Hypertension. 2004;43:993-1002
Published online before print March 8, 2004, doi: 10.1161/01.HYP.0000123072.34629.57
Published online before print March 8, 2004, doi: 10.1161/01.HYP.0000123072.34629.57
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(Hypertension. 2004;43:993.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist With Selective PPAR
–Modulating Activity
From the Department of Biological Sciences (S.C.B., C.I.H.), California State University, Hayward; Bethesda Pharmaceuticals, Inc (H.A.P.), Bakersfield, Calif; Departments of Family Medicine (H.A.P.), Kern Medical Center and the University of California, Irvine; Department of Medicinal Chemistry (A.C., P.D., M.A.A.), University of Mississippi; the Institute of Physiology (M.P.), Czech Academy of Sciences, Center for Integrated Genomics, Prague, Czech Republic; and Department of Laboratory Medicine (N.Q., J.W., T.W.K.), University of California, San Francisco.
Correspondence to Theodore W. Kurtz, MD, Professor of Laboratory Medicine, 505 Parnassus Ave, Rm L518, UCSF Medical Center, Box 0134, San Francisco, CA 94143-0134. E-mail KurtzT{at}Labmed2.ucsf.edu or Mitchell A. Avery, PhD, Professor of Medicinal Chemistry, School of Pharmacy, Faser Hall 421, University of Mississippi, University, MS 38677. E-mail Mavery@olemiss.edu
The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator–activated receptor-
(PPAR) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPAR have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPAR; influence the expression of PPAR target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPAR when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPAR have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations.
Key Words: receptors, angiotensin II • angiotensin II • renin-angiotensin system • insulin resistance • losartan
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|
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|
|
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|
|
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|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
T. Lau, P.-O. Carlsson, P.S. Leung, C. Wolfrum, E. Asilmaz, E. Luca, J.M. Friedman, M. Stoffel, J.C. Verhave, H.L. Hillege, et al. Why Less Diabetes with Blockade of the Renin-Angiotensin System?: Evidence for a Local Angiotensin-Generating System and Dose-Dependent Inhibition of Glucose-Stimulated Insulin Release by Angiotensin II in Isolated Pancreatic Islets. Diabetologia 47: 240-248, 2004 J. Am. Soc. Nephrol., March 1, 2005; 16(3): 567 - 573. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|