(620d) Computational Modeling Of Angiotensin II Signaling In The Central Regulation Of Blood Pressure

Hypertension, a disease that is characterized by sustained elevated blood pressure, affects one in three American adults and can lead to heart disease and stroke (NHLBI, 2007). Hypertensive individuals experience elevated blood pressure because their blood pressure controllers appear to have adapted to a set-point higher than that in normotensive individuals. The nucleus tractus solitarius (NTS) in the brain serves as an important blood pressure controller by orchestrating the baroreflex, the major mechanism for short-term blood pressure regulation. It is well-established that the ability of the NTS to control blood pressure effectively is compromised in hypertensive individuals but the molecular mechanisms responsible for this decrease in controller performance remain poorly understood. An improvement in the quantitative understanding of how blood pressure controllers function at the molecular level in normal and disease states is a crucial step in the development of effective treatments of hypertension. Our overall goal in this study is therefore to understand the molecular mechanisms of blood pressure regulation in the NTS.

Our current focus is on angiotensin II type 1 receptor (AT1R) signaling which plays an integral role in the synthesis of norepinephrine (NE), a neurotransmitter involved in NTS-initiated cardiovascular regulation. Activation of AT1R affects the synthesis of NE by inducing transcription of tyrosine hydroxylase (TH), the rate limiting enzyme in the production of NE. Our approach is to develop a mechanistic model to understand the dynamics of AT1R-induced TH expression so that we may gain insight into how the NTS controls blood pressure.

We discuss the model development, present a detailed analysis, and use the results to explain published experimentally observed dynamics of the signaling intermediates in neuronal cell cultures (Veerasingham and Raizada, 2003). In addition, we address our model's ability to explain published experimentally observed effects of signaling inhibitors on AT1R activation. Finally, we will discuss some insights into the NTS regulation of blood pressure in normal and disease states provided by our model.

References

National Heart Lung and Blood Institute Website, High Blood Pressure (2007). http://www.nhlbi.nih.gov/health/dci/Diseases/Hbp/HBP_WhatIs.html

Veerasingham S.J. & Raizada M.K. (2003) Brain renin?angiotensin system dysfunction in hypertension: recent advances and perspectives. Br. J. Pharmacol. 139(2):191-202.