MITOCHONDRIAL REACTIVE OXYGEN SPECIES ACTIVATE THE SLOW FORCE RESPONSE TO STRETCH IN FELINE MYOCARDIUM.

CALDIZ CI; GARCIARENA CD; DULCE RA; NOVARETTO LP; YEVES AM; ENNIS IL; CINGOLANI HE; CHIAPPE DE CINGOLANI G; PÉREZ NG

THE JOURNAL OF PHYSIOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: England; Año: 2007 vol. 584 p. 895 - 905

0022-3751

Mitochondrial reactive oxygen species activate the slow force response to stretch in feline myocardium. Caldiz CI, Garciarena CD, Dulce RA, Novaretto LP, Yeves AM, Ennis IL, Cingolani HE, Chiappe de Cingolani G, Pérez NG. Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, UNLP, 60 y 120 (1900) La Plata, Argentina. When the length of the myocardium is increased, a biphasic response to stretch occurs involving an initial rapid increase in force followed by a delayed slow increase called the slow force response (SFR). Confirming previous findings involving angiotensin II in the SFR, it was blunted by AT1 receptor blockade (losartan). The SFR was accompanied by an increase in reactive oxygen species (ROS) of approximately 30% and in intracellular Na(+) concentration ([Na(+)](i)) of approximately 2.5 mmol l(-1) over basal detected by H(2)DCFDA and SBFI fluorescence, respectively. Abolition of ROS by 2-mercapto-propionyl-glycine (MPG) and EUK8 suppressed the increase in [Na(+)](i) and the SFR, which were also blunted by Na(+)/H(+) exchanger (NHE-1) inhibition (HOE642). NADPH oxidase inhibition (apocynin or DPI) or blockade of the ATP-sensitive mitochondrial potassium channels (5HD or glybenclamide) suppressed both the SFR and the increase in [Na(+)](i) after stretch, suggesting that endogenous angiotensin II activated NADPH oxidase leading to ROS release by the ATP-sensitive mitochondrial potassium channels, which promoted NHE-1 activation. Supporting the notion of ROS-mediated NHE-1 activation, stretch increased the ERK1/2 and p90rsk kinases phosphorylation, effect that was cancelled by losartan. In agreement, the SFR was cancelled by inhibiting the ERK1/2 signalling pathway with PD98059. Angiotensin II at a dose that mimics the SFR (1 nmol l(-1)) induced an increase in .O(2)(-) production of approximately 30-40% detected by lucigenin in cardiac slices, an effect that was blunted by losartan, MPG, apocynin, 5HD and glybenclamide. Taken together the data suggest a pivotal role of mitochondrial ROS in the genesis of the SFR to stretch.