Document Detail

The p38 MAPK inhibitor, SB203580, abrogates ischaemic preconditioning in rat heart but timing of administration is critical.
MedLine Citation:
PMID:  11192368     Owner:  NLM     Status:  MEDLINE    
There is debate concerning the involvement of p38 mitogen activated protein kinase (MAPK) in the mediation of ischaemic preconditioning. Pharmacological inhibition of p38 MAPK with SB203580 has been reported to block preconditioning in some studies but not in others. We hypothesised that this divergence could be due to differences in the timing of inhibitor administration. Isolated rat hearts were perfused in the Langendorff mode and subjected to 35 min regional ischaemia followed by 120 min reperfusion. Hearts were then double stained with Evans' blue and triphenyltetrazolium chloride to determine risk (R) and infarct zones (I), expressed as I/R% ratios. Preconditioned hearts were subjected to 2 times 5 min global ischaemia with 10 min intervening reperfusion. SB203580 10 microM was perfused either during the preconditioning protocol (PC+/-SB-early),just prior to and during the first 15 min of the lethal ischaemia (PC+/-SB-late) or prior to regional ischaemia in the absence of preconditioning. Ischaemic preconditioning significantly limited infarct size (I/R 38.9 +/- 3.0% in control vs 13.4 +/- 2.4%, P < 0.01). In the PC+/-SB-early group, preconditioning was still fully protective (I/R% 14.6 +/- 1.0). However, in the PC+/-SB-late group, SB203580 completely blocked the protection afforded by preconditioning (I/R% 33.6 +/- 4.4%, P < 0.01 vs 13.4 +/- 2.4% in preconditioned hearts, p < 0.05). SB203580 alone did not affect infarct size when given prior to and during regional ischaemia (I/R 36.2 +/- 2.7%). These histological data are corroborated by a significant increase in p38 MAPK activation in the preconditioned hearts during sustained ischaemia in comparison with the controls. In conclusion the activation of p38 MAPK during lethal ischaemia, but not during the ischaemic preconditioning protocol, is essential for the mediation of protection and may resolve some of the earlier controversy surrounding the use of SB203580 in preconditioning studies.
M M Mocanu; G F Baxter; Y Yue; S D Critz; D M Yellon
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Basic research in cardiology     Volume:  95     ISSN:  0300-8428     ISO Abbreviation:  Basic Res. Cardiol.     Publication Date:  2000 Dec 
Date Detail:
Created Date:  2001-01-15     Completed Date:  2001-03-08     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0360342     Medline TA:  Basic Res Cardiol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  472-8     Citation Subset:  IM    
The Hatter Institute for Cardiovascular Studies, Division of Cardiology, University College London Hospitals & Medical School, UK.
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MeSH Terms
Coronary Circulation / drug effects
Drug Administration Schedule
Enzyme Inhibitors / administration & dosage*,  pharmacology
Heart / drug effects*,  physiopathology
Imidazoles / administration & dosage*,  pharmacology
Ischemic Preconditioning*
Mitogen-Activated Protein Kinases / antagonists & inhibitors*,  metabolism
Myocardial Infarction / pathology,  physiopathology
Myocardium / enzymology
Pyridines / administration & dosage*,  pharmacology
Rats, Sprague-Dawley
Ventricular Function, Left / drug effects
p38 Mitogen-Activated Protein Kinases
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Imidazoles; 0/Pyridines; 0/SB 203580; EC Protein Kinases; EC Mitogen-Activated Protein Kinases

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