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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.

Photoaffinity labeling (PAL) remains one of the most widely utilized methods of determining protein targets of drugs. Although useful, the scope of this technique has been limited to in vitro applications because of the inability of UV light to penetrate whole organisms. Herein, pigment-free Casper zebrafish were employed to allow in vivo PAL. A methamphetamine-related phenethylamine PAL probe, designated here as 2, demonstrated dose-dependent effects on behavior similar to methamphetamine and permitted concentration-dependent labeling of protein binding partners. Click chemistry was used to analyze binding partners via fluoroimaging. Conjugation to a biotin permitted streptavidin pull-down and proteomic analysis to define direct binding partners of the methamphetamine probe. Bioinformatic analysis revealed the probe was chiefly bound to proteins involved in phagocytosis and mitochondrial function. Future applications of this experimental paradigm combining examination of drug-protein binding interactions alongside neurobehavioral readouts via in vivo PAL will significantly enhance our understanding of drug targets, mechanism(s) of action, and toxicity/lethality.

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.

Nitric oxide (NO) mimetics and other agents capable of enhancing NO/cGMP signaling have demonstrated efficacy as potential therapies for Alzheimer’s disease. A group of thiol-dependent NO mimetics known as furoxans may be designed to exhibit attenuated reactivity to provide slow onset NO effects. The present study describes the design, synthesis, and evaluation of a furoxan library resulting in the identification of a prototype furoxan, 5a, which was profiled for use in the central nervous system. Furoxan 5a demonstrated negligible reactivity toward generic cellular thiols under physiological conditions. Nonetheless, cGMP-dependent neuroprotection was observed, and 5a (20 mg/kg) reversed cholinergic memory deficits in a mouse model of passive avoidance fear memory. Importantly, 5a can be prepared as a pharmaceutically acceptable salt and is observed in the brain 12 h after oral administration, suggesting potential for daily dosing and excellent metabolic stability. Continued investigation into furoxans as attenuated NO mimetics for the CNS is warranted.

Nitric oxide (NO) mimetics and other agents capable of enhancing NO/cGMP signaling have demonstrated efficacy as potential therapies for Alzheimer's disease. A group of thiol-dependent NO mimetics known as furoxans may be designed to exhibit attenuated reactivity to provide slow onset NO effects. The present study describes the design, synthesis, and evaluation of a furoxan library resulting in the identification of a prototype furoxan, 5a, which was profiled for use in the central nervous system. Furoxan 5a demonstrated negligible reactivity toward generic cellular thiols under physiological conditions. Nonetheless, cGMP-dependent neuroprotection was observed, and 5a (20 mg/kg) reversed cholinergic memory deficits in a mouse model of passive avoidance fear memory. Importantly, 5a can be prepared as a pharmaceutically acceptable salt and is observed in the brain 12 h after oral administration, suggesting potential for daily dosing and excellent metabolic stability. Continued investigation into furoxans as attenuated NO mimetics for the CNS is warranted.