title: NHE-1 blockade reversed changes in calcium transient in myocardial slices from isoproterenol-induced hypertrophied rat left ventricle.
abstract: We previously reported that left ventricular (LV) slices from isoproterenol (ISO)-induced hypertrophied rat hearts showed an increase of energy expenditure due to remodeling of Ca(2+) handling in excitation-contraction coupling, i.e., suppressed SERCA2a activity and enhanced Na(+)/Ca(2+)exchanger-1 (NCX-1) activity. Na(+)/H(+) exchanger-1 (NHE-1) inhibitor (NHEI) has been demonstrated to exert beneficial effects in the development of cardiac remodeling. We hypothesized that a novel NHE-1 selective inhibitor, BIIB723 prevents remodeling of Ca(2+) handling in LV slices of ISO-induced hypertrophied rat hearts mediated by inhibiting NCX-1 activity. The significant shortening in duration of multi-cellular Ca(2+) transient in ISO group was normalized in ISO+BIIB723 group. The significant increase in amplitude of multi-cellular Ca(2+) waves (CaW) generated at high [Ca(2+)](o) of LV slices in ISO group was also normalized in ISO+BIIB723 group. However, the enhanced NCX-1 activity was not antagonized by BIIB723. We recently reported that ISO-induced down-regulation of a Ca(2+) handling protein, SERCA2a, was normalized by BIIB723. Therefore, it seems likely that BIIB723 normalized shortened multi-cellular Ca(2+) transient duration and increased CaW amplitude in LV slices mediated via normalization of SERCA2a activity. Furthermore, the results presented here suggest the multi-cellular Ca(2+) transient duration and CaW amplitude in LV slices might be better indices reflecting SERCA2a activity than SERCA2a protein expression level.
authors.affiliation: Department of Physiology II, Nara Medical University, School of Medicine, Kashihara, Nara 634-8521, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hattori
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takeshita
authors.forename: Ayako
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Bongju
authors.initials: B
authors.lastname: Kim
authors.forename: Munetaka
authors.initials: M
authors.lastname: Shibata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuoka
authors.forename: Koji
authors.initials: K
authors.lastname: Obata
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mitsuyama
authors.forename: Guo-Xing
authors.initials: GX
authors.lastname: Zhang
authors.forename: Miyako
authors.initials: M
authors.lastname: Takaki
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006146:Guanidines / Q000494:pharmacology*; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*
chemical_list: C522118:BIIB 723; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D007545:Isoproterenol; D002118:Calcium