title: Coexistence of functional angiotensin II type 2 receptors mediating both vasoconstriction and vasodilation in humans.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Schinzari
authors.forename: Manfredi
authors.initials: M
authors.lastname: Tesauro
authors.forename: Valentina
authors.initials: V
authors.lastname: Rovella
authors.forename: Angelo
authors.initials: A
authors.lastname: Adamo
authors.forename: Nadia
authors.initials: N
authors.lastname: Mores
authors.forename: Carmine
authors.initials: C
authors.lastname: Cardillo
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
chemical_list: D044139:Receptor, Angiotensin, Type 2