Abstract 10746: Mineralocorticoid Receptor Activation is Crucial in the Signaling Pathway to the Anrep Effect
Since reactive oxygen species (ROS) are critical mediators in the intracellular signaling leading to the Anrep effect or slow force response (SFR) to stretch, and the autocrine action 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 on superoxide anion production (SOP). Rat cardiac slices were used to measure SOP by chemiluminescence (5 umol/L lucigenin). After 15 minutes of 1 nmol/L A2 SOP increased 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 growth factor receptor (EGFR) and the mineralocorticoid receptor (MR) we explored this possibilities. 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 both receptors. Interestingly, similar increases in SOP were promoted either by exogenous 0.1 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 to the stretch-induced ROS formation, we decided to analyze the effect of the different receptor inhibitors on the SFR generation. The Figure shows that all interventions blunted the SFR. The SFR was unaffected by inhibiting glucocorticoid receptors or protein synthesis (not shown). The results confirm the existence of an A2-MR crosstalk in the rat heart, and constitute the first demonstration that MR activation is a necessary step in the chain of events leading to the SFR
- © 2011 by American Heart Association, Inc.