Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT1 receptors
CHO‐K1 cells that were stably transfected with the gene for the human AT1 receptor (CHO‐AT1 cells) were used for pharmacological studies of non‐peptide AT1 receptor antagonists. In the presence of 10 mM LiCl, angiotensin II caused a concentration‐dependent and long‐lasting increase of inositol phosp...
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| Veröffentlicht in: | British journal of pharmacology 1999-02, Vol.126 (4), p.1057-1065 |
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| creator | Vanderheyden, P M L Fierens, F L P De Backer, J P Fraeyman, N Vauquelin, G |
| description | CHO‐K1 cells that were stably transfected with the gene for the human AT1 receptor (CHO‐AT1 cells) were used for pharmacological studies of non‐peptide AT1 receptor antagonists.
In the presence of 10 mM LiCl, angiotensin II caused a concentration‐dependent and long‐lasting increase of inositol phosphates accumulation with an EC50 of 3.4 nM. No angiotensin II responses are seen in wild‐type CHO‐K1 cells.
[3H]‐Angiotensin II bound to cell surface AT1 receptors (dissociates under mild acidic conditions) and is subject to rapid internalization.
Non‐peptide selective AT1 antagonists inhibited the angiotensin II (0.1 μM) induced IP accumulation and the binding of [3H]‐angiotensin II (1 nM) with the potency order: candesartan > EXP3174 > irbesartan > losartan. Their potencies are lower in the presence of bovine serum albumin.
Preincubation with the insurmountable antagonist candesartan decreased the maximal angiotensin II induced inositol phosphate accumulation up to 94% and, concomitantly, decreased the maximal binding capacity of the cell surface receptors. These inhibitory effects were half‐maximal for 0.6 nM candesartan and were attenuated by simultaneous preincubation with 1 μM losartan indicating a syntopic action of both antagonists.
Losartan caused a parallel rightward shift of the angiotensin II concentration‐response curves and did not affect the maximal binding capacity. EXP3174 (the active metabolite of losartan) and irbesartan showed a mixed‐type behavior in both functional and binding studies.
Reversal of the inhibitory effect was slower for candesartan as compared with EXP3174 and irbesartan and it was almost instantaneous for losartan, suggesting that the insurmountable nature of selective AT1 receptor antagonists in functional studies was related to their long‐lasting inhibition.
British Journal of Pharmacology (1999) 126, 1057–1065; doi:10.1038/sj.bjp.0702398 |
| doi_str_mv | 10.1038/sj.bjp.0702398 |
| format | Article |
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In the presence of 10 mM LiCl, angiotensin II caused a concentration‐dependent and long‐lasting increase of inositol phosphates accumulation with an EC50 of 3.4 nM. No angiotensin II responses are seen in wild‐type CHO‐K1 cells.
[3H]‐Angiotensin II bound to cell surface AT1 receptors (dissociates under mild acidic conditions) and is subject to rapid internalization.
Non‐peptide selective AT1 antagonists inhibited the angiotensin II (0.1 μM) induced IP accumulation and the binding of [3H]‐angiotensin II (1 nM) with the potency order: candesartan > EXP3174 > irbesartan > losartan. Their potencies are lower in the presence of bovine serum albumin.
Preincubation with the insurmountable antagonist candesartan decreased the maximal angiotensin II induced inositol phosphate accumulation up to 94% and, concomitantly, decreased the maximal binding capacity of the cell surface receptors. These inhibitory effects were half‐maximal for 0.6 nM candesartan and were attenuated by simultaneous preincubation with 1 μM losartan indicating a syntopic action of both antagonists.
Losartan caused a parallel rightward shift of the angiotensin II concentration‐response curves and did not affect the maximal binding capacity. EXP3174 (the active metabolite of losartan) and irbesartan showed a mixed‐type behavior in both functional and binding studies.
Reversal of the inhibitory effect was slower for candesartan as compared with EXP3174 and irbesartan and it was almost instantaneous for losartan, suggesting that the insurmountable nature of selective AT1 receptor antagonists in functional studies was related to their long‐lasting inhibition.
