Abstract 18043: P38 MAP Kinase Negatively Regulates the Slow Force Response to Myocardial Stretch by Affecting NHE1 Phosphorylation

Mechanical stretch is an important physiological and pathological stimulus to the heart. Stretch induces a biphasic increase in myocardial force generation: A first phase due to the Frank-Starling mechanism, followed by a slower increase in force called slow force response (SFR). The SFR is blunted by AT1 or ETA receptor blockade, by NHE1 inhibition and by reactive oxygen species scavenging. This suggests that it is the mechanical counterpart of an autocrine/paracrine mechanism involving release of angiotensin II (AngII) and endothelin (ET) leading to redox sensitive NHE1 phosphorylation with its consequent activation. Since previous evidence indicates that p38 MAP kinase (p38) negatively regulates the AngII/ET positive inotropic effect in the heart, we hypothesized that the same mechanism would modulate the magnitude of the SFR. Isolated rat papillary muscles were stretched from 92 to 98 % of Lmax. The SFR was 117 ± 2 % of the initial rapid phase (n=6, P<0.05 vs. rapid phase) and was significantly increa...