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Article: The novel ATP-sensitive potassium channel opener iptakalim prevents insulin resistance associated with hypertension via restoring endothelial function

TitleThe novel ATP-sensitive potassium channel opener iptakalim prevents insulin resistance associated with hypertension via restoring endothelial function
Authors
Issue Date2011
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/aps/index.html
Citation
Acta Pharmacologica Sinica, 2011, v. 32 n. 12, p. 1466-1474 How to Cite?
AbstractAIM: To investigate the effects of iptakalim on endothelial dysfunction induced by insulin resistance (IR) and to determine whether iptakalim improved IR associated with hypertension in fructose-fed rats (FFRs) and spontaneously hypertensive rats (SHRs). METHODS: Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. The levels of endothelial vasoactive mediators and eNOS protein expression were determined using radioimmunoassays, ELISAs, colorimetric assays or Western blotting. Sprague-Dawley rats were fed with a high-fructose diet. In both FFRs and SHRs, tail-cuff method was used to measure systolic blood pressure (SBP), and hyperinsulinemic- euglycemic clamp was used to evaluate IR states. RESULTS: (1) Cultured HUVECs incubated with the PI3-kinase inhibitor wortmannin (50 nmol/L) and insulin (100 nmol/L) induced endothelial dysfunction characterized by significantly reduced release of NO and expression of eNOS protein, and significantly increased production of ET-1. Pretreatment with iptakalim (0.1-10 mumol/L) could prevent the endothelial dysfunction. (2) In FFRs, the levels of SBP, fasting plasma glucose and insulin were significantly elevated, whereas the glucose infusion rate (GIR) and insulin sensitive index (ISI) were significantly decreased, and the endothelium-dependent vascular relaxation response to ACh was impaired. These changes could be prevented by oral administration of iptakalim (1, 3, or 9 mg.kg(-1).d(-1), for 4 weeks). The imbalance between serum NO and ET-1 was also ameliorated by iptakalim. (3) In 2-4 month-old SHRs (IR was established at the age of 4 months), oral administration of iptakalim (1, 3, or 9 mg.kg(-1).d(-1), for 8 weeks) significantly ameliorated hypertension and increased the GIR to the normal level. CONCLUSION: These results demonstrate that iptakalim could protect against IR-induced endothelial dysfunction, and ameliorate IR associated with hypertension, possibly via restoring the balance between NO and ET-1 signaling.
Persistent Identifierhttp://hdl.handle.net/10722/146898
ISSN
2015 Impact Factor: 3.166
2015 SCImago Journal Rankings: 1.161
ISI Accession Number ID
Funding AgencyGrant Number
National New Drug Research and Development Key Project2008ZX09101-006
2008ZXJ09004-018
2009ZX09301-002
State Key Basic Research and Development from the Ministry of Science and Technology of ChinaGT1998051112
863-High Technology Research and Development Program Plan2002AA2Z3137
National 1035 Project of China969010101
New Drug Development of Beijing Key ProjectD0204003040721
Funding Information:

This study was supported by grants from the National New Drug Research and Development Key Project (No 2008ZX09101-006, 2008ZXJ09004-018 and 2009ZX09301-002), the State Key Basic Research and Development from the Ministry of Science and Technology of China (No GT1998051112), the 863-High Technology Research and Development Program Plan (No 2002AA2Z3137), the National 1035 Project (No 969010101) of China and the New Drug Development of Beijing Key Project (No D0204003040721).

 

DC FieldValueLanguage
dc.contributor.authorWang, Yen_US
dc.contributor.authorZeng, FHen_US
dc.contributor.authorLong, CLen_US
dc.contributor.authorPan, ZYen_US
dc.contributor.authorCui, WYen_US
dc.contributor.authorWang, RHen_US
dc.contributor.authorLiu, GSen_US
dc.contributor.authorWang, H-
dc.date.accessioned2012-05-23T05:48:53Z-
dc.date.available2012-05-23T05:48:53Z-
dc.date.issued2011en_US
dc.identifier.citationActa Pharmacologica Sinica, 2011, v. 32 n. 12, p. 1466-1474en_US
dc.identifier.issn1671-4083-
dc.identifier.urihttp://hdl.handle.net/10722/146898-
dc.description.abstractAIM: To investigate the effects of iptakalim on endothelial dysfunction induced by insulin resistance (IR) and to determine whether iptakalim improved IR associated with hypertension in fructose-fed rats (FFRs) and spontaneously hypertensive rats (SHRs). METHODS: Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. The levels of endothelial vasoactive mediators and eNOS protein expression were determined using radioimmunoassays, ELISAs, colorimetric assays or Western blotting. Sprague-Dawley rats were fed with a high-fructose diet. In both FFRs and SHRs, tail-cuff method was used to measure systolic blood pressure (SBP), and hyperinsulinemic- euglycemic clamp was used to evaluate IR states. RESULTS: (1) Cultured HUVECs incubated with the PI3-kinase inhibitor wortmannin (50 nmol/L) and insulin (100 nmol/L) induced endothelial dysfunction characterized by significantly reduced release of NO and expression of eNOS protein, and significantly increased production of ET-1. Pretreatment with iptakalim (0.1-10 mumol/L) could prevent the endothelial dysfunction. (2) In FFRs, the levels of SBP, fasting plasma glucose and insulin were significantly elevated, whereas the glucose infusion rate (GIR) and insulin sensitive index (ISI) were significantly decreased, and the endothelium-dependent vascular relaxation response to ACh was impaired. These changes could be prevented by oral administration of iptakalim (1, 3, or 9 mg.kg(-1).d(-1), for 4 weeks). The imbalance between serum NO and ET-1 was also ameliorated by iptakalim. (3) In 2-4 month-old SHRs (IR was established at the age of 4 months), oral administration of iptakalim (1, 3, or 9 mg.kg(-1).d(-1), for 8 weeks) significantly ameliorated hypertension and increased the GIR to the normal level. CONCLUSION: These results demonstrate that iptakalim could protect against IR-induced endothelial dysfunction, and ameliorate IR associated with hypertension, possibly via restoring the balance between NO and ET-1 signaling.-
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/aps/index.html-
dc.relation.ispartofActa Pharmacologica Sinicaen_US
dc.subject.meshEndothelium, Vascular - drug effects - physiology-
dc.subject.meshHypertension - physiopathology - prevention and control-
dc.subject.meshInsulin Resistance-
dc.subject.meshKATP Channels - agonists-
dc.subject.meshPropylamines - pharmacology-
dc.titleThe novel ATP-sensitive potassium channel opener iptakalim prevents insulin resistance associated with hypertension via restoring endothelial functionen_US
dc.typeArticleen_US
dc.identifier.emailWang, Y: yuwanghk@hku.hken_US
dc.identifier.emailWang, H: wh9588@yahoo.com.cn-
dc.identifier.authorityWang, Y=rp00239en_US
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/aps.2011.129-
dc.identifier.pmid22056616-
dc.identifier.scopuseid_2-s2.0-82955188008-
dc.identifier.hkuros199792en_US
dc.identifier.volume32en_US
dc.identifier.issue12-
dc.identifier.spage1466en_US
dc.identifier.epage1474en_US
dc.identifier.isiWOS:000298044000006-
dc.publisher.placeUnited States-

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