Stimulation of angiotensin II type 2 receptor recruit skeletal and cardiac muscle microvasculature in humans

Acute angiotensin II (Ang II) type 1 receptor (AT₁R) blockade recruits skeletal and cardiac muscle microvasculature in healthy humans without altering insulin-mediated whole body glucose disposal. We aimed to elucidate the vascular and metabolic effects of Ang II type 2 receptor (AT₂R) stimulation in healthy humans. Following AT₁R blockade with candesartan, healthy adults received an intravenous infusion of either Ang II or saline for 180 min with or without a euglycemic hyperinsulinemic clamp superimposed during the final 120 min. Skeletal and cardiac muscle microvascular perfusion, brachial artery diameter and flow velocity, augmentation index, pulse wave velocity (PWV), and insulin-mediated whole body glucose disposal were assessed. In the presence of AT₁R blockade, Ang II infusion did not alter hemodynamic parameters or insulin-mediated whole body glucose disposal. Both insulin and Ang II increased skeletal and cardiac muscle microvascular perfusion; however, superimposing insulin on Ang II infusion did not further augment microvascular perfusion in either tissue. Infusion of Ang II, insulin, or their combination significantly increased total brachial artery blood flow. Ang II infusion increased PWV, an effect attenuated by insulin. Selective stimulation of AT₂R significantly enhanced skeletal and cardiac muscle microvascular perfusion and total tissue blood flow without altering insulin's vascular and metabolic actions in healthy humans. These findings may help explain the cardiovascular and metabolic benefits observed in individuals treated with AT₁R blockers.<b>NEW & NOTEWORTHY</b> The renin-angiotensin system critically regulates tissue perfusion, insulin action, and metabolism. Angiotensin II, via its type 1 receptor (AT₁R), promotes vasoconstriction and insulin resistance. In this study, we systemically infused angiotensin II in healthy humans during AT₁R blockade to selectively activate the type 2 receptor (AT₂R). Angiotensin II significantly increased skeletal and cardiac muscle microvascular perfusion and total blood flow without affecting insulin's vascular or metabolic actions, offering mechanistic insights into AT₁R blockers' cardiometabolic benefits.