Inhibition of p38 MAPK activity fails to attenuate contractile dysfunction in a mouse model of low-flow ischemia.
OBJECTIVE
The basal activity of p38 MAPK has recently been shown to impair myocardial contractility. This kinase is activated by ischemia and short-term hibernation. We hypothesized that p38 MAPK activation may contribute to the contractile deficit that characterizes low-flow ischemia.


METHODS
In Langendorff-perfused isolated C57BL/6 mouse hearts, perfusion pressure was reduced from 85 to 15 or 30 mm Hg for 120 min to induce ischemic left ventricular dysfunction. The effect of the p38 MAPK inhibitor SB203580 (1 microM/l) on contractile function and p38 MAPK activation was assessed.


RESULTS
Reduction in perfusion pressure to 15 or 30 mm Hg was accompanied by stable reductions in coronary flow (83+/-2% and 66+/-2%, respectively) and developed pressure (84+/-2% and 61+/-3%), with minimal infarction (15.6+/-0.69% and 10.6+/-0.98% of LV myocardium, respectively), but marked activation of p38 MAPK (reflected in pHSP27 1092+/-326% basal and 996+/-301% basal, respectively). The p38 MAPK inhibitor SB203580, present during the last 60 min of reduced pressure perfusion, prevented p38 MAPK activation (pHSP27 281+/-92% basal, p=0.01 and 186+/-72% basal, p=0.01) but, despite the presence of a contractile reserve, had no effect on developed pressure. Similarly, early treatment with SB203580 started 5 min after the onset of reduced flow also failed to attenuate contractile dysfunction.


CONCLUSIONS
The p38 MAPK activation that accompanies short-term hibernation does not appear to contribute to the contractile deficit.
Gorog
Diana A
DA
Division of Cardiology, KCL, The Rayne Institute, St. Thomas' Hospital, London, UK.
Tanno
Masaya
M
Cao
Xuebin
X
Bellahcene
Mohamed
M
Bassi
Rekha
R
Kabir
Alamgir M N
AM
Dighe
Kushal
K
Quinlan
Roy A
RA
Marber
Michael S
MS
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D009200:Myocardial Contraction / Q000187:drug effects*; D017682:Myocardial Stunning / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology; D010477:Perfusion; D011725:Pyridines / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*; D048051:p38 Mitogen-Activated Protein Kinases
D007093:Imidazoles; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580