Liraglutide and Semaglutide Induce Nitric Oxide–Dependent Contraction of Larger and Relaxation of Smaller Porcine Retinal Resistance Vessels Ex Vivo

Purpose: Drugs with glucagon-like peptide-1 (GLP-1) agonistic effects are beneficial for the treatment of diabetes and overweight but may be accompanied by an increased risk of vascular complications in the retina and the optic disc. The purpose of the present study was to investigate whether GLP-1 agonists can have vasoactive effects on retinal resistance vessels at different branching levels ex vivo and whether these effects depend on nitric oxide (NO). Methods: The diameters of retinal arterioles, precapillary arterioles, and capillaries were studied in perfused porcine hemiretinas ex vivo after intravascular administration of the GLP-1 agonists exendin-4, liraglutide, and semaglutide, alone and in the presence of the NO synthase inhibitor L-NAME. Results: Exendin-4 had no significant effect on the diameter of retinal arterioles, precapillary arterioles, and capillaries (P > 0.77 for all comparisons). However, liraglutide and semaglutide induced a significant contraction of arterioles and a significant dilatation of precapillary arterioles and capillaries (P < 0.03 for all comparisons). These vasoactive effects disappeared in the presence of the NO synthase inhibitor L-NAME (P > 0.08 for all comparisons). Conclusions: GLP-1 agonists modified to reduce degradation and facilitate binding to plasma proteins can constrict larger and dilate smaller porcine retinal resistance vessels ex vivo. NO synthesis inhibition abolishes the effects, but the specific NO synthase isoform involved, the downstream signaling pathway, and the cellular source of NO remain to be determined. The observed vascular effects may contribute to mediating the adverse effects of GLP-1 agonists on the retina and the optic disc in clinical practice.