Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity
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-gamma (PPARgamma) have been rep...
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| Veröffentlicht in: | Hypertension (Dallas, Tex. 1979) Tex. 1979), 2004-05, Vol.43 (5), p.993-1002 |
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| container_title | Hypertension (Dallas, Tex. 1979) |
| container_volume | 43 |
| creator | Benson, Stephen C Pershadsingh, Harrihar A Ho, Christopher I Chittiboyina, Amar Desai, Prashant Pravenec, Michal Qi, Nianning Wang, Jiaming Avery, Mitchell A Kurtz, Theodore W |
| description | 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-gamma (PPARgamma) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARgamma 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 PPARgamma; influence the expression of PPARgamma 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 PPARgamma 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 PPARgamma 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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In humans, mutations in the peroxisome proliferator-activated receptor-gamma (PPARgamma) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARgamma 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 PPARgamma; influence the expression of PPARgamma 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 PPARgamma 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 PPARgamma 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.</description><identifier>ISSN: 0194-911X</identifier><identifier>EISSN: 1524-4563</identifier><identifier>PMID: 15007034</identifier><identifier>CODEN: HPRTDN</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Adipocytes - drug effects ; Angiotensin II Type 1 Receptor Blockers ; Animals ; Benzimidazoles - chemistry ; Benzimidazoles - pharmacology ; Benzoates - chemistry ; Benzoates - pharmacology ; Biphenyl Compounds - pharmacology ; Blood Glucose - analysis ; Cell Differentiation - drug effects ; Cells, Cultured - drug effects ; Cercopithecus aethiops ; Drug Evaluation, Preclinical ; Gene Expression Regulation - drug effects ; Imidazoles - pharmacology ; Insulin - blood ; Losartan - pharmacology ; Male ; Mice ; Models, Molecular ; Myoblasts - drug effects ; Protein Conformation - drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Cytoplasmic and Nuclear - agonists ; Receptors, Cytoplasmic and Nuclear - chemistry ; Receptors, Cytoplasmic and Nuclear - genetics ; Structure-Activity Relationship ; Tetrazoles - pharmacology ; Thiazoles - pharmacology ; Thiazolidinediones - pharmacology ; Thiazolidines ; Transcription Factors - agonists ; Transcription Factors - chemistry ; Transcription Factors - genetics ; Triglycerides - blood ; Valine - analogs & derivatives ; Valine - pharmacology ; Valsartan ; Weight Gain - drug effects</subject><ispartof>Hypertension (Dallas, Tex. 1979), 2004-05, Vol.43 (5), p.993-1002</ispartof><rights>Copyright American Heart Association, Inc. 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In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPARgamma 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.</description><subject>Adipocytes - drug effects</subject><subject>Angiotensin II Type 1 Receptor Blockers</subject><subject>Animals</subject><subject>Benzimidazoles - chemistry</subject><subject>Benzimidazoles - pharmacology</subject><subject>Benzoates - chemistry</subject><subject>Benzoates - pharmacology</subject><subject>Biphenyl Compounds - pharmacology</subject><subject>Blood Glucose - analysis</subject><subject>Cell Differentiation - drug effects</subject><subject>Cells, Cultured - drug effects</subject><subject>Cercopithecus aethiops</subject><subject>Drug Evaluation, Preclinical</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Imidazoles - pharmacology</subject><subject>Insulin - blood</subject><subject>Losartan - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Myoblasts - drug effects</subject><subject>Protein Conformation - drug effects</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Cytoplasmic and Nuclear - agonists</subject><subject>Receptors, Cytoplasmic and Nuclear - chemistry</subject><subject>Receptors, Cytoplasmic and Nuclear - genetics</subject><subject>Structure-Activity Relationship</subject><subject>Tetrazoles - pharmacology</subject><subject>Thiazoles - pharmacology</subject><subject>Thiazolidinediones - pharmacology</subject><subject>Thiazolidines</subject><subject>Transcription Factors - agonists</subject><subject>Transcription Factors - chemistry</subject><subject>Transcription Factors - genetics</subject><subject>Triglycerides - blood</subject><subject>Valine - analogs & derivatives</subject><subject>Valine - pharmacology</subject><subject>Valsartan</subject><subject>Weight Gain - drug effects</subject><issn>0194-911X</issn><issn>1524-4563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkF9LwzAUxYMobk6_ggQffCskTdI0j2P4ZzBwyB58K1l6WzPapDapsm9vxPni04Vzf9xzzj1DcypynnFRsHM0J1TxTFH6NkNXIRwIoZxzeYlmVBAiCeNzdFzX4KJtrNHReod9gyN0vQ16jNphHbDGk7MfE2DtWusjuGAdXq_xCAaG6MekR916Z0PEXza-4wAdmGg_AW-3y9dW973Oel9PXXJwLdY_OxuP1-ii0V2Am9NcoN3jw271nG1entar5SYbSsqzHIjImeGl3IMgnFNtWMkEaKLAMFNwYCpnlEFTMFbXdaNVUxPFFNkrJWTBFuj-9-ww-tQixCqVM9B12oGfQiWporkiNIF3_8CDn0aXolV5yiClKGWCbk_QtO-hrobR9no8Vn8PZd9FOnQi</recordid><startdate>200405</startdate><enddate>200405</enddate><creator>Benson, Stephen C</creator><creator>Pershadsingh, Harrihar A</creator><creator>Ho, Christopher