| Effect of chronic and selective endothelin receptor antagonism on microvascular function in type 2 diabetes. | |
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MedLine Citation:
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PMID: 18424628 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Vascular dysfunction, which presents either as an increased response to vasoconstrictors or an impaired relaxation to dilator agents, results in worsened cardiovascular outcomes in diabetes. We have established that the mesenteric circulation in Type 2 diabetes is hyperreactive to the potent vasoconstrictor endothelin-1 (ET-1) and displays increased nitric oxide-dependent vasodilation. The current study examined the individual and/or the relative roles of the ET receptors governing vascular function in the Goto-Kakizaki rat, a mildly hyperglycemic, normotensive, and nonobese model of Type 2 diabetes. Diabetic and control rats received an antagonist to either the ET type A (ETA; atrasentan; 5 mg x kg(-1) x day(-1)) or type B (ET(B); A-192621; 15 or 30 mg x kg(-1) x day(-1)) receptors for 4 wk. Third-order mesenteric arteries were isolated, and vascular function was assessed with a wire myograph. Maximum response to ET-1 was increased in diabetes and attenuated by ETA antagonism. ETB blockade with 15 mg/kg A-192621 augmented vasoconstriction in controls, whereas it had no further effect on ET-1 hyperreactivity in diabetes. The higher dose of A-192621 showed an ETA-like effect and decreased vasoconstriction in diabetes. Maximum relaxation to acetylcholine (ACh) was similar across groups and treatments. ETB antagonism at either dose had no effect on vasorelaxation in control rats, whereas in diabetes the dose-response curve to ACh was shifted to the right, indicating a decreased relaxation at 15 mg/kg A-192621. These results suggest that ETA receptor blockade attenuates vascular dysfunction and that ETB receptor antagonism exhibits differential effects depending on the dose of the antagonists and the disease state. |
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Authors:
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Kamakshi Sachidanandam; Mostafa M Elgebaly; Alex K Harris; Jim R Hutchinson; Erin M Mezzetti; Vera Portik-Dobos; Adviye Ergul |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-04-18 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: 294 ISSN: 0363-6135 ISO Abbreviation: Am. J. Physiol. Heart Circ. Physiol. Publication Date: 2008 Jun |
Date Detail:
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Created Date: 2008-06-09 Completed Date: 2008-08-15 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H2743-9 Citation Subset: IM |
Affiliation:
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Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Medical College of Georgia, Augusta, Georgia, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylcholine
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pharmacology Animals Cardiovascular Agents / pharmacology* Diabetes Mellitus, Type 2 / complications, drug therapy*, metabolism, physiopathology Diabetic Angiopathies / etiology, metabolism, physiopathology, prevention & control* Disease Models, Animal Dose-Response Relationship, Drug Endothelin-1 / metabolism Male Mesenteric Arteries / drug effects, metabolism Microcirculation / drug effects, metabolism Myography Peptides, Cyclic / pharmacology Pyrrolidines / pharmacology* Rats Rats, Wistar Receptor, Endothelin A / antagonists & inhibitors*, metabolism Receptor, Endothelin B / antagonists & inhibitors*, metabolism Up-Regulation Vasoconstriction / drug effects Vasoconstrictor Agents / pharmacology Vasodilation / drug effects Vasodilator Agents / pharmacology Viper Venoms / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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DK-074385/DK/NIDDK NIH HHS; HL-076236/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/A 192621; 0/Cardiovascular Agents; 0/Endothelin-1; 0/Peptides, Cyclic; 0/Pyrrolidines; 0/Receptor, Endothelin A; 0/Receptor, Endothelin B; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 0/Viper Venoms; 0/atrasentan; 0/sarafotoxins s6; 136553-81-6/cyclo(Trp-Asp-Pro-Val-Leu); 51-84-3/Acetylcholine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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