CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Mineralocorticoid Receptor Activation is Crucial in the Signaling Pathway to the Anrep Effect
NÉSTOR G PÉREZ; CLAUDIA I CALDIZ; ROMINA G DÍAZ; IRENE L ENNIS; GLADYS E CHIAPPE DE CINGOLANI; HORACIO E CINGOLANI .
Congreso; AMERICAN HEART ASSOCIATION; 2011
AMERICAN HEART ASSOCIATION
Since reactive oxygen species (ROS) are critical mediators in the intracellular signalingleading to the Anrep effect or slow force response (SFR) to stretch, and the autocrineaction of Angiotensin II (A2) released after stretch is the trigger for these ROS,experiments were performed to explore the role of A2 and its downstream targets onsuperoxide anion production (SOP). Rat cardiac slices were used to measure SOP bychemiluminescence (5 umol/L lucigenin). After 15 minutes of 1 nmol/L A2 SOPincreased by 151±3 % of control (n=8, P<0.05), effect that was cancelled by Losartan(113±4 %, n=5). Since it has been suggested that A2 activates the epidermal growthfactor receptor (EGFR) and the mineralocorticoid receptor (MR) we explored thispossibilities. The A2-mediated increase in SOP was cancelled either by EGFR blockade(AG1478 98±9 %, n=5) or by two different MR inhibitors, spironolactone (108±8 %,n=7) and eplerenone (106±8 %, n=4) demonstrating the A2 crosstalk with bothreceptors. Interestingly, similar increases in SOP were promoted either by exogenous0.1 ug/ml EGF (152±9 %, n=7) or 10 nmol/L aldosterone (165±9 %, n=4). Since A2,EGF and aldosterone increase SOP and A2 triggers the intracellular signaling leading tothe stretch-induced ROS formation, we decided to analyze the effect of the differentreceptor inhibitors on the SFR generation. The Figure shows that all interventionsblunted the SFR. The SFR was unaffected by inhibiting glucocorticoid receptors orprotein synthesis (not shown). The results confirm the existence of an A2-MR crosstalkin the rat heart, and constitute the first demonstration that MR activation is a necessarystep in the chain of events leading to the SFR