Published Online
on August 26, 2002

A more recent version of this article appeared on October 1, 2002

This Article Full Text (PDF) All Versions of this Article: 40/4/516    most recent 01.HYP.0000033224.99806.8Av1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Widdop, R. E. Articles by Henrion, D. Search for Related Content PubMed PubMed Citation Articles by Widdop, R. E. Articles by Henrion, D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

Submitted on June 17, 2002
Revised on July 17, 2002

AT₂ Receptor-Mediated Relaxation Is Preserved After Long-Term AT₁ Receptor Blockade

Robert E. Widdop^*; Khalid Matrougui; Bernard I. Levy; and Daniel Henrion

From the Department of Pharmacology, Monash University (R.E.W.), Melbourne, Victoria, Australia; INSERM U541, IFR Circulation-Paris-Nord, Paris VII University (K.M., D.H.), Paris, France; and the Department of Physiology, AP-HP-Hôpital Lariboisière (B.I.L.), Paris, France.

^* To whom correspondence should be addressed. E-mail: robert.widdop{at}med.monash.edu.au.

Abstract—Angiotensin II type 2 receptor (AT₂R) stimulation may cause vasodilation per se and may contribute to the antihypertensive effect produced by Angiotensin II type 1 receptor (AT₁R) antagonists, given that AT₁R blockade increases endogenous levels of Ang II, suggesting a physiological role for the unblocked AT₂R. Thus, we first directly assessed whether or not there is desensitization to AT₂R-mediated vasorelaxation because this is an important consideration, given the raised Ang II levels and the marked desensitization that is known to occur after AT₁R stimulation. Second, we examined if AT₂R-mediated vasorelaxation is preserved after long-term treatment with the AT₁R antagonist candesartan cilexetil. Consecutive concentration-response curves to AT₂R stimulation, with either Ang II (with AT₁R blockade) or the selective agonist CGP42112, were studied in rat isolated mesenteric resistance arteries mounted in an arteriograph. AT₂R stimulation with Ang II induced a concentration-dependent relaxation without desensitization. Similarly, CGP42112 evoked highly reproducible relaxation, which, like Ang II, was abolished by the AT₂R antagonist PD123319. By contrast, AT₁R-mediated contraction exhibited marked desensitization. In rats treated with candesartan cilexetil (2 mg/kg per day for 2 weeks), AT₁R-mediated contraction was abolished, whereas AT₂R-mediated relaxation evoked by either Ang II or CGP42112 was highly reproducible, PD123319-sensitive, and of a magnitude similar to that observed in naïve animals. Therefore, this study has provided unequivocal evidence for the reproducible nature of AT₂R-mediated vasorelaxation during short-term and long-term AT₁R blockade. Such preservation of AT₂R function is a prerequisite for the consideration of physiological role(s) of AT₂R during AT₁R blockade.

Key words: receptors, angiotensin • muscle, smooth, vascular • vasodilation

This article has been cited by other articles:

				J. H. Lee, S. Xia, and L. Ragolia Upregulation of AT2 receptor and iNOS impairs angiotensin II-induced contraction without endothelium influence in young normotensive diabetic rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R144 - R154. [Abstract] [Full Text] [PDF]

				F. Pinaud, A. Bocquet, O. Dumont, K. Retailleau, C. Baufreton, R. Andriantsitohaina, L. Loufrani, and D. Henrion Paradoxical Role of Angiotensin II Type 2 Receptors in Resistance Arteries of Old Rats Hypertension, July 1, 2007; 50(1): 96 - 102. [Abstract] [Full Text] [PDF]

				R. M. Carey Angiotensin Receptors and Aging Hypertension, July 1, 2007; 50(1): 33 - 34. [Full Text] [PDF]

				L. J. Salomone, N. L. Howell, H. E. McGrath, B. A. Kemp, S. R. Keller, J. J. Gildea, R. A. Felder, and R. M. Carey Intrarenal Dopamine D1-Like Receptor Stimulation Induces Natriuresis via an Angiotensin Type-2 Receptor Mechanism Hypertension, January 1, 2007; 49(1): 155 - 161. [Abstract] [Full Text] [PDF]

				R. M. Carey and J. Park Role of Angiotensin Type 2 Receptors in Vasodilation of Resistance and Capacitance Vessels Hypertension, November 1, 2006; 48(5): 824 - 825. [Full Text] [PDF]

