A local pre-receptor mechanism of hormone stimulus amplification: focus on angiotensin II in resistance blood vessels

Abstract

The in-vivo correlation between vascular tone and the concentration of free angiotensin (Ang) II at the level of the arterioles, under (patho)physiological conditions, is not known. To examine the in-vivo kinetics of binding of Ang II to Ang II type 1 (AT1) receptors in vascular tissue. A plane vascular smooth muscle (VSM) sheet containing a single layer of cells, at one side exposed to Ang II, was the starting point for designing a mathematical model based on local receptor density and geometric considerations and on kinetic parameters of Ang II diffusion and Ang II-AT1 receptor complex formation and internalization. Calculations demonstrate that a diffusing Ang II molecule at short distance from the receptor has an almost 100% chance to be actually bound, so that the apparent binding rate constant (per unit of receptor concentration) is greatly augmented. This pre-receptor stimulus amplification (PRESTAMP) mechanism is sustained by AT1 receptor-mediated endocytosis and receptor recycling. On the other hand, PRESTAMP also enhances endocytotic receptor downregulation, and calculations predict that steady-state levels of Ang II above threshold have relatively little additional effect. The results explain why physiological concentrations of free Ang II far below the equilibrium dissociation constant of its reaction with AT1 receptors are sufficient to increase vascular resistance, and why a correlation between blood pressure and the concentration of free Ang II is often difficult to demonstrate.