THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Catalytic receptors

Background and Purpose: Hypertension is associated with gut dysbiosis. Here we have evaluated the effects of the angiotensin receptor antagonist losartan on gut microbiota in spontaneously hypertensive rats (SHR) to assess their contribution to its antihypertensive effects.Experimental Approach: Twenty-week-old Wistar Kyoto rats (WKY) and SHR were treated with losartan for 5 weeks (SHR-losartan). Faecal microbiota transplantation (FMT) was performed from donor SHR-losartan group to recipient untreated-SHR.Blood pressure (BP) was measured using tail-cuff plethysmography. Composition of the gut microbiota was assessed by amplification of the V3-V4 region of 16S rRNA gene. T cells were analysed in gut/aorta by flow cytometry.Key Results: Faeces from SHR showed gut dysbiosis, characterised by higher Firmicutes/Bacteroidetes ratios, lower acetate-and higher lactate-producing bacteria, and lower levels of strict anaerobic bacteria, effects which were restored to normal by losartan. Improvement of gut dysbiosis was linked to higher colonic integrity and lower sympathetic drive in the gut. In contrast, hydralazine reduced BP, but it neither restored gut dysbiosis nor colonic integrity. FMT from SHR-losartan to SHR reduced BP, improved the aortic endothelium-dependent relaxation to ACh, and reduced NADPH oxidase activity. These vascular changes were accompanied by both increased Treg and decreased Th17 cell populations in the vascular wall. Conclusion and Implications:In SHR, losartan treatment reduced gut dysbiosis and sympathetic drive in the gut, thus improving gut integrity. The changes induced by losartan in gut microbiota contributed, in part, to protecting the vasculature and reducing BP, possibly by modulating the immune system in the gut.

Section: Methodsmentioning

confidence: 99%

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

Robles-Vera

Toral

Visitación

et al. 2020

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al, ), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander, Christopoulos et al, ; Alexander, Cidlowski et al, ; Alexander, Fabbro et al, , b).…”

Section: Methodsmentioning

confidence: 99%

Luteolin prevents irinotecan‐induced intestinal mucositis in mice through antioxidant and anti‐inflammatory properties

Boeing

Souza

Speca

et al. 2020

Background and Purpose: Intestinal mucositis refers to mucosal damage caused by cancer treatment, and irinotecan is one of the agents most associated with this condition. Focusing on the development of alternatives to prevent this important adverse effect, we evaluated the activity of the flavonoid luteolin, which has never been tested for this purpose despite its biological potential. Experimental Approach: The effects of luteolin were examined on irinotecaninduced intestinal mucositis in mice. Clinical signs were evaluated. Moreover, histological, oxidative, and inflammatory parameters were analysed, as well as the possible interference of luteolin in the anti-tumour activity of irinotecan. Key Results: Luteolin (30 mgÁkg −1 ; p.o. or i.p.) prevented irinotecan-induced intestinal damage by reducing weight loss and diarrhoea score and attenuating the shortening of the duodenum and colon. Histological analysis confirmed that luteolin (p.o.)prevented villous shortening, vacuolization, and apoptosis of cells and preserved mucin production in the duodenum and colon. Moreover, luteolin treatment mitigated irinotecan-induced oxidative stress, by reducing the levels of ROS and LOOH and augmenting endogenous antioxidants, and inflammation by decreasing MPO enzymic activity, TNF, IL-1β, and IL-6 levels and increasing IL-4 and IL-10. Disruption of the tight junctions ZO-1 and occludin was also prevented by luteolin treatment.Importantly, luteolin did not interfere with the anti-tumour activity of irinotecan. Conclusion and Implications: Luteolin prevents intestinal mucositis induced byirinotecan and therefore could be a potential adjunct in anti-tumour therapy to control this adverse effect, increasing treatment adherence and consequently the chances of cancer remission.

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org (Guide to Pharmacology, ), the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY IUPHAR/BPS (Harding et al, ), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander, Christopoulos et al, ; Alexander, Fabbro et al, , ).…”

Section: Methodsmentioning

confidence: 99%

The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

Hachana

Fontaine

Sapieha

et al. 2020

Background and Purpose: Age-related macular degeneration (AMD) is a complex neurodegenerative disease treated by anti-VEGF intravitreal injections. As inflammation is potentially involved in retinal degeneration, the pro-inflammatory kallikreinkinin system is a possible alternative pharmacological target. Here, we investigated the effects of anti-VEGF and anti-B 1 receptor treatments on the inflammatory mechanisms in a rat model of choroidal neovascularization (CNV). Experimental Approach: Immediately after laser-induced CNV, Long-Evans rats were treated by eye-drop application of a B 1 receptor antagonist (R-954) or by intravitreal injection of B 1 receptor siRNA or anti-VEGF antibodies. Effects of treatments on gene expression of inflammatory mediators, CNV lesion regression and integrity of the blood-retinal barrier was measured 10 days later in the retina. B 1 receptor and VEGF-R2 cellular localization was assessed. Key Results: The three treatments significantly inhibited the CNV-induced retinal changes. Anti-VEGF and R-954 decreased CNV-induced up-regulation of B 1 and B 2 receptors, TNF-α, and ICAM-1. Anti-VEGF additionally reversed up-regulation of VEGF-A, VEGF-R2, HIF-1α, CCL2 and VCAM-1, whereas R-954 inhibited gene expression of IL-1β and COX-2. Enhanced retinal vascular permeability was abolished by anti-VEGF and reduced by R-954 and B 1 receptor siRNA treatments. Leukocyte adhesion was impaired by anti-VEGF and B 1 receptor inhibition. B 1 receptors were found on astrocytes and endothelial cells.Conclusion and Implications: B 1 receptor and VEGF pathways were both involved in retinal inflammation and damage in laser-induced CNV. The non-invasive, selfadministration of B 1 receptor antagonists on the surface of the cornea by eye drops might be an important asset for the treatment of AMD.