PMID- 20668453
OWN - NLM
STAT- MEDLINE
DCOM- 20110201
LR  - 20211020
IS  - 1348-4214 (Electronic)
IS  - 0916-9636 (Print)
IS  - 0916-9636 (Linking)
VI  - 33
IP  - 10
DP  - 2010 Oct
TI  - A small difference in the molecular structure of angiotensin II receptor blockers 
      induces AT(1) receptor-dependent and -independent beneficial effects.
PG  - 1044-52
LID - 10.1038/hr.2010.135 [doi]
AB  - Angiotensin II (Ang II) type 1 (AT(1)) receptor blockers (ARBs) induce multiple 
      pharmacological beneficial effects, but not all ARBs have the same effects and 
      the molecular mechanisms underlying their actions are not certain. In this study, 
      irbesartan and losartan were examined because of their different molecular 
      structures (irbesartan has a cyclopentyl group whereas losartan has a chloride 
      group). We analyzed the binding affinity and production of inositol phosphate 
      (IP), monocyte chemoattractant protein-1 (MCP-1) and adiponectin. Compared with 
      losartan, irbesartan showed a significantly higher binding affinity and slower 
      dissociation rate from the AT(1) receptor and a significantly higher degree of 
      inverse agonism and insurmountability toward IP production. These effects of 
      irbesartan were not seen with the AT(1)-Y113A mutant receptor. On the basis of the 
      molecular modeling of the ARBs-AT(1) receptor complex and a mutagenesis study, the 
      phenyl group at Tyr(113) in the AT(1) receptor and the cyclopentyl group of 
      irbesartan may form a hydrophobic interaction that is stronger than the 
      losartan-AT(1) receptor interaction. Interestingly, irbesartan inhibited MCP-1 
      production more strongly than losartan. This effect was mediated by the 
      inhibition of nuclear factor-kappa B activation that was independent of the AT(1) 
      receptor in the human coronary endothelial cells. In addition, irbesartan, but 
      not losartan, induced significant adiponectin production that was mediated by 
      peroxisome proliferator-activated receptor-gamma activation in 3T3-L1 adipocytes, and 
      this effect was not mediated by the AT(1) receptor. In conclusion, irbesartan 
      induced greater beneficial effects than losartan due to small differences between 
      their molecular structures, and these differential effects were both dependent on 
      and independent of the AT(1) receptor.
FAU - Fujino, Masahiro
AU  - Fujino M
AD  - Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
FAU - Miura, Shin-ichiro
AU  - Miura S
FAU - Kiya, Yoshihiro
AU  - Kiya Y
FAU - Tominaga, Yukio
AU  - Tominaga Y
FAU - Matsuo, Yoshino
AU  - Matsuo Y
FAU - Karnik, Sadashiva S
AU  - Karnik SS
FAU - Saku, Keijiro
AU  - Saku K
LA  - eng
GR  - R01 HL057470/HL/NHLBI NIH HHS/United States
GR  - R01 HL083243/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100729
PL  - England
TA  - Hypertens Res
JT  - Hypertension research : official journal of the Japanese Society of Hypertension
JID - 9307690
RN  - 0 (Adiponectin)
RN  - 0 (Angiotensin II Type 1 Receptor Blockers)
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Chemokine CCL2)
RN  - 0 (NF-kappa B)
RN  - 0 (PPAR gamma)
RN  - 0 (Receptor, Angiotensin, Type 1)
RN  - 0 (Tetrazoles)
RN  - J0E2756Z7N (Irbesartan)
RN  - JMS50MPO89 (Losartan)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Adiponectin/metabolism
MH  - Angiotensin II Type 1 Receptor Blockers/*chemistry/*pharmacology
MH  - Animals
MH  - Biphenyl Compounds/chemistry/pharmacology
MH  - COS Cells
MH  - Cell Line
MH  - Cells, Cultured
MH  - Chemokine CCL2/metabolism
MH  - Chlorocebus aethiops
MH  - Endothelium, Vascular/cytology/drug effects/metabolism
MH  - Fibroblasts/cytology/drug effects/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Irbesartan
MH  - Kidney/cytology/drug effects/metabolism
MH  - Losartan/chemistry/pharmacology
MH  - Mice
MH  - NF-kappa B/metabolism
MH  - PPAR gamma/metabolism
MH  - Receptor, Angiotensin, Type 1/*drug effects/*physiology
MH  - Tetrazoles/chemistry/pharmacology
PMC - PMC3891520
MID - NIHMS542144
COIS- CONFLICT OF INTEREST The authors declare no conflict of interest.
EDAT- 2010/07/30 06:00
MHDA- 2011/02/02 06:00
PMCR- 2014/01/14
CRDT- 2010/07/30 06:00
PHST- 2010/07/30 06:00 [entrez]
PHST- 2010/07/30 06:00 [pubmed]
PHST- 2011/02/02 06:00 [medline]
PHST- 2014/01/14 00:00 [pmc-release]
AID - hr2010135 [pii]
AID - 10.1038/hr.2010.135 [doi]
PST - ppublish
SO  - Hypertens Res. 2010 Oct;33(10):1044-52. doi: 10.1038/hr.2010.135. Epub 2010 Jul 
      29.