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Introduction: Sex differences in salt-sensitive hypertension and pharmacotherapy are commonly recognized. However, the mechanisms are largely unknown. ACE inhibitor is less effective in females than males, suggesting a better protective mechanism of the renin angiotensin system (RAS) in female hypertension. Angiotensin converting enzyme (ACE) 2, located on the X chromosome, is thereby a central candidate of sex differences in hypertension and pharmacotherapy. Thus, our objective is to test the sex specific protective role of ACE2 in salt hypertension. Since the females have a more regulatory RAS than males, we hypothesized that absence of ACE2 resulted in a higher blood pressure and more inflammation in females than males. Methods: ACE2 exon 2 was globally deleted using CRISPR/Cas9, resulting in a novel rat model in the Dahl salt-sensitive (S) background: male Ace2-/y and female Ace2-/+, Ace2-/-. Blood pressure was measured by telemetry in male (S n=7; S Ace2-/y n=6) and female (S n=7; Ace2-/+ n=7; Ace2-/- n=5) rats on 3 weeks high salt diets. Serum ACE2 activity was measured using ELISA. Spleen as the harbor of systemic immunity was studied for Inflammatory markers by gene expression analysis and flow cytometry. Results: Compared to sex-matched S rats, (1) serum ACE2 activity was decreased in female Ace2-/- (0.28 fold, p NIH R21AI164449 and R21AG079357. This is the full abstract presented at the American Physiology Summit 2023 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.

Introduction: We previously identified the effect of Coprococcus come, a common human gut microflora, on blood pressure regulation due to its metabolism of angiotensin-converting enzyme inhibitors (ACEi). Despite being reported as a butyrate-producer, there are no studies on C. comes in its direct role in hypertension and inflammation. Importantly, C. comes was enriched in the African American hypertensive population, almost three-fourths of whom were found salt sensitive. Therefore, we hypothesized that C. comes increased blood pressure and associated systemic inflammation in a salt-dependent manner. Methods: Once per day for 13 consecutive days, male Dahl salt-sensitive (S) rats (N=7-8/group) were administered 109 CFU of C. comes via oral gavage on both low and high salt diet. Systolic blood pressure, diastolic blood pressure, and mean arterial pressure were recorded on day 13 by radio-telemetry. On day 14, spleen (the key organ in systemic inflammation) and kidney (the key organ in salt hypertension) were collected for analyses of inflammatory markers by real time PCR and flow cytometry. Results: In low salt rats, the administration of C. comes did not significantly change blood pressures, but resulted in immunosuppression in the spleen, as evidenced by decreased inflammatory markers Il6 (0.79 fold, p This study is funded by NIH R21AG079357 and AHA CDA 852969. This is the full abstract presented at the American Physiology Summit 2023 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.

Both the gut per se and its residents, the gut microbiota are linked to blood pressure (BP) regulation, whereby, the gut can be recognized as a previously neglected target organ for hypertension. Hypertension and gut diseases such as inflammatory bowel disease (IBD) share commonalities of host inflammation in the gut and microbiota dysbiosis. Therefore, we reasoned that current treatments to remedy gut inflammation and dysbiosis in IBD could be repurposed to ameliorate hypertension. IBD is commonly treated with 5-Aminosalicylic acid (5-ASA, Mesalamine), which is a selective PPAR-γ agonist to prevent gut inflammation. Clinical use of 5-ASA is also reported to ameliorate gut dysbiosis in IBD. Based on this premise, in this study we chose to test our hypothesis that 5-ASA is an antihypertensive drug owing to its dual ability to enhance PPAR-γ in the gut and to correct gut dysbiosis. 2 groups of 11-12 weeks old male genetically hypertensive Dahl salt-sensitive (S) rats were radiotelemetrically monitored for BP, and orally gavaged with (n=9) or without (n=7) 5-ASA (150 mg/kg) for 4 weeks. PPAR-γ expression was assessed by RT-qPCR. Fecal microbiota were profiled by 16S gene sequencing. Lastly, for translational significance, F/B ratio of non-IBD (n=611) patients was compared with that of IBD (n=631) patients in the American Gut Project data for their Firmicutes/Bacteroidetes (F/B) ratio, elevation of which is a marker of gut dysbiosis. 5-ASA significantly lowered BP of the S rat (mean BP without 5-ASA, 153±1 mm Hg; mean BP with 5-ASA, 145±1 mm Hg, P

Microbiota colonization begins at birth and continuously reshapes throughout the course of our lives, resulting in tremendous interindividual heterogeneity. Given that the gut microbiome, similar to the liver, houses many categories of catalytic enzymes, there is significant value in understanding drug-bacteria interactions. The discovery of this link could enhance the therapeutic value of drugs that would otherwise have a limited or perhaps detrimental effect on patients. Resistant hypertension is one such subset of the hypertensive population that poorly responds to antihypertensive medications, resulting in an increased risk for chronic cardiovascular illnesses and its debilitating effects that ultimately have a detrimental impact on patient quality of life. We recently demonstrated that the gut microbiota is involved in the metabolism of antihypertensive drugs and thus contributes to the pathophysiology of resistant hypertension. Due to a lack of knowledge of the mechanisms, novel therapeutic approaches that account for the gut microbiota may allow for better therapeutic outcomes in resistant hypertension. Therefore, the purpose of this review is to summarize our current, albeit limited, understanding of how the gut microbiota may possess particular enzymatic activities that influence the efficacy of antihypertensive drugs.

