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ROLE OF p38‐MITOGEN‐ACTIVATED PROTEIN KINASE IN ISCHAEMIC PRECONDITIONING IN RAT HEART
Author(s) -
Bell James R,
Eaton Philip,
Shattock Michael J
Publication year - 2008
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2007.04794.x
Subject(s) - p38 mitogen activated protein kinases , mapk/erk pathway , perfusion , ischemic preconditioning , ischemia , medicine , cardioprotection , pharmacology , protein kinase a , kinase , chemistry , biochemistry
SUMMARY1 Activation of p38‐mitogen‐activated protein kinase (MAPK) has been implicated in the signalling cascade leading to protection by ischaemic preconditioning. This, however, is controversial and there is a plethora of conflicting data in the literature. Although many experimental differences may contribute to this, two in particular may be confounding: (i) the failure to account for p38‐MAPK activation during aerobic perfusion; and (ii) the use of the anti‐oxidant dimethylsulphoxide (DMSO) as the vehicle for the commonly used p38‐MAPK inhibitor SB203580. We have investigated the effects of aerobic perfusion, ischaemia and preconditioning on p38‐MAPK activation. In addition, we have used water‐soluble SB203580 hydrochloride (SB203580.HCl) and DMSO to probe the role of p38‐MAPK in preconditioning and ischaemic injury. 2 Activation of p38‐MAPK in rat isolated hearts was assessed using a dual phosphospecific antibody during cannulation, aerobic perfusion and index, autolytic and preconditioned ischaemia. The effect of SB203580.HCl (10 mmol/L) in ischaemic preconditioning and ischaemia/reperfusion was tested using recovery of function and tetrazolium (TTC) staining as end‐points. 3 Aerobic perfusion induced rapid activation (34% of maximal ischaemia‐induced increase; P < 0.05) of p38‐MAPK after 2 min that returned to baseline after 30 min. Index, autolytic and preconditioned ischaemia activated p38‐MAPK, with index ischaemia peaking after 15 min (520% of basal; P < 0.05) before declining. SB203580.HCl blocked p38‐MAPK activity, but did not block ischaemic preconditioning when bracketing the trigger phase and was not protective when given during ischaemia. 4 In the rat isolated heart, activation of p38‐MAPK is neither a unique feature of preconditioning nor a prerequisite. Previous studies using SB203580 may have been complicated by failure to account for the activation of p38‐MAPK by the protocol itself and the anti‐oxidant properties of the most commonly used vehicle DMSO.