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(2)). 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(G)-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(G)-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.
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(2)). 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(G)-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(G)-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.
Authors: Mark M Smits; Marcel H A Muskiet; Lennart Tonneijck; Trynke Hoekstra; Mark H H Kramer; Michaela Diamant; Daniël H van Raalte Journal: Br J Clin Pharmacol Date: 2016-01-25 Impact factor: 4.335
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