title: Na/H exchange isoform 1 is involved in mineralocorticoid/salt-induced cardiac injury.
abstract: Long-term exposure of uninephrectomized rats to desoxycorticosterone acetate (DOCA)/salt induces cardiac fibrosis and hypertrophy through mineralocorticoid receptors (MRs). However, the underlying cellular mechanisms remain unclear. To determine whether Na/H exchange isoform 1 (NHE1) is involved in the cellular mechanisms, we examined the effects of a specific NHE1 inhibitor, cariporide, and an MR antagonist, spironolactone, on DOCA/salt-induced cardiac fibrosis and hypertrophy. Uninephrectomized rats were given 20 mg of DOCA (single subcutaneous injection) plus 0.9% NaCl/0.3% KCl to drink and were killed at 8 days. Two groups of rats given DOCA/salt were treated with either spironolactone (50 mg/kg per day SC) or cariporide (30 mg/kg per day PO) for 8 days. Control rats were treated with only high salt after the operation. The DOCA/salt-induced perivascular collagen deposition was completely abolished by cariporide and spironolactone. DOCA/salt-induced interstitial collagen deposition was partially and completely suppressed by spironolactone and cariporide, respectively. The rats exposed to DOCA/salt had cardiocyte hypertrophy in the subendocardial and subepicardial regions, a finding that was completely inhibited by cariporide but not by spironolactone. In rats given DOCA/salt, NHE1 protein expression was markedly increased. This was partially and completely reversed by spironolactone and cariporide, respectively. We concluded that cardiac NHE1 contributes to DOCA/salt-induced cardiac fibrosis and hypertrophy and that the NHE1 inhibitor cariporide completely prevents the detrimental effects of DOCA/salt on the heart. We also demonstrated that DOCA/salt-induced cardiac injury through the MRs partly occurs through NHE1 activation.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical School, Minamikawachi, Tochigi, 329-0498 Japan. genrfjs@attglobal.net
authors.forename: Genro
authors.initials: G
authors.lastname: Fujisawa
authors.forename: Koji
authors.initials: K
authors.lastname: Okada
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Muto
authors.forename: Nobuya
authors.initials: N
authors.lastname: Fujita
authors.forename: Naoki
authors.initials: N
authors.lastname: Itabashi
authors.forename: Eiji
authors.initials: E
authors.lastname: Kusano
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D003094:Collagen / Q000032:analysis; D003900:Desoxycorticosterone / Q000494:pharmacology*; D005355:Fibrosis; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000494:pharmacology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology*; D013148:Spironolactone / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology
chemical_list: D006146:Guanidines; D000451:Mineralocorticoid Receptor Antagonists; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; D013148:Spironolactone; D003900:Desoxycorticosterone; D012965:Sodium Chloride; C093373:cariporide; D003094:Collagen