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Cardiovascular Research 2003 57(4):1004-1014; doi:10.1016/S0008-6363(02)00793-9
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Contribution of Na+/H+ exchange to Na+ overload in the ischemic hypertrophied hyperthyroid rat heart

Marianna I Bak* and Joanne S Ingwall

Department of Medicine, NMR Laboratory for Physiological Chemistry, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Room BLI 247, Boston, MA 02115, USA

mbak{at}amwaw.edu.pl

* Corresponding author. Tel.: +1-617-732-6994; fax: +1-617-732-6990. Present address: Department of Metabolic Diseases, Medical University of Warsaw, Banacha 1a, III-D, 02-097 Warsaw, Poland. Tel.: +48-22-648-2812; fax: +48-22-659-7563. mbak{at}rics.bwh.harvard.edu

Objective: The mechanisms responsible for intracellular ion homeostasis in ischemic hypertrophied myocardium are not fully known. Moderately hypertrophied hyperthyroid hearts (T3) are characterized by the bioenergetic changes and increased Na+/H+ exchange (NHE) activity comparable with those observed in humans and experimental models of hypertrophy. Here we test the hypothesis whether NHE inhibition in T3 heart improves ion homeostasis during ischemia and contractile function during recovery. Methods: We compared intracellular H+ (H+i) and Na+ (Na+i) accumulations during 28 min global ischemia in isolated perfused T3 and euthyroid (EUT) rat hearts with and without NHE inhibition by using 31P and 23Na NMR. Heart function was measured during control perfusion and 30 min following ischemic insult. Results: In T3 hearts ischemia caused: (1) faster and greater Na+i accumulation (534±25% of preischemic level versus 316±22% in EUT, P<0.001); (2) lower acidification (pHi 6.66±0.66 versus 6.12±0.12 in EUT, P<0.001); and (3) faster hydrolysis of ATP. NHE inhibition (amiloride 1 mM) in T3 hearts lead to: (1) delayed and lower Na+i accumulation by 35±5%; (2) faster and greater acidification (pHi 6.45±0.15, P<0.05); (3) delayed ATP degradation; and (4) improved heart function during recovery. When NHE was inhibited, all T3 hearts (n=11) recovered 68±10% of their preischemic rate pressure product (RPP), while only two untreated T3 hearts (from 11) recovered ~40% of preischemic RPP. Conclusions: These data suggest that NHE inhibition could be useful intervention for the prevention of ischemic/reperfusion cell injury and could improve the function of the hypertrophied heart after acute ischemia.

KEYWORDS Hypertrophy; Ion transport; Ischemia; Na/H-exchanger; Reperfusion


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