title: Facilitated diffusion of angiotensin II from perivascular interstitium to AT1 receptors of the arteriole. A regulating step in vasoconstriction.
abstract: BACKGROUND
  A kinetic model for the binding of angiotensin (Ang) II to AT1 receptors (AT1R) in arterioles in vivo did suggest a novel mechanism of stimulus amplification.
  
  
  OBJECTIVE
  To further clarify the role of this mechanism in the functioning of the local renin-angiotensin systems, as opposed to circulating Ang II.
  
  
  RESULTS
  The model was refined in order to account for geometric characteristics of the vascular smooth muscle (VSM) cells in arterioles with a single VSM cell layer. Results show that, unlike experiments in vitro, the graph of AT1R occupancy, that is, [Rec(occ)]/[Rec(total)] where [Rec(total)]=[Rec(occ)]+[Rec(free)], as a function of log [Ang II], is shifted to the left at higher [Rec(total)]. This leads to the concept of association rate amplification (ASRA) and facilitated Ang II diffusion. Considering that abluminal Ang II has to cross a diffusion fluid-barrier 1-10 times the glycocalyx to reach VSM AT1R, it appears that the ASRA factor is 1500 to 150 respectively, whereas more than 90% of Ang II is captured, at 10% occupancy, and with [Ang II] as low as 10(-15)-10(-14) mol/ml. Due to the presence of endothelium, intraluminal [Ang II] needs to be 20-30 times higher. ASRA favors a low [Ang II] threshold for AT1R stimulation, but it also favors a flat stimulus/response curve by promoting receptor-mediated endocytosis and receptor downregulation.
  
  
  CONCLUSIONS
  The model predicts that, in small resistance vessels, abluminal rather than intraluminal Ang II is important for maintaining vasoconstrictor tone. ASRA minimizes the overflow of de-novo generated tissue Ang II into the circulation. It explains why Ang II acts at levels far below K(D), why AT1R blockers are effective in hypertension even when [Ang II] is low, and why the constrictor action of Ang II appears so much suppressed by sodium depletion.
authors.affiliation: Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Maarten A D H
authors.initials: MA
authors.lastname: Schalekamp
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D002478:Cells, Cultured; D004705:Endocytosis; D006801:Humans; D008024:Ligands; D011336:Probability; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D014661:Vasoconstriction
chemical_list: D008024:Ligands; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II