p38 MAP kinase (p38) negatively regulates the slow force response (SFR) to myocardial stretch

PÉREZ NG; DÍAZ RG; ZAVALA MR; ENNIS IL; CINGOLANI HE; VILLA-ABRILLE MC

Foz de Iguazú

Congreso; PANAM - 1st PanAmerican Congress of Physiological Sciences; 2014

The SFR is the mechanical counterpart of a stretch-triggered autocrine mechanism that involves the release of angiotensin II/endothelin leading to the redox sensitive NHE1 phosphorylation/activation. Since p38 inhibition strengthens the angiotensin II-induced NHE1 activation in vascular smooth muscle, we hypothesized that it should modulate the SFR in the myocardium. In isolated rat papillary muscles the SFR was significantly increased by p38 inhibition with 10μmol/L SB202190, (27±2 vs 17±2 % of initial rapid phase, n=6, p<0.05), suggesting that p38 activation after stretch negatively regulates the SFR. Consistently, p38 phosphorylation (activation) significantly increased after stretch (134±10%, n=4, p<0.05 vs non stretched), effect cancelled by SB202190 (104±4%, n=6). Since NHE1 activity is crucial for the SFR, we next explored the effect of SB202190 on NHE1 activation during intracellular pH recovery from an acidic load. Maximal NHE1 activity wassignificantly increased by SB202190: JH+ (mmol/L/min) 3.7±0.4 (n=4) vs. 2.3±0.2 (n=5), p<0.05. Finally, p38 inhibition promoted a greater increase in the stretch-induced phosphorylation of ERK1/2 [in % of non stretched control: 232±14 (stretch+SB202190, n=3) vs 166±16(stretch, n=3), p<0.05], and NHE1 [in % of non stretched control: 148±9 (stretch+SB202190, n=4) vs 119±2 (stretch, n=4), P<0.05]. In conclusion, our results suggest that p38 activation after stretch restricts ERK1/2 and NHE1 phosphorylation limiting the inotropic response.