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(Hypertension. 2001;37:1141.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Angiotensin-(1-7) Downregulates the Angiotensin II Type 1 Receptor in Vascular Smooth Muscle Cells

Michelle A. Clark; Debra I. Diz; E. Ann Tallant

From The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to E. Ann Tallant, PhD, The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1032. E-mail atallant{at}wfubmc.edu

Abstract—Angiotensin (Ang)-(1-7) is a biologically active peptide of the renin-angiotensin system that has both vasodilatory and antiproliferative activities that are opposite the constrictive and proliferative effects of angiotensin II (Ang II). We studied the actions of Ang-(1-7) on the Ang II type 1 (AT₁) receptor in cultured rat aortic vascular smooth muscle cells to determine whether the effects of Ang-(1-7) are due to its regulation of the AT₁ receptor. Ang-(1-7) competed poorly for [¹²⁵I]Ang II binding to the AT₁ receptor on vascular smooth muscle cells, with an IC₅₀ of 2.0 µmol/L compared with 1.9 nmol/L for Ang II. The pretreatment of vascular smooth muscle cells with Ang-(1-7) followed by treatment with acidic glycine to remove surface-bound peptide resulted in a significant decrease in [¹²⁵I]Ang II binding; however, reduced Ang II binding was observed only at micromolar concentrations of Ang-(1-7). Scatchard analysis of vascular smooth muscle cells pretreated with 1 µmol/L Ang-(1-7) showed that the reduction in Ang II binding resulted from a loss of the total number of binding sites [B_max 437.7±261.5 fmol/mg protein in Ang-(1-7)–pretreated cells compared with 607.5±301.2 fmol/mg protein in untreated cells, n=5, P<0.05] with no significant effect on the affinity of Ang II for the AT₁ receptor. Pretreatment with the AT₁ receptor antagonist L-158,809 blocked the reduction in [¹²⁵I]Ang II binding by Ang-(1-7) or Ang II. Pretreatment of vascular smooth muscle cells with increasing concentrations of Ang-(1-7) reduced Ang II–stimulated phospholipase C activity; however, the decrease was significant (81.2±6.4%, P<0.01, n=5) only at 1 µmol/L Ang-(1-7). These results demonstrate that pharmacological concentrations of Ang-(1-7) in the micromolar range cause a modest downregulation of the AT₁ receptor on vascular cells and a reduction in Ang II–stimulated phospholipase C activity. Because the antiproliferative and vasodilatory effects of Ang-(1-7) are observed at nanomolar concentrations of the heptapeptide, these responses to Ang-(1-7) cannot be explained by competition of Ang-(1-7) at the AT₁ receptor or Ang-(1-7)–mediated downregulation of the vascular AT₁ receptor.

Key Words: angiotensin II • muscle, smooth, vascular • receptors, angiotensin-(1-7)

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