Eplerenone potentiates protective effects of amlodipine against cardiovascular injury in salt-sensitive hypertensive rats

Abstract

The clinical value of the combination of amlodipine and eplerenone is unclear. This study was undertaken to test whether eplerenone potentiates the protective effects of amlodipine against hypertensive cardiovascular injury. Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats) were given (1) vehicle, (2) an antihypertensive dose of amlodipine, (3) a non-antihypertensive dose of eplerenone or (4) combined amlodipine and eplerenone for 6 weeks, and the effects on cardiovascular injuries were compared. There was no significant difference among the four groups regarding plasma aldosterone, urine volume or urinary electrolytes. A subpressor dose of eplerenone markedly ameliorated vascular endothelial dysfunction, cardiac inflammation and fibrosis in DS rats to a similar degree as an antihypertensive dose of amlodipine. Addition of eplerenone to amlodipine, without affecting blood pressure, enhanced the improvement by amlodipine of vascular endothelial function, cardiac inflammation, fibrosis and diastolic dysfunction in DS rats. Additive beneficial effects of eplerenone were attributed to additive potentiation of eNOS and Akt phosphorylation and additive reduction of oxidative stress. Eplerenone significantly attenuated cardiovascular NADPH oxidase activity by reducing gp91(phox) upregulation and attenuated the upregulation of cardiovascular AT1 receptor, but amlodipine failed to affect them. Thus, the normalization by eplerenone of gp91(phox) and AT1 receptor upregulation seems to be at least partially responsible for the additive benefits of eplerenone in the prevention of hypertensive cardiovascular injury. The combination of amlodipine and eplerenone may be a promising therapeutic strategy for cardiovascular disease in salt-sensitive hypertension.

Mineralocorticoid Receptors in Vascular Disease: Connecting Molecular Pathways to Clinical Implications

“…A recent study in a rat model of salt-sensitive hypertension found that eplerenone treatment potentiated the protective effects of the L-type calcium channel blocker amlodipine against cardiovascular injury. This finding supports that MRA/L-type calcium channel blocker combination therapy could potentially reduce the cardiovascular morbidity and mortality in hypertensive patients more effectively than either drug alone and at lower doses that might limit side effects [90]. In addition, hypertension is predominantly a disease of the elderly, affecting more than 60% of people over 60 years of age and up to 80% of the growing population over 80.…”

Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism

“…Calcium channel blockers decrease aldosterone synthesis in human adrenocortical cells [24] and in hypertensive patients [25]. Nakamura et al reported that eplerenone potentiates the protective effects of amlodipine against cardiovascular injury in salt-sensitive hypertensive rats independently of blood pressure [26]. In this study, 30-40% of patients needed to use amlodipine to achieve BP <140/90 mmHg.…”

Caveolin 1-related autophagy initiated by aldosterone-induced oxidation promotes liver sinusoidal endothelial cells defenestration

“…However, Cav1 interacts with MR and form a MR/Cav1 complex, which mediates a rapid signaling cascade of oxidation initiated by aldosterone [10]. Aldosterone induced more abundant of MR/Cav1 complexes to interacted with NOX4, leading to oxidation [34]. These indicate that the effects of Cav1 on redox modification may be different with a variety of cell types.…”