A local pre-receptor mechanism of hormone stimulus amplification: focus on angiotensin II in resistance blood vessels.
| Autor: | Schalekamp MA; Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands. a.danser@erasmusmc.nl |
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| Jazyk: | angličtina |
| Zdroj: | Journal of hypertension [J Hypertens] 2006 Sep; Vol. 24 (9), pp. 1787-96. |
| DOI: | 10.1097/01.hjh.0000242403.91332.70 |
| Abstrakt: | Background: 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. Objective: To examine the in-vivo kinetics of binding of Ang II to Ang II type 1 (AT1) receptors in vascular tissue. Methods and Results: 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. Conclusion: 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. |
| Databáze: | MEDLINE |
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