Sodium glucose co-transporter 2 inhibition does not improve arteriolar vasodilation in young or aged mice

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SLGT2i) are a class of drugs commonly used in diabetes to inhibit glucose reabsorption in the proximal tubule of the kidney, increasing glucose excretion and lowering blood glucose. Recently, these compounds have also demonstrated positive effects in mitigating cardiovascular risk and improving outcomes in patients with cardiovascular disease (CVD), but the mechanisms remain to be elucidated. Advancing age is associated with vascular dysfunction which contributes to increased risk for both CVD and diabetes, positioning older individuals as prime candidates to receive SGLT2i therapy. Therefore, we investigated the effect of acute SGLT2i on vasodilation in arterioles from young and old mice to: 1) determine whether these compounds have local vasoactive properties independent of systemic cardiovascular and/or metabolic alterations and 2) assess whether advanced age impacts these vasoactive responses. We hypothesized that SGLT2i would improve vasodilatory responses in old mice. METHODS: Using pressure myography in isolated mesenteric arterioles from young (4-6 mo; n=10) and old (24-26 mo; n=10) C57BL/6 mice, we assessed endothelium-dependent dilation (EDD) via acetylcholine (ACh; [10-9-10-4M]) and -independent dilation (EID) via sodium nitroprusside (SNP; [10-10-10-4M]) or the cAMP activator forskolin ([10-9-10-4M]). Thereafter, arterioles were incubated with the SGLT2i empagliflozin (EMPA [1 µM]) and concentration responses were repeated in the absence and presence of the nitric oxide synthase (NOS) inhibitor, L-NAME [10-5M]. RESULTS: We confirmed that aging blunts endothelium-dependent dilation (EDD) (P=0.0017). EDD was blunted (~43%) in the presence of EMPA in arterioles from both young (P=0.0003 vs. control) and old (P< 0.0001 vs. control) mice, preserving age-related differences in EDD (P=0.0010). The lower EDD induced by EMPA was abolished in the presence of L-NAME in both young and old arterioles (P< 0.0025 vs. EMPA for both). Endothelium-independent dilation (EID) to SNP was reduced (~15%) with EMPA treatment in both young (P=0.0009) and old (P=0.0265) arterioles; however, forskolin-induced dilation was not altered (P >0.10 in young and old). CONCLUSIONS: These findings suggest that acute in vitro SGLT2i with EMPA does not improve vasodilation in mesenteric arterioles from young or old mice. In contrast, SGLT2i impaired EDD, which appears to be mediated, at least in part, through NOS. Furthermore, the blunted EID to SNP, but not forskolin, with SGLT2i supports that these effects may occur via the NO-sGC-cGMP pathway. These results highlight the need to further interrogate the mechanisms by which SGLT2i’s, such as EMPA, improve CVD outcomes. Future investigations will seek to delineate the pathways involved, assess vascular bed-specificity, and compare vascular function with local versus systemic administration. Funding: Nora Eccles Treadwell Foundation; R01AG076748 (A.J.D., L.A.L.), R01AG077751 (L.A.L); VA Special Fellowship in Geriatrics (K.M.S.); Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant: T32HL007576 (A.G.H). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.