title: Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment.
abstract: Glucagon-like peptide-1 (GLP-1) causes vasodilation and increases muscle glucose uptake independent of insulin. Recently, we have shown that GLP-1 recruits muscle microvasculature and increases muscle glucose use via a nitric oxide (NO)-dependent mechanism. Protein kinase A (PKA) is a major signaling intermediate downstream of GLP-1 receptors. To examine whether PKA mediates GLP-1's microvascular action in muscle, GLP-1 was infused to overnight-fasted male rats for 120 min in the presence or absence of H89, a PKA inhibitor. Hindleg muscle microvascular recruitment and glucose use were determined. GLP-1 infusion acutely increased muscle microvascular blood volume within 30 min without altering microvascular blood flow velocity or blood pressure. This effect persisted throughout the 120-min infusion period, leading to a significant increase in muscle microvascular blood flow. These changes were paralleled with an approximately twofold increase in plasma NO levels and hindleg glucose extraction. Systemic infusion of H89 completely blocked GLP-1-mediated muscle microvascular recruitment and increases in NO production and muscle glucose extraction. In cultured endothelial cells, GLP-1 acutely increased PKA activity and stimulated endothelial NO synthase phosphorylation at Ser(1177) and NO production. PKA inhibition abolished these effects. In ex vivo studies, perfusion of the distal saphenous artery with GLP-1 induced significant vasorelaxation that was also abolished by pretreatment of the vessels with PKA inhibitor H89. We conclude that GLP-1 recruits muscle microvasculature by expanding microvascular volume and increases glucose extraction in muscle via a PKA/NO-dependent pathway in the vascular endothelium. This may contribute to postprandial glycemic control and complication prevention in diabetes.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Dong
authors.forename: Weidong
authors.initials: W
authors.lastname: Chai
authors.forename: Wenhui
authors.initials: W
authors.lastname: Wang
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Fu
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology* / Q000502:physiology; D007328:Insulin / Q000097:blood; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D007328:Insulin; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D052216:Glucagon-Like Peptide 1; D017868:Cyclic AMP-Dependent Protein Kinases