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Journal of Hypertension:
doi: 10.1097/HJH.0b013e32835d6d11
ORIGINAL PAPERS: Renin-angiotensin system

How does the angiotensin II type 1 receptor ‘trump’ the type 2 receptor in blood pressure control?

Schalekamp, Maarten A.D.H.; Danser, A.H. Jan

Supplemental Author Material
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Abstract

Background: A kinetic model for the binding of angiotensin II (Ang II) to AT1 receptors (AT1Rs) in arterioles did suggest a novel mechanism of association rate amplification and facilitated Ang II diffusion in vivo.

Aim of study: To examine how this mechanism, acting on AT1R, will affect the stimulation of AT2R.

Method: The model distinguishes between the diffusion of plasma Ang II across the endothelium layer (thickness 10−4 – 5 × 10−4 cm) into the vascular smooth muscle (VSM) layer (5 × 10−4 cm), and the diffusion of tissue Ang II from perivascular interstitium (thickness of micromilieu fluid layer at abluminal VSM surface 10−6 – 10−5 cm, i.e. 1 to 10 times the glycocalyx). Thus, Ang II concentration [Ang II] is taken to be 0 at the abluminal and adluminal VSM cell surfaces, respectively. Tissue Ang II is defined as originating from local generation and/or from the capillary circulation. [Ang II]/AT1R and [Ang II]/AT2R occupancy curves for the two directions of diffusion are constructed from the model-based calculations.

Results: Ang II, at 10−15–10−13 mol/ml (∼1–100 pg/ml), is much less likely to react with vascular AT2R than AT1R, though it has similar affinity for the receptor types. With plasma [Ang II] = 10−15–10−13 mol/ml, AT2R occupancy is less than 10% of maximum on endothelium, and virtually 0 on VSM, whereas AT1R occupancy on VSM is virtually 0 at plasma [Ang II] < 10−14 mol/ml, and between 0 and 30% at plasma [Ang II] = 10−13 mol/ml. With tissue [Ang II] = 10−15–10−13 mol/ml, VSM AT2R occupancy is close to 0, whereas VSM AT1R occupancy is 40–60% in the absence of endocytotic AT1R down-regulation, and up to 70–90% in its presence.

Conclusion: The threshold concentration of Ang II needed for response is much higher for AT2R than for AT1R. Plasma Ang II rather than tissue Ang II is the agonist of AT2R, and the reverse applies to AT1R. Thus, AT2R stimulation may come into play only at unusually high circulating levels of Ang II.

© 2013 Lippincott Williams & Wilkins, Inc.

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