Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist With Selective PPARγ–Modulating Activity

Hypertension - Tập 43 Số 5 - Trang 993-1002 - 2004
Stephen C. Benson1, Harrihar A. Pershadsingh1, Christopher Ho1, Amar G. Chittiboyina1, Prashant Desai1, Michal Pravenec1, Nanshan Qi1, Jiaming Wang1, Mitchell A. Avery1, Theodore W. Kurtz1
1From 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...

Tóm tắt

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-γ (PPARγ) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARγ 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 PPARγ; influence the expression of PPARγ 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 PPARγ 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 PPARγ 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.

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Hypertension

Tập 43 Số 5

993-1002

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