Sustained Captopril‐Induced Reduction in Blood Pressure Is Associated With Alterations in Gut‐Brain Axis in the Spontaneously Hypertensive Rat

Abstract

Background We have demonstrated that the antihypertensive effect of the angiotensin‐converting enzyme inhibitor, captopril ( CAP ), is associated with beneficial effects on gut pathology. Coupled with the evidence that CAP exerts prolonged reduction in blood pressure ( BP ) after discontinuation of treatment, we investigate whether persistent beneficial actions of CAP are linked to alterations of gut microbiota and improvement of hypertension‐induced gut pathology. Methods and Results Spontaneously hypertensive rats ( SHR ) and Wistar Kyoto rats were treated with CAP (250 mg/kg/day) for 4 weeks followed by withdrawal for 16 weeks. Gut microbiota, gut pathology, BP, and brain neuronal activity were assessed. CAP resulted in a ≈60 mm Hg decrease in systolic BP after 3 weeks of treatment in SHR , and the decrease remained significant at least 5 weeks after CAP withdrawal. In contrast, CAP caused modest decrease in systolic BP in Wistar Kyoto. 16S rRNA gene‐sequencing–based gut microbial analyses in SHR showed sustained alteration of gut microbiota and increase in Allobaculum after CAP withdrawal. Phylogenetic investigation of communities by reconstruction of unobserved states analysis revealed significant increase in bacterial sporulation upon CAP treatment in SHR . These were associated with persistent improvement in gut pathology and permeability. Furthermore, manganese‐enhanced magnetic resonance imaging showed significantly decreased neuronal activity in the posterior pituitary of SHR 4 weeks after withdrawal. Conclusions Decreased BP , altered gut microbiota, improved gut pathology and permeability, and dampened posterior pituitary neuronal activity were maintained after CAP withdrawal in the SHR . They suggest that CAP influences the brain‐gut axis to maintain the sustained antihypertensive effect of CAP after withdrawal.

Maternal N-Acetylcysteine Therapy Prevents Hypertension in Spontaneously Hypertensive Rat Offspring: Implications of Hydrogen Sulfide-Generating Pathway and Gut Microbiota

“…Moreover, the beneficial effects of NAC therapy are related to the high abundance of genera Holdemania and Allobaculum. Our results tie well with previous studies showing that Holdemania and Allobaculum abundance was negatively correlated with SBP in SHR [47,48]. Nevertheless, there is still a need to validate above-mentioned microbial markers for hypertension identified in the current study in other hypertensive models.…”

Changes to the gut microbiota induced by losartan contributes to its antihypertensive effects

“…Abundant evidence has demonstrated an association between gut dysbiosis and hypertension (Li et al, ; Mell et al, ; Sun et al, ; Toral et al, , ; Yang et al, ). Our results are consistent with the main features of dysbiotic microbiota described in SHR (Toral et al, , ; Yang et al, ; Yang et al, ): (a) a reduced richness and diversity, (b) an increased F/B ratio, and (c) a reduction in acetate‐ and propionate‐producing bacteria, with higher proportion of lactate‐producing bacteria. Losartan treatment tended to increase richness and diversity, whereas separated bacteria clusters from SHR towards WKY, normalised F/B ratio, and SCFAs‐producing bacteria.…”

“…We have recently described that FMT from WKY to SHR reduced neuroinflammation, sympathetic nervous system activity, and BP (Toral et al, ). In addition, the antihypertensive effect of the ACE inhibitor captopril has sustained influence on the brain–gut axis even after the withdrawal of captopril (Yang et al, ). When we explore the effects of FMT from donors SHR‐losartan to receptors SHR, we found decreased F/B ratio, thus improving gut dysbiosis, and increased the prevalence of acetate‐producing bacteria and those of the genus Bacteroides acidifaciens.…”

“…In addition, increased permeability of gut epithelial barrier, intestinal inflammatory status, and dysbiosis were associated with BP elevation in angiotensin II‐infused mice (Kim et al, ). In fact, the inhibition of the renin‐angiotensin system (RAS) by the ACE inhibitor captopril reduces BP, reverses gut pathology (Santisteban et al, ), and shifts the gut microbiota composition in SHR (Yang et al, ). However, whether BP reduction by other inhibitors of the RAS, such as the angiotensin receptor antagonist losartan, shifts the gut microbiota composition is unclear.…”

The gut microbiota and its interactions with cardiovascular disease

“…Several studies have suggested that antihypertensive medications may lower BP via effects on the gut microbiota. Captopril (CAP) is an angiotensin‐converting enzyme inhibitor used clinically in antihypertensive applications, and increased Allobaculum levels can maintain a sustained antihypertensive effect even after CAP withdrawal (Yang, et al , ). Ang II receptor blockers, such as candesartan and irbesartan, are also commonly used as antihypertensive medications, and they have been reported to normalize the F/B ratio, preserve Lactobacillus levels and prevent gut microbial disruption (Yisireyili, et al , ; Wu et al , , ) (Table ).…”