PMID- 21471190
OWN - NLM
STAT- MEDLINE
DCOM- 20110830
LR  - 20211020
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 338
IP  - 1
DP  - 2011 Jul
TI  - Distinct actions of endothelin A-selective versus combined endothelin A/B 
      receptor antagonists in early diabetic kidney disease.
PG  - 263-70
LID - 10.1124/jpet.111.178988 [doi]
AB  - Selective endothelin A (ET(A)) and combined ET(A) and ET(B) receptor antagonists 
      are being investigated for use in treating diabetic nephropathy. However, the 
      receptor-specific mechanisms responsible for producing the potential benefits 
      have not been discerned. Thus, we determined the actions of ET(A) and ET(B) 
      receptors on measures of glomerular function and renal inflammation in the early 
      stages of diabetic renal injury in rats through the use of selective and combined 
      antagonists. Six weeks after streptozotocin (STZ)-induced hyperglycemia, rats 
      were given 
      2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic 
      acid (ABT-627) (5 mg/kg/day), a selective ET(A) antagonist; 
      (2R,3R,4S)-4-(benzo[d][1,3]dioxol-5-yl)-2-(3-fluoro-4-methoxyphenyl)-1-(2-(N-propylpentylsulfonamido)ethyl)pyrrolidine-3-carboxylic 
      acid hydrochloride (A-182086) (10 mg/kg/day), a combined ET(A/B) antagonist; or 
      vehicle for 1 week. Sham controls received STZ vehicle (saline). Hyperglycemia 
      led to significant proteinuria, increased glomerular permeability to albumin 
      (P(alb)), nephrinuria, and an increase in total matrix metalloprotease (MMP) and 
      transforming growth factor-beta1 (TGF-beta1) activities in glomeruli. Plasma and 
      glomerular soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte 
      chemoattractant protein-1 (MCP-1) were elevated after 7 weeks of hyperglycemia. 
      Daily administration of both ABT-627 and A-182086 for 1 week significantly 
      attenuated proteinuria, the increase in P(alb), nephrinuria, and total MMP and 
      TGF-beta1 activity. However, glomerular sICAM-1 and MCP-1 expression was attenuated 
      with ABT-627, but not A-182086, treatment. In summary, both selective ET(A) and 
      combined ET(A/B) antagonists reduced proteinuria and glomerular permeability and 
      restored glomerular filtration barrier component integrity, but only 
      ET(A)-selective blockade had anti-inflammatory and antifibrotic effects. We 
      conclude that selective ET(A) antagonists are more likely to be preferred for the 
      treatment of diabetic kidney disease.
FAU - Saleh, Mohamed A
AU  - Saleh MA
AD  - Department of Pharmacology and Toxicology, Georgia Health Sciences University, 
      Augusta, Georgia 30907-2500, USA.
FAU - Pollock, Jennifer S
AU  - Pollock JS
FAU - Pollock, David M
AU  - Pollock DM
LA  - eng
GR  - R01 HL064776/HL/NHLBI NIH HHS/United States
GR  - HL60653/HL/NHLBI NIH HHS/United States
GR  - P01 HL095499/HL/NHLBI NIH HHS/United States
GR  - HL64776/HL/NHLBI NIH HHS/United States
GR  - HL95499/HL/NHLBI NIH HHS/United States
GR  - R01 HL060653/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110406
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (A 182086)
RN  - 0 (Endothelin A Receptor Antagonists)
RN  - 0 (Endothelin B Receptor Antagonists)
RN  - 0 (Pyrrolidines)
RN  - 0 (Receptor, Endothelin A)
RN  - 0 (Receptor, Endothelin B)
RN  - 0 (Sulfonamides)
RN  - V6D7VK2215 (Atrasentan)
SB  - IM
MH  - Animals
MH  - Atrasentan
MH  - Diabetes Mellitus, Experimental/*drug therapy/metabolism
MH  - Diabetic Nephropathies/*drug therapy/metabolism
MH  - *Endothelin A Receptor Antagonists
MH  - *Endothelin B Receptor Antagonists
MH  - Male
MH  - Pyrrolidines/*pharmacology/therapeutic use
MH  - Random Allocation
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, Endothelin A/metabolism
MH  - Receptor, Endothelin B/metabolism
MH  - Stereoisomerism
MH  - Sulfonamides/*pharmacology/therapeutic use
PMC - PMC3126640
EDAT- 2011/04/08 06:00
MHDA- 2011/08/31 06:00
PMCR- 2012/07/01
CRDT- 2011/04/08 06:00
PHST- 2011/04/08 06:00 [entrez]
PHST- 2011/04/08 06:00 [pubmed]
PHST- 2011/08/31 06:00 [medline]
PHST- 2012/07/01 00:00 [pmc-release]
AID - jpet.111.178988 [pii]
AID - 3695523 [pii]
AID - 10.1124/jpet.111.178988 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2011 Jul;338(1):263-70. doi: 10.1124/jpet.111.178988. Epub 
      2011 Apr 6.