From Anrep’s Phenomenon to myocardial hypertrophy: Role of the Na+/H+ exchanger.

ENNIS IL; CINGOLANI HE; GARCIARENA CD; CAMILIÓN DE HURTADO MC; VILLA-ABRILLE MCM; AIELLO EA; PÉREZ NG

Current Cardiology Reviews

Bentham Science Publishers

Año: 2007 vol. 3 p. 149 - 164

1573-403X

When the length of themyocardium is increased, a biphasic response to stretch occurs involvingan initial rapid increase in force followed by a delayed slowincrease called the slowforce response(SFR). Confirming previous findings involving angiotensin II in the SFR, it was blunted byAT1 receptor blockade (losartan). The SFR was accompanied by an increase in reactive oxygenspecies (ROS) of ∼30% and in intracellular Na+ concentration ([Na+]i) of ∼2.5 mmol l−1over basal detected by H2DCFDA and SBFI fluorescence, respectively. Abolition of ROS by2-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 oxidaseinhibition (apocynin orDPI) or blockade of theATP-sensitive mitochondrialpotassium 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 releaseby 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 andp90rsk kinases phosphorylation, effect that was cancelled by losartan. In agreement, the SFRwas cancelled by inhibiting the ERK1/2 signalling pathway with PD98059. Angiotensin II at adose that mimics the SFR (1 nmol l−1) induced an increase in ·O2− 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 inthe genesis of the SFR to stretch.