Abstract 4893: Selective Aldosterone Blocker Enhances Protective Effects of Calcium Channel Blocker (CCB) Against Salt-sensitive Hypertension-induced Cardiovascular Injury, Independently of Blood Pressure
Purpose: The effects of aldosterone blocker against hypertension (HTN)-induced cardiovascular injury are still unclear.
We compared the protective effects of eplerenone (EPL), an aldosterone blocker and amlodipine (AML), a CCB on salt-sensitive HTN-induced cardiovascular injury,
and examined these combined effects on cardiovascular protection.
Methods: Dahl salt-sensitive rats fed on 8% NaCl containing diet were divided into vehicle, EPL (100mg/kg), AML (10mg/kg), and EPL combined with AML.
EPL monotherapy, without affecting blood pressure (BP) and plasma renin activity, significantly suppressed HTN-induced cardiac macrophage infiltration and interstitial fibrosis, coronary arterial remodeling, and improved HTN-induced vascular endothelial dysfunction, to a similar extent to strongly BP lowering AML.
Beneficial effects of the combination therapy against HTN-induced cardiac inflammation, fibrosis, and vascular endothelial dysfunction were greater than AML monotherapy despite no lowering BP. Moreover, combination of EPL and AML markedly improved HTN-induced cardiac diastolic dysfunction compared with vehicle.
These additive amelioration by the combination against hypertensive cardiac injury compared with AML monotherapy were associated with more attenuation of cardiac MCP-1, IL-6 and TGF-β1 expressions, and more reduction of cardiac superoxide partially derived from NADPH oxidase. Furthermore, improvement of vascular endothelial dysfunction by the combination compared with AML monotherapy was attributed to not only more reduction of vascular NADPH oxidase-mediated superoxide but also more increase of NO by vascular endothelial NO synthase phosphorylation. It is interesting that the amelioration of endothelial fucntion by EPL was associated with the attenuation of HTN-induced vascular apoptosis signal-regulating kinase 1 (ASK1) activation. Actually, we found that vascular ASK1 deficiency markedly reduced vascular superoxide, and improved vascular endothelial dysfunction caused by aldosterone/salt-induced HTN in ASK1 deficient mice.
Conclusions: Without lowering BP, aldosterone blocker enhanced protective effects of CCB against salt sensitive HTN-induced cardiovascular injury.