British Journal of Pharmacology (1999) 126, 1057–1065; doi:10.1038/sj.bjp.0702398</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/sj.bjp.0702398</identifier><identifier>PMID: 10193788</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Angiotensin II ; Angiotensin II - metabolism ; Angiotensin II - pharmacology ; Angiotensin Receptor Antagonists ; Animals ; antagonist ; Antihypertensive agents ; AT1 receptors ; Benzimidazoles - pharmacology ; Biological and medical sciences ; calcium transients ; candesartan ; Cardiovascular system ; Cattle ; CHO Cells ; Cricetinae ; Dose-Response Relationship, Drug ; extracellular acidification ; Humans ; Inositol Phosphates - metabolism ; inositol trisphosphate ; insurmountable ; Medical sciences ; Pharmacology. Drug treatments ; Receptors, Angiotensin - metabolism ; Recombinant Proteins - antagonists & inhibitors ; surmountable ; Tetrazoles - pharmacology ; Transfection</subject><ispartof>British journal of pharmacology, 1999-02, Vol.126 (4), p.1057-1065</ispartof><rights>1999 Nature Publishing Group</rights><rights>1999 INIST-CNRS</rights><rights>Copyright 1999, Nature Publishing Group 1999 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571230/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571230/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1711809$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10193788$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vanderheyden, P M L</creatorcontrib><creatorcontrib>Fierens, F L P</creatorcontrib><creatorcontrib>De Backer, J P</creatorcontrib><creatorcontrib>Fraeyman, N</creatorcontrib><creatorcontrib>Vauquelin, G</creatorcontrib><title>Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT1 receptors</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>CHO‐K1 cells that were stably transfected with the gene for the human AT1 receptor (CHO‐AT1 cells) were used for pharmacological studies of non‐peptide AT1 receptor antagonists.
In the presence of 10 mM LiCl, angiotensin II caused a concentration‐dependent and long‐lasting increase of inositol phosphates accumulation with an EC50 of 3.4 nM. No angiotensin II responses are seen in wild‐type CHO‐K1 cells.
[3H]‐Angiotensin II bound to cell surface AT1 receptors (dissociates under mild acidic conditions) and is subject to rapid internalization.
Non‐peptide selective AT1 antagonists inhibited the angiotensin II (0.1 μM) induced IP accumulation and the binding of [3H]‐angiotensin II (1 nM) with the potency order: candesartan > EXP3174 > irbesartan > losartan. Their potencies are lower in the presence of bovine serum albumin.
Preincubation with the insurmountable antagonist candesartan decreased the maximal angiotensin II induced inositol phosphate accumulation up to 94% and, concomitantly, decreased the maximal binding capacity of the cell surface receptors. These inhibitory effects were half‐maximal for 0.6 nM candesartan and were attenuated by simultaneous preincubation with 1 μM losartan indicating a syntopic action of both antagonists.
Losartan caused a parallel rightward shift of the angiotensin II concentration‐response curves and did not affect the maximal binding capacity. EXP3174 (the active metabolite of losartan) and irbesartan showed a mixed‐type behavior in both functional and binding studies.
Reversal of the inhibitory effect was slower for candesartan as compared with EXP3174 and irbesartan and it was almost instantaneous for losartan, suggesting that the insurmountable nature of selective AT1 receptor antagonists in functional studies was related to their long‐lasting inhibition.
British Journal of Pharmacology (1999) 126, 1057–1065; doi:10.1038/sj.bjp.0702398</description><subject>Angiotensin II</subject><subject>Angiotensin II - metabolism</subject><subject>Angiotensin II - pharmacology</subject><subject>Angiotensin Receptor Antagonists</subject><subject>Animals</subject><subject>antagonist</subject><subject>Antihypertensive agents</subject><subject>AT1 receptors</subject><subject>Benzimidazoles - pharmacology</subject><subject>Biological and medical sciences</subject><subject>calcium transients</subject><subject>candesartan</subject><subject>Cardiovascular system</subject><subject>Cattle</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Dose-Response Relationship, Drug</subject><subject>extracellular acidification</subject><subject>Humans</subject><subject>Inositol Phosphates - metabolism</subject><subject>inositol trisphosphate</subject><subject>insurmountable</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Receptors, Angiotensin - metabolism</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>surmountable</subject><subject>Tetrazoles - pharmacology</subject><subject>Transfection</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVksFu1DAURS0EotPCliXyArHLYMdx7GyQ2qEwIyqVRVlbjvMydZTYIXZaZscn8AP8HF-CRx2gs7J0333nynoXoVeULClh8l3olnU3LokgOavkE7SghSgzziR9ihaEEJFRKuUJOg2hIyQNBX-OTiihFRNSLtCvDzZE60y03uEa4j2Aw2GeBj-7qOsesHYNtu5ICtBD2rgDfH5D8QQGxuin5Ix6610CBlzv8BwA-xav1te_f_z8TLGBvg8Yvo8ThGDdFt_Og3Zpa2t9BJckvNkcEcML9KzVfYCXh_cMff14ebNaZ1fXnzar86usY7xkGa8Z1wCyoZBzXjChSSNMQRpJC0NZLRivK9PIJHOWt9BwKk2VNyWpy7xpK3aG3j9wx7keoDHg4qR7NU520NNOeW3V8cTZW7X1d4pyQXNGEuDtATD5bzOEqAYb9h_WDvwcVFmVouByn_T6cdK_iL8XSYY3B4MORvftpJ2x4b9PpHuSPYc92O5tD7tHGLWvhQqdSrVQh1qoiy_rFMDYHyRwsFU</recordid><startdate>199902</startdate><enddate>199902</enddate><creator>Vanderheyden, P