Angiotensin II type 1 and type 2 receptors regulate basal skeletal muscle microvascular volume and glucose use

Abstract

Angiotensin II causes vasoconstriction via the type 1 receptor (AT(1)R) and vasodilatation through the type 2 receptor (AT(2)R). Both are expressed in muscle microvasculature, where substrate exchanges occur. Whether they modulate basal muscle microvascular perfusion and substrate metabolism is not known. We measured microvascular blood volume (MBV), a measure of microvascular surface area and perfusion, in rats during systemic infusion of angiotensin II at either 1 or 100 ng/kg per minute. Each caused a significant increase in muscle MBV. Likewise, administration of the AT(1)R blocker losartan increased muscle MBV by >3-fold (P<0.001). Hindleg glucose extraction and muscle interstitial oxygen saturation simultaneously increased by 2- to 3-fold. By contrast, infusing AT(2)R antagonist PD123319 significantly decreased muscle MBV by >or=80% (P<0.001). This was associated with a significant decrease in hindleg glucose extraction and muscle oxygen saturation. AT(2)R antagonism and inhibition of NO synthase each blocked the losartan-induced increase in muscle MBV and glucose uptake. In conclusion, angiotensin II acts on both AT(1)R and AT(2)R to regulate basal muscle microvascular perfusion. Basal AT(1)R tone restricts muscle MBV and glucose extraction, whereas basal AT(2)R activity increases muscle MBV and glucose uptake. Pharmacological manipulation of the balance of AT(1)R and AT(2)R activity affords the potential to improve glucose metabolism.

Figures

Fig. 1

Ang II infusion increases muscle MBV independent of changes in blood pressure. Panel A. Changes in muscle MBV. Panel B. Changes in MAP. Compared with basal level, * p

Fig. 2

AT2R activity increases muscle MBV and glucose extraction. Each rat received an intravenous injection of losartan (0.3 mg/kg) at time 0 to block AT1R activity and to reveal AT2R activity. Panel A: Changes in muscle MBV. Panel B: Example of CEU images before and after losartan injection. Dotted line denotes the region of interest. Panel C. Changes in hindleg A-V glucose differences. Panel D: Femoral artery blood flow (FBF, closed circle) and mean arterial blood pressure (MAP, open circle). n=6. Compared to baseline (time 0) * p<0.01, ** p<0.001, # p<0.05, ## p<0.02, ### p<0.01.

Fig. 3

AT1R activity decreases muscle MBV and glucose extraction. Each rat received continuous intravenous infusion of PD123319 (50 µg/kg/min), began at time 0, to block AT2R activity and to reveal AT1R activity. Panel A: Changes in muscle MBV. Panel B: Example of CEU images before and 60 min after initiation of PD123319 infusion. Dotted line denotes the region of interest. Panel C: Changes in hindleg A-V glucose differences. Panel D: Femoral artery flow (FBF, closed circle) and mean arterial blood pressure (MAP, open circle). n=4–7. Compared to baseline (time 0) * p<0.001, # p<0.004, ## p<0.01.

Fig. 4

AT2R blockade abolishes losartan-induced increase in muscle MBV and glucose extraction. Each rat received an intravenous injection of losartan (0.3 mg/kg) 10 min after the initiation of a continuous intravenous infusion of PD123319 (50 µg/kg/min). Panel A: Changes in muscle MBV. Panel B: Changes in hindleg A-V glucose differences. n=5.

Fig. 5

Inhibition of NOS abrogates losartan-induced increase in muscle MBV and glucose extraction. Each rat received an intravenous injection of losartan (0.3 mg/kg) 30 min after the initiation of a continuous intravenous infusion of L-NAME (50 µg/kg/min). Panel A: Changes in muscle MBV. Panel B: Changes in hindleg A-V glucose differences. n=4.

Fig. 6

AT1R blockade increases while AT2R blockade decreases muscle interstitial oxygenation. Each rat received either an intravenous injection of losartan (0.3 mg/kg) or a continuous intravenous infusion of PD123319 (50 µg/kg/min). n=5–6.

Fig. 7

Proposed mechanisms of Ang II action in muscle microvasculature. Solid line – stimulation. Dashed line – inhibition.