|A novel Sartan derivative with very low angiotensin II type 1 receptor affinity protects the kidney in type 2 diabetic rats.|
|PMID: 18658044 Owner: NLM Status: MEDLINE|
|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.|
|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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|Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-07-24|
|Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 28 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2008 Oct|
|Created Date: 2008-09-18 Completed Date: 2008-10-09 Revised Date: -|
Medline Journal Info:
|Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States|
|Languages: eng Pagination: 1767-73 Citation Subset: IM|
|Center for Translational and Advanced Research, Tohoku University Graduate School of Medicine, Sendai, Japan.|
|APA/MLA Format Download EndNote Download BibTex|
Angiotensin II Type 1 Receptor Blockers
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
Imidazoles / pharmacokinetics, pharmacology*
Kidney / drug effects*, metabolism, pathology
Oxidative Stress / drug effects
Rats, Inbred SHR
Receptor, Angiotensin, Type 1 / metabolism
Thiazolidinediones / pharmacokinetics, pharmacology*
|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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