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Endocrinology Vol. 144, No. 6 2184-2190
Copyright © 2003 by The Endocrine Society

Minireview: Computer Simulations of Blood Pressure Regulation by the Renin-Angiotensin System

Nobuyuki Takahashi, John R. Hagaman, Hyung-Suk Kim and Oliver Smithies

Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7525

Address all correspondence and requests for reprints to: Nobuyuki Takahashi, M.D., Ph.D., Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, North Carolina 27599-7525. E-mail: ntakaha{at}med.unc.edu.

Gene targeting experiments in mice have been used by us and others to test whether quantitative changes in gene expression in the renin-angiotensin system affect blood pressure. Surprisingly, these studies showed that blood pressure does not change with mild quantitative changes in the expression of the angiotensin converting enzyme (ACE). Yet, ACE inhibitors are widely used for the treatment of hypertension. This apparent paradox motivated us to develop a simple computer simulation, which qualitatively reconciled the paradox. We have now improved the simulation by including blood pressure as an explicit variable and by adding the kallikrein-kinin system and feedback control of plasma renin via plasma angiotensin II levels. The new simulation now matches quantitative aspects of the experimental data and suggests that a decrease in bradykinin plays an important role in the increased risk of diabetic nephropathy associated with genetically determined higher levels of ACE activity. This emphasizes that the value of these types of simulation lies in the thoughts that they provoke rather than in their ability to replicate experimental data.




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