A novel Sartan derivative with very low angiotensin II type 1 receptor affinity protects the kidney in type 2 diabetic rats.
Arterioscler Thromb Vasc Biol
; 28(10): 1767-73, 2008 Oct.
Article
em En
| MEDLINE
| ID: mdl-18658044
ABSTRACT
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 ANDRESULTS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tiazolidinedionas
/
Bloqueadores do Receptor Tipo 1 de Angiotensina II
/
Diabetes Mellitus Tipo 2
/
Nefropatias Diabéticas
/
Imidazóis
/
Rim
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Assunto da revista:
ANGIOLOGIA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Japão