NHE-1-dependent intracellular sodium overload in hypertrophic hereditary cardiomyopathy: prevention by NHE-1 inhibitor.
The purpose of this study was to verify whether myocardial intracellular Na(+) overload may take place in the hereditary cardiomyopathic hamster (CMH), as a result of an increased activity of the Na(+)-H(+) exchanger isoform-1 (NHE-1). Our results showed that simultaneous intracellular Na(+) and Ca(2+) overloads as well as an increase of NHE-1 protein level took place during the development of necrosis and hypertrophy in the CMH. Treatment of 30-day-old CMHs during the development of necrosis and in the absence of hypertrophy with the specific NHE-1 inhibitor EMD87580 (EMD) for 50 days significantly prevented the increase of NHE-1 protein level and intracellular Na(+) and Ca(2+) overloads as well as necrosis. Treatment of CMHs during the development of hypertrophy with EMD for 198 days prevented the development of both necrosis and hypertrophy. In conclusion, our results suggest that NHE-1 overexpression as well as Na(+) and Ca(2+) overloads do take place during the development of necrosis and hypertrophy in hereditary CMHs. Moreover, our results suggest that the blockade of NHE-1 by EMD87580 prevents these diseases by preventing the increase of Na(+) influx through the NHE-1.
Chahine
Mirna
M
Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 - 12th Avenue North, Sherbrooke, Québec, Canada J1H 5N4.
Bkaily
Ghassan
G
Nader
Moni
M
Al-Khoury
Johny
J
Jacques
Danielle
D
Beier
Norbert
N
Scholz
Wolfgang
W
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism / Q000517:prevention & control*; D006224:Cricetinae; D005260:Female; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009206:Myocardium / Q000473:pathology; D009336:Necrosis / Q000517:prevention & control; D012964:Sodium / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*
D006146:Guanidines; C481648:N-(2-methyl-4,5-bis(methylsulfonyl)benzoyl)guanidine; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; D012964:Sodium; D002118:Calcium