Facilitated diffusion of angiotensin II from perivascular interstitium to AT1 receptors of the arteriole. A regulating step in vasoconstriction

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. METHODS AND 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. CONCLUSION: 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.