Abstract 5148: Coexistence of Functional Angiotensin II Type 2 Receptors Mediating Both Vasoconstriction and Vasodilation in the Human Forearm Circulation
Angiotensin (Ang) II type 2 (AT2) receptors have been shown to mediate vasodilation in animal models, but data to support this concept in humans have failed to clearly define AT2 receptor-dependent effects. In this study, therefore, we investigated the hemodynamic response to modulation of AT2 receptors under different conditions in healthy humans (n=7) by use of the forearm perfusion technique. Intra-arterial infusion of graded doses of Ang II (12.5, 25 and 50 pmol/min) led to concentration-dependent vasoconstriction (−51±4% [mean±SEM] was the maximum decrease in forearm blood flow (FBF) from baseline; P<0.001). The Ang II type 1 receptor antagonist telmisartan (30 μg/min) induced a mild increase in unstimulated FBF (15±5%; P=0.10) and reversed the vasoconstrictor effect of Ang II into vasodilation (15±4%; P=0.02). The AT2 receptor antagonist PD 123,319 (10 μg/min) also resulted in a mild vasodilation (16±3%; P=0.08) and blunted the vasoconstrictor effect of Ang II (−8±3%; P=0.57). Most importantly, combined infusion of telmisartan and PD 123,319 was associated with a greater vasodilator effect (28±5%; P=0.02) than separate blockade of each Ang II receptor subtype; this response was unrelated to endothelial, nitric oxide (NO)-dependent mechanisms, because it was unaffected (27±5%; P=0.03) by the “NO clamp” (NO synthase inhibitor L-NMMA (4 μmol/min) coinfused with the NO donor sodium nitroprusside (0.2 to 0.4 μg/min) in order to simulate normal basal NO activity during complete inhibition of NO synthesis). By contrast, AT2 receptor challenging with the ligand CGP 42112A (2 and 4 μg/min) resulted in a vasodilator response (37±5% at the highest dose; P=0.02) that was abolished by the NO clamp (3±1%; P=0.94). In conclusion, AT2 receptors contributing to Ang II-mediated vasoconstriction, likely located on vascular smooth muscle, coexist in the human forearm circulation with functional endothelial AT2 receptors, mediating NO-dependent vasodilation. These results suggest that imbalance between these opposing effects in conditions with endothelial dysfunction contribute to Ang II-mediated vascular damage. Our current findings might also have implications for strategies targeting Ang II for treatment of hypertension.