				S. Guimaraes and H. Pinheiro Functional evidence that in the cardiovascular system AT1 angiotensin II receptors are AT1B prejunctionally and AT1A postjunctionally Cardiovasc Res, August 1, 2005; 67(2): 208 - 215. [Abstract] [Full Text] [PDF]

				L. M. Duke, R. G. Evans, and R. E Widdop AT2 receptors contribute to acute blood pressure-lowering and vasodilator effects of AT1 receptor antagonism in conscious normotensive but not hypertensive rats Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2289 - H2297. [Abstract] [Full Text] [PDF]

				R. M. Carey Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor: The AT2 Receptor Comes of Age Hypertension, May 1, 2005; 45(5): 840 - 844. [Full Text] [PDF]

				M. Gonzalez, L. Lobos, F. Castillo, L. Galleguillos, N. C. Lopez, and L. Michea High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries Hypertension, May 1, 2005; 45(5): 853 - 859. [Abstract] [Full Text] [PDF]

				B. T. Andresen, K. Shome, E. K. Jackson, and G. G. Romero AT2 receptors cross talk with AT1 receptors through a nitric oxide- and RhoA-dependent mechanism resulting in decreased phospholipase D activity Am J Physiol Renal Physiol, April 1, 2005; 288(4): F763 - F770. [Abstract] [Full Text] [PDF]

				D. You, L. Loufrani, C. Baron, B. I. Levy, R. E. Widdop, and D. Henrion High Blood Pressure Reduction Reverses Angiotensin II Type 2 Receptor-Mediated Vasoconstriction Into Vasodilation in Spontaneously Hypertensive Rats Circulation, March 1, 2005; 111(8): 1006 - 1011. [Abstract] [Full Text] [PDF]

				B. Somoza, M. C. Gonzalez, J. M. Gonzalez, F. Abderrahim, S. M. Arribas, and M. S. Fernandez-Alfonso Modulatory role of the adventitia on noradrenaline and angiotensin II responses: Role of endothelium and AT2 receptors Cardiovasc Res, February 1, 2005; 65(2): 478 - 486. [Abstract] [Full Text] [PDF]

				M. A. F. de Godoy, A. M. de Oliveira, and S. Rattan Angiotensin II-Induced Relaxation of Anococcygeus Smooth Muscle via Desensitization of AT1 Receptor, and Activation of AT2 Receptor Associated with Nitric-Oxide Synthase Pathway J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 394 - 401. [Abstract] [Full Text] [PDF]

				R. M. Carey Angiotensin Type-1 Receptor Blockade Increases ACE 2 Expression in the Heart Hypertension, May 1, 2004; 43(5): 943 - 944. [Full Text] [PDF]

				B. T. Andresen, G. G. Romero, and E. K. Jackson AT2 Receptors Attenuate AT1 Receptor-Induced Phospholipase D Activation in Vascular Smooth Muscle Cells J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 425 - 431. [Abstract] [Full Text]

				R. Caballero, R. Gomez, I. Moreno, L. Nunez, T. Gonzalez, C. Arias, M. Guizy, C. Valenzuela, J. Tamargo, and E. Delpon Interaction of angiotensin II with the angiotensin type 2 receptor inhibits the cardiac transient outward potassium current Cardiovasc Res, April 1, 2004; 62(1): 86 - 95. [Abstract] [Full Text] [PDF]

				B. I. Levy Can Angiotensin II Type 2 Receptors Have Deleterious Effects in Cardiovascular Disease?: Implications for Therapeutic Blockade of the Renin-Angiotensin System Circulation, January 6, 2004; 109(1): 8 - 13. [Full Text] [PDF]

				R. M. Carey and H. M. Siragy Newly Recognized Components of the Renin-Angiotensin System: Potential Roles in Cardiovascular and Renal Regulation Endocr. Rev., June 1, 2003; 24(3): 261 - 271. [Abstract] [Full Text] [PDF]

				A. Nap, J. C Balt, M. Pfaffendorf, and P. A van Zwieten No involvement of the AT2-receptor in angiotensin II-enhanced sympathetic transmission in vitro Journal of Renin-Angiotensin-Aldosterone System, June 1, 2003; 4(2): 100 - 105. [Abstract] [PDF]