| A novel Sartan derivative with very low angiotensin II type 1 receptor affinity protects the kidney in type 2 diabetic rats. | |
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MedLine Citation:
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PMID: 18658044 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Antihypertensive angiotensin II receptor blockers (ARBs) protect the kidney, at least in part, independently of blood pressure lowering. Still, the extent to which blood pressure lowering is related to renoprotection remains unclear. METHODS AND RESULTS: 139 newly synthesized ARB-derivatives were assayed for inhibition of advanced glycation (AGEs). The 9 most powerful compounds were then tested for transition metal chelation, angiotensin II type 1 receptor (AT1R) affinity, and pharmacokinetic parameters. R-147176 was eventually selected as it strongly inhibits advanced glycation but is 6700 times less effective than olmesartan in AT1R binding. It is orally bioavailable and toxicologically safe. Despite a minimal blood pressure lowering effect, it provides significant renoprotection in 3 experimental rat models with renal injury, ie, obese, hypertensive, type 2 diabetic rats (SHR/NDmcr-cp), normotensive type 2 diabetic rats (Zucker diabetic fatty), and remnant kidney rats. CONCLUSIONS: R-147176 retains renal protective properties despite a minimal blood pressure-lowering effect. Clearly, the renal benefits of ARBs do not necessarily depend on blood pressure lowering and AT1R affinity, but rather on the inhibition of AGEs and oxidative stress inherent to their chemical structure. R-147176 opens new avenues in the treatment of cardiovascular and kidney diseases. |
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Authors:
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Yuko Izuhara; Toshio Sada; Hiroaki Yanagisawa; Hiroyuki Koike; Shuichi Ohtomo; Takashi Dan; Sadayoshi Ito; Masaomi Nangaku; Charles van Ypersele de Strihou; Toshio Miyata |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-07-24 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 28 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2008 Oct |
Date Detail:
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Created Date: 2008-09-18 Completed Date: 2008-10-09 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 1767-73 Citation Subset: IM |
Affiliation:
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Center for Translational and Advanced Research, Tohoku University Graduate School of Medicine, Sendai, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Angiotensin II Type 1 Receptor Blockers
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pharmacokinetics,
pharmacology*,
toxicity Animals Antihypertensive Agents / pharmacology Antioxidants / pharmacology Blood Pressure / drug effects Cell Survival / drug effects Chelating Agents / pharmacology Diabetes Mellitus, Type 2 / complications, drug therapy*, metabolism, physiopathology Diabetic Nephropathies / etiology, metabolism, physiopathology, prevention & control* Disease Models, Animal Glycosylation End Products, Advanced / metabolism Hela Cells Humans Imidazoles / pharmacokinetics, pharmacology* Kidney / drug effects*, metabolism, pathology Male Nephrectomy Oxidative Stress / drug effects Protein Binding Rats Rats, Inbred SHR Rats, Wistar Rats, Zucker Receptor, Angiotensin, Type 1 / metabolism Thiazolidinediones / pharmacokinetics, pharmacology* Time Factors |
| Chemical | |
Reg. No./Substance:
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0/Angiotensin II Type 1 Receptor Blockers; 0/Antihypertensive Agents; 0/Antioxidants; 0/Chelating Agents; 0/Glycosylation End Products, Advanced; 0/Imidazoles; 0/R 147176; 0/Receptor, Angiotensin, Type 1; 0/Thiazolidinediones |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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