this low-RAS setting. The morphological changes of the myocardium largely mirrored the blood pressure responses across treatment groups, reinforcing the hemodynamic basis of structural remodeling in SHR. Lisinopril and olmesartan markedly increased Ang I and Ang 1-7, but lisinopril suppressed Ang II while olmesartan increased Ang II. Aliskiren further reduced Ang II and Ang 1–7. Across treatment strategies, dual RAS blockade frequently decreased both renal and circulating Ang 1–7 despite greater hemodynamic efficacy. Tissue analyses revealed minimal intrinsic Ang II synthesis in the left ventricle, consistent with AT₁-dependent uptake of circulating Ang II, while renal peptide profiles indicated some local enzymatic activity with differential reliance on ACE and neprilysin. Our results advocate a cautious, mechanism-aware approach to combination RAS blockade and support therapeutic strategies that balance blood pressure lowering with preservation of the Ang 1–7 axis.