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Mitochondrial reactive oxygen species activate the slow force response to stretch in feline myocardium
Author(s) -
Caldiz Claudia I.,
Garciarena Carolina D.,
Dulce Raúl A.,
Novaretto Leonardo P.,
Yeves Alejandra M.,
Ennis Irene L.,
Cingolani Horacio E.,
Chiappe de Cingolani Gladys,
Pérez Néstor G.
Publication year - 2007
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.141689
Subject(s) - apocynin , losartan , chemistry , nadph oxidase , reactive oxygen species , angiotensin ii , angiotensin ii receptor type 1 , sodium–hydrogen antiporter , atp sensitive potassium channel , biochemistry , biophysics , endocrinology , sodium , receptor , biology , glibenclamide , organic chemistry , diabetes mellitus
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 ∼30% and in intracellular Na + concentration ([Na + ] i ) of ∼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 ∼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.