| Autor: |
Espejo MS; Centro de Investigaciones Cardiovasculares 'Dr. Horacio E. Cingolani', Facultad de Ciencias Médicas, Universidad Nacional de La Plata-CONICET, Calle 60 y 120, 1900, La Plata, Argentina., Aiello I; Centro de Investigaciones Cardiovasculares 'Dr. Horacio E. Cingolani', Facultad de Ciencias Médicas, Universidad Nacional de La Plata-CONICET, Calle 60 y 120, 1900, La Plata, Argentina., Sepúlveda M; Centro de Investigaciones Cardiovasculares 'Dr. Horacio E. Cingolani', Facultad de Ciencias Médicas, Universidad Nacional de La Plata-CONICET, Calle 60 y 120, 1900, La Plata, Argentina., Vila Petroff MG; Centro de Investigaciones Cardiovasculares 'Dr. Horacio E. Cingolani', Facultad de Ciencias Médicas, Universidad Nacional de La Plata-CONICET, Calle 60 y 120, 1900, La Plata, Argentina., Aiello EA; Centro de Investigaciones Cardiovasculares 'Dr. Horacio E. Cingolani', Facultad de Ciencias Médicas, Universidad Nacional de La Plata-CONICET, Calle 60 y 120, 1900, La Plata, Argentina. aaiello@ciclaplata.org.ar., De Giusti VC; Centro de Investigaciones Cardiovasculares 'Dr. Horacio E. Cingolani', Facultad de Ciencias Médicas, Universidad Nacional de La Plata-CONICET, Calle 60 y 120, 1900, La Plata, Argentina. vdegiusti@med.unlp.edu.ar. |
| Abstrakt: |
The force-frequency relationship (FFR) is an important intrinsic regulatory mechanism of cardiac contractility. However, a decrease (negative FFR) or no effect (flat FFR) on contractile force in response to an elevation of heart rate is present in the normal rat or in human heart failure. Reactive oxygen species (ROS) can act as intracellular signaling molecules activating diverse kinases as calcium-calmodulin-dependent protein kinase II (CaMKII) and p-38 MAP kinase (p-38K). Our aim was to elucidate the intracellular molecules implicated in the FFR of isolated rat ventricular myocytes. The myocytes were field-stimulated via two-platinum electrodes. Sarcomere length was recorded with a video camera. Ca 2+ transients and intracellular pH i were recorded by epifluorescence. Increasing frequency from 0.5 to 3 Hz decreased cell shortening without changes in pH i . This negative FFR was changed to positive FFR when the myocytes were pre-incubated with the ROS scavenger MPG, the NADPH oxidase blocker apocynin, or by inhibiting mitochondrial ROS production with 5-HD. Similar results were obtained when the cells were pre-incubated with the CaMKII blocker, KN-93, or the p-38K inhibitor, SB-202190. Consistently, the levels of phosphorylation of p-38K and the oxidation of CaMKII were significantly higher at 2 Hz than at 0.5 Hz. Despite the presence of positive inotropic effect during stimulation frequency enhancement, Ca 2+ transient amplitudes were reduced in MPG- and SB-202190-treated myocytes. In conclusion, our results indicate that the activation of the intracellular pathway involving ROS-CaMKII-p-38K contributes to the negative FFR of rat cardiomyocytes, likely by desensitizing the response of contractile myofilaments to Ca 2+ . |
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