CONICET | Buscador de Institutos y Recursos Humanos

Two consecutive phases charaterize the increase in force after myocardial stretch: one immediate due to a sudden increase in myofilament Ca2+ responsiveness and the slow force response (SFR) due to an increase in the Ca2+ transient (CaT) and representing the Anrep´s phenomenon. It has been proposed that the increase in CaT is secondary to an increase in [Na+]i, due to an angiotensin II (AngII) and/or endothelin (ET)-mediated increase in the Na+/H+ exchanger (NHE) activity. Since both peptides are known to generate reactive oxygen species (ROS), our objective was to explore the possible role of ROS in the signal transduction pathway of the SFR. Experiments were performed in cat isolated papillary muscles. Force, [Na+]i (SBFI fluorescence) and ROS (H2DCFD fluorescence) were measured. After 15 minutes of stretch the SFR was 122±1 % of the immediate phase (n=5, P<0.05). Non-specific blockade of ET receptors (1 mmol/L TAK044) or specific ETA receptors blockade (300 nmol/L BQ123) significantly reduced the SFR to 104±0.5 % (n=5) and 103±3 % (n=4) respectively (P<0.05 vs. control). The SFR was accompanied by an increase in [Na+]i that reached a value 2.6±0.4 mmol/L (n=5, P<0.05) over control after 15 minutes and was cancelled by NHE inhibition with 1 mmol/L HOE642 (-0.1±0.1 mmol/L, n=4) and by ET converting enzyme inhibition with 100 mmol/L phosphoramidon (-0.2±0.3 mmol/L, n=5). Stretching increased ROS to 128±4 % of control (n=5, P<0.05). ROS scavenging with 2 mmol/L MPG suppressed the increase in ROS (94±2 %, n=5) and [Na+]i (-0.1±0.2 mmol/L, n=5) and the SFR (100±1%, n=5). The results suggest a key role of ROS in the stretch-triggered chain of events leading to NHE activation by ET, and demonstrate that ROS can be involved in a physiological signal transduction pathway leading to an increase in CaT determining the SFR.