Background: Despite the availability of various classes of antihypertensive medications, a large proportion of hypertensive individuals remain resistant to treatments. The reason for what contributes to low efficacy of antihypertensive medications in these individuals is elusive. The knowledge that gut microbiota is involved in pathophysiology of hypertension and drug metabolism led us to hypothesize that gut microbiota catabolize antihypertensive medications and compromised their blood pressure (BP)-lowering effects. Methods and Results: To test this hypothesis, we examined the BP responses to a representative ACE (angiotensin-converting enzyme) inhibitor quinapril in spontaneously hypertensive rats (SHR) with or without antibiotics. BP-lowering effect of quinapril was more pronounced in the SHR+antibiotics, indicating that gut microbiota of SHR lowered the antihypertensive effect of quinapril. Depletion of gut microbiota in the SHR+antibiotics was associated with decreased gut microbial catabolism of quinapril as well as significant reduction in the bacterial genus Coprococcus . C. comes , an anaerobic species of Coprococcus , harbored esterase activity and catabolized the ester quinapril in vitro. Co-administration of quinapril with C. comes reduced the antihypertensive effect of quinapril in the SHR. Importantly, C. comes selectively reduced the antihypertensive effects of ester ramipril but not nonester lisinopril. Conclusions: Our study revealed a previously unrecognized mechanism by which human commensal C. comes catabolizes ester ACE inhibitors in the gut and lowers its antihypertensive effect.

Local shear wave (S-wave) velocity structure and sedimentary cover thickness are essential parameters that control local amplification of ground motion and associated seismic hazard during earthqua...

The role of the gut microbiota in the initiation and progression of hypertension has been newly identified, suggesting that targeting the gut microbiota may provide a new treatment strategy. This entails a complicated interaction between the gut microbiota and different host systems (e.g., immune system) or organs (e.g., gut, spleen) that contribute to blood pressure control. The significance of the gut microbiota in treatment-resistant hypertension is still unknown, owing to a lack of appropriate animal models. Given that the gut microbiota has a variety of enzymatic activities, we hypothesized that the gut microbiota may be involved in the metabolism of antihypertensive medications, causing treatment-resistant hypertension. We investigated this hypothesis in a simple, new hypertension paradigm and found that hypertensive rats pretreated with antibiotics to reduce the gut microbiota had a better response to the angiotensin-converting enzyme inhibitor captopril. This is a simple rodent model for testing the effectiveness of antihypertensive medications. Further mechanistic research may shed light on the pathogenic function of the gut microbiota in resistant hypertension. Our method presents a novel model that has the potential to be employed in the research of resistant hypertension.

Introduction: Treatment resistant hypertension (rHTN) is present in ~20% of all hypertensive patients. rHTN is critical in African American patients who experience early onset, severe outcomes, and weak responsiveness to angiotensin converting enzyme inhibitor (ACEi). The mechanism for drug resistance is unknown. Gut microbiota harbors biotransformative enzymes such as esterase, which may hydrolyze ACEis, reducing absorption. Our study was to identify microbe responsible for ACEi resistance. Methods: 16-week-old male Spontaneously Hypertensive Rats (SHR) were gavaged with (N=12) or without (N=6) Vancomycin, Meropenem, and Omeprazole (VMO) 50 mg/kg/day for five days to deplete the gut microbiota. A single 8mg/kg dose of quinapril was given to SHR and SHR+VMO before blood pressure (BP) recording via telemetry. Quinapril catabolism was quantified by liquid chromatography-mass spectrometry. Bacterial esterase activity was monitored by hydrolysis of p-nitro-phenylbutyrate. Cecal microbiota was analyzed by 16S rDNA. Fecal microbiota were analyzed by metagenomics in 29 (16 black, 13 white) HTN patients. Results: Quinapril lowered BP more in the SHR+VMO than SHR ( P P Coprococcus ( P P =0.0065); (3) a 50% lower reduction in quinapril quantity (nmol) after incubation with 1mg of cecal lysate for 3 hr ( P P Coprococcus positively correlated with genes in drug metabolism ( P C. comes, a species in Coprococcus genus, reduced the BP-lowering effects of quinapril in the SHR ( P C. comes in the black hypertensives (poor ACEi responder) than the white (ACEi responder) ( P =0.0167). Conclusion: We, for the first time, demonstrate a previously unrecognized role of gut microbes in reducing ACEi effectiveness. This serves a foundation for expanding clinical management of antihypertensive drug resistance via manipulation of gut microbiota.