M L</creator><creator>Fierens, F L P</creator><creator>De Backer, J P</creator><creator>Fraeyman, N</creator><creator>Vauquelin, G</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>199902</creationdate><title>Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT1 receptors</title><author>Vanderheyden, P M L ; Fierens, F L P ; De Backer, J P ; Fraeyman, N ; Vauquelin, G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j3563-5b35aee8d1e255437a0d7c40d814c13b735b9cd8a0d532fed518c92d60b62df93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Angiotensin II</topic><topic>Angiotensin II - metabolism</topic><topic>Angiotensin II - pharmacology</topic><topic>Angiotensin Receptor Antagonists</topic><topic>Animals</topic><topic>antagonist</topic><topic>Antihypertensive agents</topic><topic>AT1 receptors</topic><topic>Benzimidazoles - pharmacology</topic><topic>Biological and medical sciences</topic><topic>calcium transients</topic><topic>candesartan</topic><topic>Cardiovascular system</topic><topic>Cattle</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Dose-Response Relationship, Drug</topic><topic>extracellular acidification</topic><topic>Humans</topic><topic>Inositol Phosphates - metabolism</topic><topic>inositol trisphosphate</topic><topic>insurmountable</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Receptors, Angiotensin - metabolism</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>surmountable</topic><topic>Tetrazoles - pharmacology</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vanderheyden, P M L</creatorcontrib><creatorcontrib>Fierens, F L P</creatorcontrib><creatorcontrib>De Backer, J P</creatorcontrib><creatorcontrib>Fraeyman, N</creatorcontrib><creatorcontrib>Vauquelin, G</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vanderheyden, P M L</au><au>Fierens, F L P</au><au>De Backer, J P</au><au>Fraeyman, N</au><au>Vauquelin, G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT1 receptors</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>1999-02</date><risdate>1999</risdate><volume>126</volume><issue>4</issue><spage>1057</spage><epage>1065</epage><pages>1057-1065</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><coden>BJPCBM</coden><abstract>CHO‐K1 cells that were stably transfected with the gene for the human AT1 receptor (CHO‐AT1 cells) were used for pharmacological studies of non‐peptide AT1 receptor antagonists.
In the presence of 10 mM LiCl, angiotensin II caused a concentration‐dependent and long‐lasting increase of inositol phosphates accumulation with an EC50 of 3.4 nM. No angiotensin II responses are seen in wild‐type CHO‐K1 cells.
[3H]‐Angiotensin II bound to cell surface AT1 receptors (dissociates under mild acidic conditions) and is subject to rapid internalization.
Non‐peptide selective AT1 antagonists inhibited the angiotensin II (0.1 μM) induced IP accumulation and the binding of [3H]‐angiotensin II (1 nM) with the potency order: candesartan > EXP3174 > irbesartan > losartan. Their potencies are lower in the presence of bovine serum albumin.
Preincubation with the insurmountable antagonist candesartan decreased the maximal angiotensin II induced inositol phosphate accumulation up to 94% and, concomitantly, decreased the maximal binding capacity of the cell surface receptors. These inhibitory effects were half‐maximal for 0.6 nM candesartan and were attenuated by simultaneous preincubation with 1 μM losartan indicating a syntopic action of both antagonists.
Losartan caused a parallel rightward shift of the angiotensin II concentration‐response curves and did not affect the maximal binding capacity. EXP3174 (the active metabolite of losartan) and irbesartan showed a mixed‐type behavior in both functional and binding studies.
Reversal of the inhibitory effect was slower for candesartan as compared with EXP3174 and irbesartan and it was almost instantaneous for losartan, suggesting that the insurmountable nature of selective AT1 receptor antagonists in functional studies was related to their long‐lasting inhibition.
British Journal of Pharmacology (1999) 126, 1057–1065; doi:10.1038/sj.bjp.0702398</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>10193788</pmid><doi>10.1038/sj.bjp.0702398</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Angiotensin II Angiotensin II - metabolism Angiotensin II - pharmacology Angiotensin Receptor Antagonists Animals antagonist Antihypertensive agents AT1 receptors Benzimidazoles - pharmacology Biological and medical sciences calcium transients candesartan Cardiovascular system Cattle CHO Cells Cricetinae Dose-Response Relationship, Drug extracellular acidification Humans Inositol Phosphates - metabolism inositol trisphosphate insurmountable Medical sciences Pharmacology. Drug treatments Receptors, Angiotensin - metabolism Recombinant Proteins - antagonists & inhibitors surmountable Tetrazoles - pharmacology Transfection |
| title | Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT1 receptors |
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