Cardiac Damage Prevention by Eplerenone: Comparison With Low Sodium Diet or Potassium Loading

Abstract

To determine the extent to which dietary sodium modulates aldosterone-induced cardiovascular damage, and to determine whether increased dietary potassium can prevent this damage, we used the Nω -nitro- l -arginine methyl ester (L-NAME)/angiotensin II (Ang II) rat model of cardiac injury. This model is dependent on the presence of aldosterone for the occurrence of myocardial damage. Two sets of experiments were performed. In the first set, the following groups were studied: (1) 1% NaCl to drink (control group); (2) L-NAME/Ang II with water to drink (low salt group); (3) L-NAME/Ang II/1% NaCl (high salt group); (4) L-NAME/Ang II/1% NaCl/eplerenone (eplerenone group). Systolic blood pressure increased similarly in all groups compared with controls. Compared with the controls, the high salt group, but not the low salt or eplerenone groups, developed significant myocardial damage. In the second set of experiments three groups of animals were studied: (1) L-NAME/Ang II/1%NaCl (high salt group) (2) L-NAME/Ang II/1%NaCl/eplerenone (eplerenone group), and (3) L-NAME/Ang II/1%NaCl with an extra 1% KCl in food (high dietary potassium group). Eplerenone, but not dietary potassium supplementation, prevented the development of cardiac damage. Thus, mineralocorticoid receptor antagonist treatment and low sodium diet were effective in preventing cardiac damage, which suggests that a minimal level of aldosterone and a moderately high sodium diet are both required for the development of the cardiovascular damage in the L-NAME/Ang II model. The inability of potassium supplementation to reduce myocardial damage suggests that eplerenone’s protective effect is not due to its potassium-sparing ability, but is rather related to some other feature of its selective aldosterone antagonism.

Eplerenone offsets cardiac and aortic adverse remodeling in spontaneously hypertensive rats

“…Eplere- none prevented cardiac damage without reducing systolic BP in l-NAME (inhibitor of the nitric oxide synthesis)/Ang II treated rats at either low or high sodium diet [24]. In the present study, although eplerenone or enalapril partially prevented the progressive increase of BP, the combined therapy was more effective for the antihypertensive effect.…”

Effect of Aldosterone and Mineralocorticoid Receptor Blockade on Vascular Inflammation

“…In the L-NAME/Ang II animal model, dietary potassium supplementation does not prevent the development of cardiac damage, suggesting that the beneficial effects of MR antagonists are not mediated by increases in body potassium stores [20]. Similarly, potassium supplementation does not reduce cardiovascular injury in the aldosterone-infused uninephrectomized rat model [9].…”

“…This dependence on dietary sodium intake is illustrated by the finding that L-NAME/Ang II animals fed a low-salt diet do not develop vascular damage. Furthermore, the lack of damage occurs in the setting of a 10-fold increase in plasma aldosterone levels compared to animals on a high-salt diet suggesting that blood levels of aldosterone are not a good predictor of aldosterone-mediated vascular injury [20].…”

“…Administration of an MR antagonist reduces vascular injury without significantly lowering blood pressure in the L-NAME/Ang II model, Ang II infused rat, aldosterone infused uninephrectomized rat, and stroke-prone spontaneously hypertensive rat [3,5,6,11,20]. Additionally, blood pressure elevation is prevented in the aldosterone-infused uninephrectomized rat by intracerebral administration of an MR antagonist; however, cardiac fibrosis and hypertrophy still occur [9].…”

Aldosterone receptor antagonists: Biology and novel therapeutic applications

“…Thus, several other mechanisms of action should be considered, such as the blockade of the nonepithelial, MR-mediated effects of aldosterone in the heart and blood vessels. The recent availability of the SARA eplerenone has shown that, in a rat model of cardiac injury, treatment with this compound prevented the development of cardiac damage and exerted significant renal protective effects [44,45]. More recently, the EPHESUS study has evaluated treatment with eplerenone initiated during the acute phase of MI among patients with LV ejection fraction (LVEF) <40% [9•].…”