PMID- 20615400
OWN - NLM
STAT- MEDLINE
DCOM- 20101207
LR  - 20100817
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 644
IP  - 1-3
DP  - 2010 Oct 10
TI  - Comparison of MEK/ERK pathway inhibitors on the upregulation of vascular 
      G-protein coupled receptors in rat cerebral arteries.
PG  - 128-37
LID - 10.1016/j.ejphar.2010.06.053 [doi]
AB  - Organ culture is an in vitro method for investigating cellular mechanisms 
      involved in upregulation of vasocontractile G-protein coupled receptors. We 
      hypothesize that mitogen-activated-protein kinase (MEK) and/or 
      extracellular-signal-regulated kinase (ERK) specific inhibitors will attenuate 
      the G-protein coupled receptor expression following organ culture. Rat cerebral 
      arteries were incubated 48h in the presence of MEK/ERK specific inhibitors U0126, 
      PD98059, SL327, or AG126 for different time periods. Contractile responses by 
      activation of endothelin receptor type A and type B, serotonin receptor 5-HT(1B), 
      prostanoid TP receptor, and angiotensin II receptor type 1 and type 2 were 
      investigated. Results were verified by measurement of mRNA with real time PCR and 
      by protein immunohistochemistry. Organ culture induced transcriptional 
      upregulation of endothelin ET(B) receptor and of serotonin 5-HT(1B) receptor on 
      translational level and increased respective contractions. The prostanoid TP 
      receptor mediated contraction curve was left-wards shifted by organ culture. 
      Organ culture was associated with elevated pERK1/2 in the vascular smooth muscle 
      cells: the MEK1/2 inhibitor U0126 attenuated the endothelin ET(B) receptor 
      mediated contraction at post-translational level or by changing the receptor 
      affinities. The serotonin 5-HT(1B) receptor and prostanoid TP receptor mediated 
      contractions were abolished by U0126. Administration of U0126 6h after start of 
      incubation blocked the receptor upregulation. In conclusion, MEK specific 
      inhibitor U0126 is a potent inhibitor of G-protein coupled receptor alteration 
      seen during organ culture. Given the ability to inhibit G-protein coupled 
      receptor alteration at the clinically relevant time-point 6h post incubation 
      makes it an attractive therapeutic agent for in vivo studies.
CI  - Copyright 2010 Elsevier B.V. All rights reserved.
FAU - Sandhu, Hardip
AU  - Sandhu H
AD  - Department of Clinical Experimental Research, Glostrup Research Institute, 
      Glostrup University Hospital, Denmark. sandhu.hardip@gmail.com
FAU - Ansar, Saema
AU  - Ansar S
FAU - Edvinsson, Lars
AU  - Edvinsson L
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100706
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptor, Endothelin B)
RN  - 0 (Receptor, Serotonin, 5-HT1B)
RN  - 0 (Receptors, Thromboxane)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Extracellular Signal-Regulated MAP Kinases/*antagonists & inhibitors
MH  - Male
MH  - Middle Cerebral Artery/drug effects/metabolism
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors
MH  - Organ Culture Techniques
MH  - Polymerase Chain Reaction
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, Endothelin B/*drug effects/genetics
MH  - Receptor, Serotonin, 5-HT1B/*drug effects/genetics
MH  - Receptors, Thromboxane/drug effects/metabolism
MH  - Time Factors
MH  - Up-Regulation/drug effects
EDAT- 2010/07/10 06:00
MHDA- 2010/12/14 06:00
CRDT- 2010/07/10 06:00
PHST- 2010/01/15 00:00 [received]
PHST- 2010/06/04 00:00 [revised]
PHST- 2010/06/24 00:00 [accepted]
PHST- 2010/07/10 06:00 [entrez]
PHST- 2010/07/10 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
AID - S0014-2999(10)00661-8 [pii]
AID - 10.1016/j.ejphar.2010.06.053 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2010 Oct 10;644(1-3):128-37. doi: 10.1016/j.ejphar.2010.06.053. 
      Epub 2010 Jul 6.