Oral Carnosine Supplementation Preserves Vascular Function of Sprague Dawley Rats on a High-Salt Diet via Restored Antioxidative Defence

<b>Backgrounds/Objectives</b>: Following previous findings on high-salt (HS)-intake-related increase of oxidative stress, this study explored whether carnosine (CAR; β-alanyl-L-histidine), a reactive oxygen species (ROS) scavenger, enhanced antioxidative defence and vascular function following HS, potentially via the NRF2 or HIF-1α signalling pathway. <b>Methods</b>: Sprague Dawley rats (64, 8-10 weeks old, both sexes) were divided into four groups (n = 6/group): CTRL (0.4% NaCl), HS (4% NaCl for 7 days), CTRL + CAR (0.4% NaCl and 150 mg/kg/day oral CAR supplementation), and HS + CAR (4% NaCl and CAR). Acetylcholine-induced relaxation (AChIR) and hypoxia-induced relaxation (HIR) were evaluated in norepinephrine-precontracted (NE, 10^-7 M) aortic rings. HIR was also tested with NRF2 (ML-385, 5 × 10^-6 M) and HIF-1α (LW6, 10^-4 M) inhibitors. Gene expression of superoxide dismutases 1, 2, and 3 (<i>SOD1, 2</i> and <i>3</i>), glutathione peroxidases (<i>GPx1</i> and <i>4)</i>, catalase (<i>CAT</i>), <i>NRF2</i>, and NAD(P)H dehydrogenase (quinone 1) (<i>NQO1</i>) in aortic tissue was measured by RT-qPCR. Ferric reducing antioxidant power (FRAP) and advanced oxidation protein products (AOPPs) assays were performed on serum samples. All experimental procedures conformed to the European Guidelines (directive 86/609) and were approved by the local and national Ethical Committees (#2158-61-46-23-36, EP355/2022). <b>Results:</b> HS impaired AChIR and HIR, both preserved by CAR. NRF2 and HIF-1α inhibitors suppressed HIR in the HS and HS + CAR groups. CAR significantly increased <i>SOD1</i> and <i>2</i>, <i>NRF2</i>, and <i>NQO1</i> expression and SOD activity compared to the CTRL and HS groups. <i>GPx1</i> and <i>GPx4</i> were upregulated in HS + CAR compared to HS. CAR prevented an increase in AOPPs, which were elevated in HS, while FRAP was highest in HS + CAR. <b>Conclusions:</b> Carnosine enhances antioxidative defence by upregulating antioxidant enzymes and activities and preserves vascular relaxation, likely via NRF2 signalling.