Short‐term captopril treatment causes persistently decreased blood pressure associated with long‐lasting shifts in gut microbiota and improvement in gut pathology

Abstract

IntroductionAngiotensin‐converting enzyme inhibitors such as captopril (CAP), are widely used and preferred treatment option for high blood pressure (BP) control. It has been shown that only ~30% of orally administrated CAP is absorbed by the rat intestine. Increasing importance of gut microbiota in drug metabolism coupled with dysbiosis linked to high BP has raised interesting questions regarding the role of gut microbial community in drug‐resistant hypertension. In addition, previous studies found sustained effects of CAP on BP after withdrawal of CAP in spontaneously hypertensive rats (SHR). Thus, our objective was to test the effects of CAP on gut microbiota and whether any alteration in gut microbiota and pathology is preserved after withdrawal of CAP, which may be involved in the maintenance of lowered BP.MethodsMale normotensive Wistar Kyoto (WKY) and SHR were kept either with or without CAP (250mg/day/kg) in the drinking water for 4 weeks, and then all rats were placed on regular water until week 16. BP was measured by tail cuff on week 3 (CAP ON) and week 6 (CAP OFF). Fecal microbiota collected on week 4 (CAP ON) and week 8 (CAP OFF) was analyzed. Intestinal morphology was evaluated at week 16.ResultsCAP treatment for 4 weeks altered gut microbial composition in WKY and SHR, and the altered gut microbiota was preserved 4 weeks after CAP withdrawal, characterized by aggregated clusters of CAP ON and CAP OFF groups for both WKY and SHR in principal coordinate analysis. Microbial richness was significantly increased in SHR in the presence of CAP for 4 weeks (control: 6386±514.6 vs CAP ON: 8637±271.8, P=0.0014), and maintained a trend to be increased at 8 weeks (control: 6386±514.6 vs CAP OFF: 7601±355.5, P=0.0688). Intestine H&E staining demonstrated significant and sustained improvement in the fibrotic area (control: 12.98±0.81% vs CAP OFF: 10.23±0.69%, P=0.036), goblet cell number (control: 39±3.57 cells/villi vs CAP OFF: 65±5.29 cells/villi, P=0.0006) and villi length (control: 271.4±9.85 μm vs CAP OFF: 388.8±12.29 μm, P<0.0001) in the SHR 12 weeks post‐withdrawal of CAP. In line with microbial and intestinal changes, a significant decrease in systolic BP was observed in the CAP‐treated SHR (control: 166.8±7.1 mmHg vs CAP ON: 107.0±5.4 mmHg, P<0.0001). After withdrawal of CAP, the reduction in systolic BP in CAP‐treated SHR (control: 208.8±3.5 mmHg vs CAP OFF: 182.2±9.5 mmHg, P=0.03) was sustained.ConclusionOral administration of CAP significantly improved gut microbiota and pathology in SHR. Persistent reduction in BP during and post‐withdrawal of CAP was associated with sustained gut microbial alterations and pathological improvement, indicating potential contribution of gut microbiota in the CAP‐mediated reduction in BP.Support or Funding InformationU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) ‐ 5R01HL033610‐32 [Raizada]U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) ‐ 5R01HL132448‐02 [Raizada]This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.