THE SLOW FORCE RESPONSE DEVELOPMENT IN THE HYPERTROPHIC MYOCARDIUM OF THE SPONTANEOUSLY HYPERTENSIVE RAT

MAITE R. ZAVALA,; ROCÍO GARCIA ; ROMINA DÍAZ; NÉSTOR G PEREZ; MARÍA CELESTES VILLA ABRILLE

Congreso; International Society for Heart Research (ISHR) Latin American Section,; 2023

Mechanical stretch is an important physiological mechanism to adapt cardiac force to changes in hemodynamic conditions, but it may also induce hypertrophy if it is chronically sustained. Stretch increases cardiac developed force in two consecutive phases: the first one occurs immediately after stretch and is the expression of the Frank-Starling mechanism, while the second phase, called slow force response (SFR), occurs gradually and is due to an increase in intracellular calcium. An important step in the chain of events leading to the SFR generation is the increased production of reactive oxygen species (ROS) leading to ERK1/2- p90RSK-mediated Na+/H+ exchanger (NHE1) phosphorylation/activation. Despite the importance of NHE1 activity to maintain basal cell function, its hyperactivity was associated to cardiac pathologies. Interestingly, the hypertrophic myocardium of the spontaneously hypertensive rats (SHR) is characterized by an increased NHE1 activity. In this context, the aim of the present study was to evaluate whether the SFR is greater in the myocardium of SHR. Material and methods: Isolated rat papillary muscles and cardiac slices from the left ventricle were used for the experiments. The muscles were mounted horizontally and superfused with CO2/HCO3--buffer for SFR determination (pH ~7.40, 30°C). Isometric contractions (0.2 Hz) were recorded. The SFR was determined after an abrupt stretch of the muscles from 92 to 98% of their maximal length. To study the expression and phosphorylation of proteins involved in the SFR, the samples were frozen and homogenized in RIPA buffer to perform a western blot. Results: The development of SFR was similar in both strains (Wistar: 116.15 ± 0.53% of the initial rapid phase, n=4; SHR: 118.07 ± 4.28%, n=5, ns). Since we recently demonstrated that p38-MAPK activation after stretch negatively regulates the SFR by DUSP6 (Dual Specificity Phosphatase 6) up-regulation, limiting NHE-1 phosphorylation/activation, we thought to analyse these mediators in cardiac samples of SHR. Although basal expression of DUSP6 was greater in SHR (100.00 ± 8.09 n=8, vs. 149.74 ± 5.18, p