Comparison Of Transient ACE Inhibitor Vs. Angiotensin Receptor Blocker Treatment On Angiotensin II-Induced Oxidative Stress In The Heart Of Spontaneously Hypertensive Rats
Authors: Silva Junior Sebastião , Floyd Dana , Hale Taben 
Published: May 2024

Angiotensin II (Ang II) is a primary mediator of the renin angiotensin system (RAS) with strong profibrotic effects, mediated in part through increased levels of reactive oxygen species (ROS). We have previously shown that transient treatment with an Ang II converting enzyme inhibitor (ACEi) produces long-term protection against Ang II-induced fibrosis. Our goal was to compare the impact of prior transient AT1 receptor antagonist (ARB) vs. ACEi treatment on the oxidative stress response and fibrotic signaling profile in the left ventricle (LV) in response to Ang II. Male and female spontaneously hypertensive rats were initially treated with vehicle, ARB (losartan, 30mg/kg per day) or ACEi (enalapril, 30mg/kg per day) for two weeks. To assess long term protection of ARB and ACEi treatment, after two-weeks of washout, the rats then received Ang II (400ng/kg/day) for 2 additional weeks. Protein levels of pro-oxidant (NOX-2) and antioxidant (SOD1, SOD2) enzymes, fibrosis marker (LOX) in the left ventricle (LV) were measured by western blotting. Cardiac hypertrophy was evaluated by the LV mass/tibia Length (LV/TL) ratio. Data were analyzed by 2-way ANOVA. After a transient ARB treatment, Ang II promoted an increase in LV/TL in both male (+7%) and female (+9%) rats when compared to vehicle+Ang II (treatment effect, p<0.009). Ang II had no effect on LV/TL in rats previously treated with ACEi or vehicle. In response to Ang II, male and female rats that were previously treated with ACEi showed a decrease in LOX expression (treatment effect, p=0.02) in both male (-21%) and female (-22%) rats. No changes were observed in LOX in response to Ang II after ARB treatment. In rats transiently treated with ARB or ACEi, the expression of NOX2 was reduced after Ang II infusion. In the ARB group the NOX2 was reduced 25% in male and 28% in female (treatment effect, P=0.003). Similarly, in the ACEi group, NOX2 was reduced 27% in male and 26% in female rats (treatment effect, p<0.0001). Prior ACEi and ARB produced sex-selective changes in SOD1 expression following Ang II infusion. Specifically, following transient ARB treatment, Ang II increased SOD1 in females (24%), but not males (sex x ARB treatment interaction: p=0.0033). Similarly, prior treatment with ACEi produced sex-dependent effects, whereby AngII increased SOD1 in females (10%) and decreased expression in males (-8%, ACEi x sex interaction: p=0.043). Neither ARB, ACEi nor Ang II affected the expression of SOD2 Our data indicate a sex and treatment-specific response to Ang II following transient ARB or ACEi treatment. Both ARB and ACEi showed a long-term beneficial effect on oxidative stress. However, ARB appeared to sensitize males and females to a hypertrophy response to AngII. Future studies will evaluate this differential response observed in cardiac hypertrophy and the mechanisms leading to cardiac fibrosis. NHBL R01HL153112. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.