Angiotensin â…¡ Receptors And Insulin Resistance Of Skeletal Muscle Microvascular

Part One Angiotensin II Type1and Type2Receptors Regulate Basal Skeletal Muscle Microvascular Volume and Glucose UseObjective Angiotensin11causes vasoconstriction via the type1receptor (AT1R) and vasodilatation through the type2receptor (AT2R). Both are expressed in muscle microvasculature. where substrate exchanges occur. Whether they modulate basal muscle microvascular perfusion and substrate metabolism is not known.Methods We measured microvascular blood volume (MBV), a measure of microvascular surface area and perfusion, in rats during systemic infusion of angiotensin Ⅱ at either1or100ng/kg per minute.Results Each caused a significant increase in muscle MBV. Likewise, administration of the AT1R blocker losartan increased muscle MBV by3-fold (P<0.001). Hindleg glucose extraction and muscle interstitial oxygen saturation simultaneously increased by2-to3-fold. By contrast, infusing AT2R antagonist PD123319significantly decreased muscle MBV by80%(P<0.001). This was associated with a significant decrease in hindleg glucose extraction and muscle oxygen saturation. AT2R antagonism and inhibition of NO synthase each blocked the losartan-induced increase in muscle MBV and glucose uptake.Conclusions In conclusion, angiotensin Ⅱ acts on both AT1R and AT2R to regulate basal muscle microvascular perfusion. Basal AT1R tone restricts muscle MBV and glucose extraction, whereas basal AT2R activity increases muscle MBV and glucose uptake. Pharmacological manipulation of the balance of ATI R and AT2R activity affords the potential to improve glucose metabolism. Part Two:Angiotensin Ⅱ Receptors Modulate Muscle Micro vascular and Metabolic Responses to Insulin in VivoObjective Angiotensin (ANG) Ⅱ interacts with insulin signaling pathways to regulate insulin sensitivity. The type1(AT1R) and type2(AT2R) receptors reciprocally regulate basal perfusion of muscle microvasculature. Unopposed AT2R activity increases muscle microvascular blood volume (MBV) and glucose extraction, whereas unopposed AT1R activity decreases both. The current study examined whether ANG Ⅱ receptors modulate muscle insulin delivery and sensitivity.Research Design and Methods Overnight-fasted rats were studied. In protocol1. rats received a2-h infusion of saline, insulin (3mU/kg/min). insulin plus PD123319(AT2R blocker), or insulin plus losartan (AT1R blocker, intravenously). Muscle MBV, microvascular flow velocity, and microvascular blood flow (MBF) were determined. In protocol2. rats received1251-insulin with or without PD123319, and muscle insulin uptake was determined.Results Insulin significantly increased muscle MBV and MBF. AT2R 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 by50%with insulin and insulin plus losartan but not with insulin plus PD123319. PD123319markedly decreased muscle insulin uptake and insulin-stimulated Akt phosphorylation.Conclusions We conclude that both AT1Rs and AT2Rs regulate insulin’s microvascular and metabolic action in muscle. Although AT1R activity restrains muscle metabolic responses to insulin via decreased microvascular recruitment and insulin delivery, AT2R activity is required for normal microvascular responses to insulin. Thus, pharmacologic manipulation aimed at increasing the AT2R-to-AT1R activity ratio may afford the potential to improve muscle insulin sensitivity and glucose metabolism.