GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 35; no. 6; pp. 1538 - 1543
• Main Authors: Smits, Mark M, Muskiet, Marcel H.A, Tonneijck, Lennart, Kramer, Mark H.H, Diamant, Michaela, van Raalte, Daniël H, Serné, Erik H
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01-06-2015
• Subjects: Adult; Blood Glucose - metabolism; Blood Pressure - drug effects; Capillaries - drug effects; Cross-Over Studies; Glucagon-Like Peptide 1 - agonists; Humans; Insulin - blood; Male; Microcirculation - drug effects; Microscopy, Video; Nitric Oxide - metabolism; omega-N-Methylarginine - pharmacology; Overweight - physiopathology; Peptides - pharmacology; Skin - blood supply; Venoms - pharmacology; Young Adult; nitric oxide; capillaries; glucagon-like peptide-1
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.115.305447

OBJECTIVE—The insulinotropic gut–derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide–dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans.
APPROACH AND RESULTS—We included 10 healthy overweight men (age, 20–27 years; body mass index, 26–31 kg/m). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide–synthase inhibitor L-N-monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P=0.016). Concomitant L-N-monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements (R=−5.6%; P=0.092), which was strongly and inversely associated with capillary perfusion (R=−0.928; P=0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged.
CONCLUSIONS—Acute exenatide infusion increases capillary perfusion via nitric oxide–independent pathways in healthy overweight men, suggesting direct actions of this GLP-1RA on microvascular perfusion or interaction with vasoactive factors.