I</creator><creator>Chittiboyina, Amar</creator><creator>Desai, Prashant</creator><creator>Pravenec, Michal</creator><creator>Qi, Nianning</creator><creator>Wang, Jiaming</creator><creator>Avery, Mitchell A</creator><creator>Kurtz, Theodore W</creator><general>American Heart Association, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>200405</creationdate><title>Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity</title><author>Benson, Stephen C ; Pershadsingh, Harrihar A ; Ho, Christopher I ; Chittiboyina, Amar ; Desai, Prashant ; Pravenec, Michal ; Qi, Nianning ; Wang, Jiaming ; Avery, Mitchell A ; Kurtz, Theodore W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p814-2e0523c487be50441ac3835ea09ec3c64e392313ef633dddfa9fd09390b995763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Adipocytes - drug effects</topic><topic>Angiotensin II Type 1 Receptor Blockers</topic><topic>Animals</topic><topic>Benzimidazoles - chemistry</topic><topic>Benzimidazoles - pharmacology</topic><topic>Benzoates - chemistry</topic><topic>Benzoates - pharmacology</topic><topic>Biphenyl Compounds - pharmacology</topic><topic>Blood Glucose - analysis</topic><topic>Cell Differentiation - drug effects</topic><topic>Cells, Cultured - drug effects</topic><topic>Cercopithecus aethiops</topic><topic>Drug Evaluation, Preclinical</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Imidazoles - pharmacology</topic><topic>Insulin - blood</topic><topic>Losartan - pharmacology</topic><topic>Male</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Myoblasts - drug effects</topic><topic>Protein Conformation - drug effects</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Cytoplasmic and Nuclear - agonists</topic><topic>Receptors, Cytoplasmic and Nuclear - chemistry</topic><topic>Receptors, Cytoplasmic and Nuclear - genetics</topic><topic>Structure-Activity Relationship</topic><topic>Tetrazoles - pharmacology</topic><topic>Thiazoles - pharmacology</topic><topic>Thiazolidinediones - pharmacology</topic><topic>Thiazolidines</topic><topic>Transcription Factors - agonists</topic><topic>Transcription Factors - chemistry</topic><topic>Transcription Factors - genetics</topic><topic>Triglycerides - blood</topic><topic>Valine - analogs & derivatives</topic><topic>Valine - pharmacology</topic><topic>Valsartan</topic><topic>Weight Gain - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Benson, Stephen C</creatorcontrib><creatorcontrib>Pershadsingh, Harrihar A</creatorcontrib><creatorcontrib>Ho, Christopher I</creatorcontrib><creatorcontrib>Chittiboyina, Amar</creatorcontrib><creatorcontrib>Desai, Prashant</creatorcontrib><creatorcontrib>Pravenec, Michal</creatorcontrib><creatorcontrib>Qi, Nianning</creatorcontrib><creatorcontrib>Wang, Jiaming</creatorcontrib><creatorcontrib>Avery, Mitchell A</creatorcontrib><creatorcontrib>Kurtz, Theodore W</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Benson, Stephen C</au><au>Pershadsingh, Harrihar A</au><au>Ho, Christopher I</au><au>Chittiboyina, Amar</au><au>Desai, Prashant</au><au>Pravenec, Michal</au><au>Qi, Nianning</au><au>Wang, Jiaming</au><au>Avery, Mitchell A</au><au>Kurtz, Theodore W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity</atitle><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle><addtitle>Hypertension</addtitle><date>2004-05</date><risdate>2004</risdate><volume>43</volume><issue>5</issue><spage>993</spage><epage>1002</epage><pages>993-1002</pages><issn>0194-911X</issn><eissn>1524-4563</eissn><coden>HPRTDN</coden><abstract>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-gamma (PPARgamma) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARgamma 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 PPARgamma; influence the expression of PPARgamma 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 PPARgamma 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 PPARgamma 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.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>15007034</pmid><tpages>10</tpages></addata></record> |
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| identifier | ISSN: 0194-911X |
| ispartof | Hypertension (Dallas, Tex. 1979), 2004-05, Vol.43 (5), p.993-1002 |
| issn | 0194-911X 1524-4563 |
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| source | MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Ovid Autoload |
| subjects | Adipocytes - drug effects Angiotensin II Type 1 Receptor Blockers Animals Benzimidazoles - chemistry Benzimidazoles - pharmacology Benzoates - chemistry Benzoates - pharmacology Biphenyl Compounds - pharmacology Blood Glucose - analysis Cell Differentiation - drug effects Cells, Cultured - drug effects Cercopithecus aethiops Drug Evaluation, Preclinical Gene Expression Regulation - drug effects Imidazoles - pharmacology Insulin - blood Losartan - pharmacology Male Mice Models, Molecular Myoblasts - drug effects Protein Conformation - drug effects Rats Rats, Sprague-Dawley Receptors, Cytoplasmic and Nuclear - agonists Receptors, Cytoplasmic and Nuclear - chemistry Receptors, Cytoplasmic and Nuclear - genetics Structure-Activity Relationship Tetrazoles - pharmacology Thiazoles - pharmacology Thiazolidinediones - pharmacology Thiazolidines Transcription Factors - agonists Transcription Factors - chemistry Transcription Factors - genetics Triglycerides - blood Valine - analogs & derivatives Valine - pharmacology Valsartan Weight Gain - drug effects |
| title | Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity |
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