title: Blood pressure variability activates cardiac mineralocorticoid receptor and induces cardiac remodeling in hypertensive rats.
abstract: BACKGROUND
  Hypertensive patients with large blood pressure variability (BPV) have aggravated target organ damage. Because the aldosterone/mineralocorticoid receptor (MR) system is a possible mechanism of hypertensive organ damage, we investigated in spontaneously hypertensive rats (SHRs) whether a specific MR blocker, eplerenone, would prevent BPV-induced aggravation of hypertensive cardiac remodeling.
  
  
  RESULTS
  A rat model of a combination of hypertension and large BPV was created by performing bilateral sinoaortic denervation (SAD) in SHRs. SAD increased BPV without changing mean BP. SAD induced perivascular macrophage infiltration and aggravated myocardial fibrosis and cardiac hypertrophy, resulting in LV systolic dysfunction. Immunohistostaining revealed SAD-induced translocation of MRs into the nuclei (ie, MR activation) of the intramyocardial arterial medial cells and cardiac myocytes. SAD increased phosphorylation of p21-activated kinase1 (PAK1), a regulator of MR nuclear translocation. Chronic administration of a subdepressor dose of eplerenone prevented MR translocation, macrophage infiltration, myocardial fibrosis, cardiac hypertrophy, and LV dysfunction, while not affecting BPV. Circulating levels of aldosterone and cortisol were not changed by SAD.
  
  
  CONCLUSIONS
  Eplerenone inhibited the aggravation of cardiac inflammation and hypertensive cardiac remodeling, and thereby prevented progression of LV dysfunction in SHRs with large BPV. This suggests that the PAK1-MR pathway plays a role in cardiac inflammation and remodeling induced by large BPV superimposed on hypertension, independent of circulating aldosterone.
authors.affiliation: Department of Internal Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Yasuoka
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kai
authors.forename: Hidemi
authors.initials: H
authors.lastname: Kajimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kudo
authors.forename: Narimasa
authors.initials: N
authors.lastname: Takayama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Anegawa
authors.forename: Mitsuhisa
authors.initials: M
authors.lastname: Koga
authors.forename: Takanobu
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Mifune
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kage
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hirooka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D000077545:Eplerenone; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D009124:Muscle Proteins; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; C515906:Pak1 protein, rat; D054462:p21-Activated Kinases; D006854:Hydrocortisone