title: 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.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Masaya
authors.initials: M
authors.lastname: Fukuda
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kataoka
authors.forename: Hisato
authors.initials: H
authors.lastname: Nako
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tokutomi
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Dong
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Yasuda
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
mesh_terms: D000450:Aldosterone / Q000097:blood; D017311:Amlodipine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D000077545:Eplerenone; D006321:Heart / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D009206:Myocardium / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013481:Superoxides / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D000451:Mineralocorticoid Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D017673:Sodium Chloride, Dietary; D013481:Superoxides; D017311:Amlodipine; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt