Quantification of the contribution of type 1 and type 2 angiotensin II receptors to the net tissue specific effect of angiotensin II.

Abstract

Numerous studies have demonstrated changes in receptor number, protein concentration, or mRNA levels and have proposed that these subcellular changes produce physiologic effects. To date, no adequate mathematical analysis has been available to provide a framework for interpretation of such data. In the present study we have combined measurements of angiotensin receptor protein levels with the development of a mathematical model that includes two receptors with opposing actions for a single ligand. This model was used to quantify the net, physiologic response of each receptor population to ANG II stimulation and the effect of altering the expression of receptor populations by a physiologic stimulus. Altered sodium intake was used as the physiologic stimulus and quantification of Western blot analysis and revealed that high sodium diet significantly suppressed AT1 receptor protein in the adrenal gland and aorta and augmented AT2 receptor protein in the aorta. A high sodium diet did not significantly alter AT2 receptor protein in the adrenal gland. Modeling the measured sodium-induced changes in receptor concentration demonstrated that small, subcellular changes in receptor concentration can have a large impact on the net physiologic effect. This model for dual receptor-single ligand interactions should be amenable for other systems.