Abstract 077: Captopril-Induced Sustained Reduction in Blood Pressure is Associated With Alterations in Gut-Brain Axis in the Spontaneously Hypertensive Rats

Abstract

Objective: The anti-hypertensive effect of captopril (CAP) is prolonged even when the treatment is discotinued. Our recent findings indicate the beneficial effect of CAP on hypertension-linked gut pathology. Given the roles of brain and gut/microbiota in hypertension, we hypothesized that prolonged anti-hypertensive effect of CAP is through impacts on the brain-gut axis. Accordingly, we tested if CAP induced alterations in the brain and the gut, and if the changes are preserved in the SHR following CAP withdrawal. Methods: Male SHR and normotensive Wistar Kyoto (WKY) rats were treated with CAP (250mg/kg/day) in water for 4 weeks followed by its withdrawal for 16 weeks (weeks 5-20). Systolic BP was measured by tailcuff at weeks 3, 5, and 9. Fecal microbiota was analyzed at week 4 and week 8. Brain neuronal activity was measured by manganese-enhanced MRI (MEMRI) at weeks 4 and 8. Gut pathology was assessed at week 20. Results: Unweighted principal coordinate analysis showed that CAP treatment significantly altered gut microbial composition, characterized by separate clusters between untreated and 4 weeks CAP-treated SHR. The composition change was preserved 4 weeks post-withdrawal of CAP. Sustained improvement in fibrotic area (untreated: 12.98±0.81% vs week 20: 10.23±0.69%, P=0.036), goblet cell number (untreated: 39±3.57 cells/villi vs week 20: 65±5.29 cells/villi, P=0.0006), and villi length (untreated: 271.4±9.85 μm vs week 20: 388.8±12.29 μm, P<0.0001) was observed at week 20 compared with untreated SHR. MEMRI demonstrated sustained decrease in neuronal activity in autonomic brain regions, with the most pronounced decrease in the posterior pituitary area in SHR treated with CAP (week 4) and withdrawal of CAP (week 8), compared with untreated control (untreated: 1.57±0.11 vs week 4: 1.14±0.074 vs week 8: 1.05±0.14, P=0.0162). In contrast, CAP-treated WKY showed little change in BP, gut pathology or neuronal activity, but distinct changes in gut microbiota. Conclusion: Oral CAP persistently lowered BP, altered gut microbiota, improved gut pathology and reduced posterior pituitary neuronal activity in the SHR even post-withdrawal of CAP, indicating persistent antihypertensive effect of CAP may result from altered brain-gut communication.