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

Schinzari, Francescaa; Tesauro, Manfredic; Rovella, Valentinac; Adamo, Angeloa; Mores, Nadiab; Cardillo, Carminea

doi: 10.1097/HJH.0b013e328349ae0d
Original papers: Pathophysiological aspects

Objectives: Angiotensin (Ang) II type 1 (AT1) receptors mediate the majority of cardiovascular effects of Ang II, whereas the role of type 2 (AT2) receptors is still controversial. The present study, therefore, investigated regional hemodynamic responses mediated by AT2 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 AT1 or AT2 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 AT1 and AT2 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). AT2 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 AT2 receptors coexist with AT2 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 AT2 receptors in human disease.

aDepartment of Internal Medicine

bDepartment of Pharmacology, Università Cattolica del Sacro Cuore

cDepartment of Internal Medicine, Università di Tor Vergata, Rome, Italy

Correspondence to Carmine Cardillo, Istituto di Patologia Speciale Medica e Semeiotica, Medica, Università Cattolica, Largo Gemelli 8, 00168 Rome, ItalyTel: +39 06 30154846; fax: +39 06 30157232; e-mail: carmine.cardillo@rm.unicatt.it

Abbreviations: Ang II, angiotensin II; AT1, angiotensin II type 1 receptor; AT2, angiotensin II type 2 receptor; eNOS, endothelial nitric oxide synthase

Received 19 February, 2011

Revised 7 May, 2011

Accepted 8 June, 2011

© 2011 Lippincott Williams & Wilkins, Inc.