title: Angiotensin II receptors modulate muscle microvascular and metabolic responses to insulin in vivo.
abstract: OBJECTIVE
  Angiotensin (ANG) II interacts with insulin-signaling pathways to regulate insulin sensitivity. The type 1 (AT(1)R) and type 2 (AT(2)R) receptors reciprocally regulate basal perfusion of muscle microvasculature. Unopposed AT(2)R activity increases muscle microvascular blood volume (MBV) and glucose extraction, whereas unopposed AT(1)R activity decreases both. The current study examined whether ANG II receptors modulate muscle insulin delivery and sensitivity.
  
  
  METHODS
  Overnight-fasted rats were studied. In protocol 1, rats received a 2-h infusion of saline, insulin (3 mU/kg/min), insulin plus PD123319 (AT(2)R blocker), or insulin plus losartan (AT(1)R blocker, intravenously). Muscle MBV, microvascular flow velocity, and microvascular blood flow (MBF) were determined. In protocol 2, rats received (125)I-insulin with or without PD123319, and muscle insulin uptake was determined.
  
  
  RESULTS
  Insulin significantly increased muscle MBV and MBF. AT(2)R blockade abolished insulin-mediated increases in muscle MBV and MBF and decreased insulin-stimulated glucose disposal by ~30%. In contrast, losartan plus insulin increased muscle MBV by two- to threefold without further increasing insulin-stimulated glucose disposal. Plasma nitric oxide increased by >50% with insulin and insulin plus losartan but not with insulin plus PD123319. PD123319 markedly decreased muscle insulin uptake and insulin-stimulated Akt phosphorylation.
  
  
  CONCLUSIONS
  We conclude that both AT(1)Rs and AT(2)Rs regulate insulin's microvascular and metabolic action in muscle. Although AT(1)R activity restrains muscle metabolic responses to insulin via decreased microvascular recruitment and insulin delivery, AT(2)R activity is required for normal microvascular responses to insulin. Thus, pharmacologic manipulation aimed at increasing the AT(2)R-to-AT(1)R activity ratio may afford the potential to improve muscle insulin sensitivity and glucose metabolism.
authors: Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, Virginia, USA.
authors: Weidong
authors: W
authors: Chai
authors: Wenhui
authors: W
authors: Wang
authors: Zhenhua
authors: Z
authors: Dong
authors: Wenhong
authors: W
authors: Cao
authors: Zhenqi
authors: Z
authors: Liu
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000493:pharmacokinetics / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D055806:Microvessels / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply*; D009569:Nitric Oxide / Q000097:blood; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D007004:Hypoglycemic Agents; D007328:Insulin; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose