Coexistence of functional angiotensin II type 2 receptors mediating both vasoconstriction and vasodilation in humans

Objectives Angiotensin (Ang) II type 1 (AT(1)) receptors mediate the majority of cardiovascular effects of Ang II, whereas the role of type 2 (AT(2)) receptors is still controversial. The present study, therefore, investigated regional hemodynamic responses mediated by AT(2) receptors in humans. Methods Studies were performed in 20 healthy individuals (eight men; mean age 37 +/- 3 years) through intra-arterial infusion of agonists and antagonists of Ang II receptors by use of strain-gauge plethysmography. Results Selective blockade of either AT(1) or AT(2) receptors by telmisartan or PD 123319, respectively, resulted in mild forearm blood flow increase (15 +/- 5% and 10 +/- 4, respectively; both P>0.05); combined AT(1) and AT(2) receptor antagonism, however, was associated with greater vasodilator response (25 +/- 5%; P=0.02). This effect was unrelated to increased nitric oxide activity, being unaffected (27 +/- 5%; P=0.65) by a 'nitric oxide clamp' (coinfusion of the nitric oxide synthase inhibitor L-NMMA and the nitric oxide donor sodium nitroprusside). Graded doses of Ang II induced a progressive vasoconstrictor response that was blunted not only by telmisartan, but also by PD 123319 and by the combination of PD 123319 and telmisartan (all P<0.001 vs. Ang II alone). AT(2) receptor stimulation by CGP 42112A resulted in a dose-dependent vasodilation P<0.001 vs. baseline), that was abolished by the nitric oxide clamp and by PD 123319 (both P<0.001 vs. CGP 42112A alone). Conclusion In the human forearm, vasoconstrictor AT(2) receptors coexist with AT(2) receptors mediating nitric oxide-dependent vasodilation. These findings suggest that imbalance between these opposing hemodynamic actions may affect vascular homeostasis and foster further investigation about the role of AT(2) receptors in human disease. J Hypertens 29:1743-1748 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.