Accumulation of angiotensin II (Ang II) in tissues is an Ang II receptor-mediated process. In pigs, acute angiotensin receptor blockade (ARB) reduced the heart-to-plasma ratio of Ang II following acute infusion. However in rats, chronic ARB treatment increased heart Ang II levels, suggesting that a differential response to ARB treatment may exist in the mammalian heart. Furthermore, the changes in heart aldosterone following chronic ARB treatment are not well described. To address the discrepancy in heart Ang II concentrations following ARB treatment, and to address the functional relevance of increased aldosterone in the heart two studies were undertaken. The first study consisted of three groups (n= 6) of rats, chronically studied: (1) control; (2) angiotensin II (Ang II; 80 ng/min for 28 d); and (3) angiotensin II + olmesartan (ARB; 10mg/kg/d for 21 d). Ang II-infusion increased intracardiac Ang II by 40% and intrarenal Ang II over 2-fold, and chronic ARB treatment decreased Ang II by 48% in the heart and over twofold in the kidney, suggesting that accumulation of Ang II in the heart is receptor-mediated as in the kidney. Ang II increased plasma aldosterone 2.5-fold and was exacerbated by ARB treatment. Intracardiac aldosterone was exacerbated by ARB treatment in the study. Suppression of intracardiac Ang II with ARB is consistent with the existing view of Ang II receptor-mediated uptake by tissues. Ang II stimulates the release of aldosterone, and the chronic blockade of the AT1 in the previous study increased aldosterone, as did the chronic blockade of mineralocorticoid receptor (MR). To evaluate the contribution of increased aldosterone to cardiovascular damage, an MR agonist was used in a second study, with and without an ARB to differentially assess the contributions of the respective receptors. This study included two additional experimental groups and a different ARB: 1) control (n=11); 2) angiotensin II (n=14), (Ang II; 80 ng/min for 28 d); 3) angiotensin II + losartan (n=17) (ARB; 10mg/kg/d for 21 d); 4) angiotensin II + MR blocker (n=14)(EPL; 100 mg eplerenone/kg/d in diet; Pfizer, St. Louis, MO, and 5) angiotensin II + ARB + MR blocker (Combo)(n=14). 8-isoprostane (8-iso-prostaglandin PGF2α) is a marker of oxidative damage and studies have shown it to be correlated to risk factors in coronary heart disease (40, 75). Nitrotyrosine is a marker of inflammation and nitrositive damage linked to heart disease (19, 56). Measuring these biomarkers indicates oxidative/nitrositive damage and inflammation. Blockade of the MR had no effect on blood pressure (158.7 ± 6.9 vs 165.1 ± 15.9 Ang II), but substantially increased cardioprotective actions demonstrated by a 57% decrease of urinary 8- isoprostane that was further abated when combined with the ARB achieving an additional decrease of 27%. Additionally, the nitrotyrosine concentrations were also ameliorated by receptor blockade; the combo blockade (54% of Control) have a 68% decrease from the Ang II (144% of Control). The data suggests that damage to the cardiovascular system by Ang II and aldosterone occurs via their respective receptors and in the case of aldosterone, independent from high blood pressure. There is evidence from the combined studies that in spite of increased aldosterone with ARB, there is a reduction in cardiac hypertrophy, inflammation and nitrositive damage by blocking AT1 and MR. Ang II and aldosterone both contribute to cardiovascular damage via their respective receptors and blocking either one still resulted in decreased oxidative damage. Blocking both receptors did seem to add some additional improvement, but not significantly. These mechanisms may be better explained by studying the respective signaling pathways or looking closer at local hormone production that perhaps initiate receptor cross-talk. Additional studies are needed to further elucidate alternate pathways.