title: Angiotensin II type 2 receptors contribute to vascular responses in spontaneously hypertensive rats treated with angiotensin II type 1 receptor antagonists.
abstract: BACKGROUND
  Vasoconstrictive, proliferative and oxidative effects of angiotensin II (Ang II) are mediated by Ang II type 1 (AT1) receptors. The effects of Ang II via the Ang II type 2 (AT2) receptor subtype (AT2R) are less well defined. Growing evidence shows the existence of cross-talk between the Ang II receptor subtypes, which is revealed by AT1R blockade. Hence, under certain conditions, AT2R may act as an antagonistic system with respect to the AT1R.
  
  
  METHODS
  The present study was designed to investigate the effects of long-term treatment with the AT1R antagonist losartan on the AT2R-mediated response to Ang II in thoracic aortas isolated from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Untreated animals from both groups were used as controls. The mRNA expression of AT1R and AT2R was measured by reverse transcription-polymerase chain reaction.
  
  
  RESULTS
  During contraction in response to norepinephrine, Ang II induced concentration-dependent relaxation only in aortas isolated from SHR chronically treated with losartan (8 weeks; 30 mg/kg/day in drinking water). These relaxations were inhibited by the selective AT2R blocker PD123319, N(G)-nitro-L-arginine methyl ester (L-NAME), and B2receptor antagonist HOE-140. Accordingly, nitric oxide (NO) production was increased by Ang II only in the aortas of treated SHR. After AT1R blockade, AT2R mRNA was significantly increased. These findings demonstrate that, in hypertensive rats, chronic AT1R blockade is associated with an inverted vasomotor response to Ang II via AT2R-mediated NO production.
  
  
  CONCLUSIONS
  The losartan-unmasked AT2R-vasorelaxation could significantly contribute to the beneficial hemodynamic effects of AT1R blockade. In view of this, our study highlights the importance of the integrated Ang II receptor network, which may help to define further the mechanisms of the well-established vascular protective effects of AT1R blockers.
authors.affiliation: Division of Cardiology, 2nd Faculty of Medicine, University La Sapienza, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cosentino
authors.forename: Carmine
authors.initials: C
authors.lastname: Savoia
authors.forename: Paola
authors.initials: P
authors.lastname: De Paolis
authors.forename: Pietro
authors.initials: P
authors.lastname: Francia
authors.forename: Alessandro
authors.initials: A
authors.lastname: Russo
authors.forename: Angelo
authors.initials: A
authors.lastname: Maffei
authors.forename: Vanessa
authors.initials: V
authors.lastname: Venturelli
authors.forename: Marzia
authors.initials: M
authors.lastname: Schiavoni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
authors.forename: Massimo
authors.initials: M
authors.lastname: Volpe
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction; D014664:Vasodilation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D009599:Nitroprusside; D009569:Nitric Oxide; D019808:Losartan; D000109:Acetylcholine; D009638:Norepinephrine