Angiotensin II type 2 receptors contribute to vascular responses in spontaneously hypertensive rats treated with angiotensin II type 1 receptor antagonists

• Published in: American journal of hypertension 2005-04, Vol.18 (4), p.493-499
• Main Authors: Cosentino, Francesco, Savoia, Carmine, De Paolis, Paola, Francia, Pietro, Russo, Alessandro, Maffei, Angelo, Venturelli, Vanessa, Schiavoni, Marzia, Lembo, Giuseppe, Volpe, Massimo
• Format: Article
• Language: English
• Subjects: Acetylcholine - pharmacology; Angiotensin II - pharmacology; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiopathology; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; Experimental diseases; Heart Rate - drug effects; hypertension; Hypertension - physiopathology; Losartan - pharmacology; Male; Medical sciences; nitric oxide; Nitric Oxide - biosynthesis; Nitroprusside - pharmacology; Norepinephrine - pharmacology; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; receptors; renin-angiotensin system; RNA, Messenger - metabolism; Vasoconstriction; Vasodilation
• ISSN: 0895-7061; 1879-1905; 1941-7225
• DOI: 10.1016/j.amjhyper.2004.11.007

Vasoconstrictive, proliferative and oxidative effects of angiotensin II (Ang II) are mediated by Ang II type 1 (AT 1) receptors. The effects of Ang II via the Ang II type 2 (AT 2) receptor subtype (AT 2R) are less well defined. Growing evidence shows the existence of cross-talk between the Ang II receptor subtypes, which is revealed by AT 1R blockade. Hence, under certain conditions, AT 2R may act as an antagonistic system with respect to the AT 1R. The present study was designed to investigate the effects of long-term treatment with the AT 1R antagonist losartan on the AT 2R-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 AT 1R and AT 2R was measured by reverse transcription-polymerase chain reaction. 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 AT 2R blocker PD123319, N G -nitro- l-arginine methyl ester (L-NAME), and B 2receptor antagonist HOE-140. Accordingly, nitric oxide (NO) production was increased by Ang II only in the aortas of treated SHR. After AT 1R blockade, AT 2R mRNA was significantly increased. These findings demonstrate that, in hypertensive rats, chronic AT 1R blockade is associated with an inverted vasomotor response to Ang II via AT 2R-mediated NO production. The losartan-unmasked AT 2R-vasorelaxation could significantly contribute to the beneficial hemodynamic effects of AT 1R 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 AT 1R blockers.