Angiotensin-(1-7) recruits muscle microvasculature and enhances insulin's metabolic action via mas receptor.
Angiotensin-(1-7) [Ang-(1-7)], an endogenous ligand for the G protein-coupled receptor Mas, exerts both vasodilatory and insulin-sensitizing effects. In skeletal muscle, relaxation of precapillary arterioles recruits microvasculature and increases the endothelial surface area available for nutrient and hormone exchanges. To assess whether Ang-(1-7) recruits microvasculature and enhances insulin action in muscle, overnight-fasted adult rats received an intravenous infusion of Ang-(1-7) (0, 10, or 100 ng/kg per minute) for 150 minutes with or without a simultaneous infusion of the Mas inhibitor A-779 and a superimposition of a euglycemic insulin clamp (3 mU/kg per minute) from 30 to 150 minutes. Hind limb muscle microvascular blood volume, microvascular flow velocity, and microvascular blood flow were determined. Myographic changes in tension were measured on preconstricted distal saphenous artery. Ang-(1-7) dose-dependently relaxed the saphenous artery (P<0.05) ex vivo. This effect was potentiated by insulin (P<0.01) and abolished by either endothelium denudement or Mas inhibition. Systemic infusion of Ang-(1-7) rapidly increased muscle microvascular blood volume and microvascular blood flow (P<0.05, each) without altering microvascular flow velocity. Insulin infusion alone increased muscle microvascular blood volume by 60% to 70% (P<0.05). Adding insulin to the Ang-(1-7) infusion further increased muscle microvascular blood volume and microvascular blood flow (≈2.5 fold; P<0.01). These were associated with a significant increase in insulin-mediated glucose disposal and muscle protein kinase B and extracellular signal-regulated kinase 1/2 phosphorylation. A-779 pretreatment blunted the microvascular and insulin-sensitizing effects of Ang-(1-7). We conclude that Ang-(1-7) by activating Mas recruits muscle microvasculature and enhances the metabolic action of insulin. These effects may contribute to the cardiovascular protective responses associated with Mas activation and explain the insulin-sensitizing action of Ang-(1-7).
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, PO Box 801410, Charlottesville, VA 22908. zl3e@virginia.edu.
Zhuo
Z
Fu
Lina
L
Zhao
Kevin W
KW
Aylor
Robert M
RM
Carey
Eugene J
EJ
Barrett
Zhenqi
Z
Liu
D000803:Angiotensin I / Q000008:administration & dosage / Q000494:pharmacology*; D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001783:Blood Flow Velocity / Q000187:drug effects; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D055806:Microvessels / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
C092006:7-Ala-angiotensin (1-7); D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D000803:Angiotensin I; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C118790:angiotensin I (1-7); D005947:Glucose
angiotensins; endothelial cells; microvasculature; muscles