title: Tetrodotoxin attenuates isoproterenol-induced hypertrophy in H9c2 rat cardiac myocytes.
abstract: Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either α- or β- adrenergic stimulation. The present study was carried out to determine whether the reversible sodium channel blocker tetrodotoxin (TTX) exerts a direct anti-hypertrophic effect on isoproterenol (ISO)-induced cell hypertrophy and find the underlying mechanism that regulate [Na(+)]( i ). The experiments were performed on cultured H9c2 cells exposed to ISO (10 μM) alone or combined with TTX (1 μM) for 48 h. Our results showed that ISO significantly increased cell surface area by 30 % and atrial natriuretic peptide gene expression by nearly twofold (p < 0.05 for both). These effects were associated with a significant reduction in the gene expression of Na(+)/K(+)-ATPase isoforms α2 and α3, whereas the α1 isoform was unaffected. Conversely, ISO increased Na(+)-H(+) exchanger 1 (NHE-1) gene expression by approximately 40 % and significantly increased [Na(+)]( i ) level by 50 % (p < 0.05 for both). ISO was also found to significantly increase aquaporin 4 gene expression by nearly ninefold (p < 0.05). All these effects were prevented when identical experiments were carried out in the presence of TTX, but the expression of NHE-1. The expression of sodium channel protein type 5 subunit alpha was unaffected by either ISO or TTX. When taken together, these studies show that TTX attenuates the hypertrophic effect of ISO and suggest a possible approach to limiting ISO-induced hypertrophy in clinical treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology, Basic Medical Science College, Harbin Medical University, No. 194 Xue-fu Road, Nan-gang District, Harbin 150081, Heilongjiang, People's Republic of China.
authors.forename: Ming-Zi
authors.initials: MZ
authors.lastname: Chen
authors.forename: Qing-Ting
authors.initials: QT
authors.lastname: Bu
authors.forename: Shu-Chao
authors.initials: SC
authors.lastname: Pang
authors.forename: Feng-Lan
authors.initials: FL
authors.lastname: Li
authors.forename: Mei-Na
authors.initials: MN
authors.lastname: Sun
authors.forename: Er-Fu
authors.initials: EF
authors.lastname: Chu
authors.forename: Hui
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D007545:Isoproterenol / Q000494:pharmacology*; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D002316:Cardiotonic Agents; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol