(Circulation. 2000;101:2749.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Na+/H+ Exchange Inhibition With HOE642 Improves Postischemic Recovery due to Attenuation of Ca2+ Overload and Prolonged Acidosis on Reperfusion
From the Medizinische Universitätsklinik (H.S., M.C.H.d.G., M.H., C.F., A.L., S.N.), Würzburg, Germany; Harvard-Thorndike Laboratory (J.P.M.), Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; and the HMR Deutschland GmbH (W.S.), Frankfurt/Main, Germany.
Correspondence to Hinrik Strömer, MD, Medizinische Universitätsklinik, Josef-Schneider-Straße 2, 97080 Würzburg, Germany. E-mail stromer{at}mail.uni-wuerzburg.de
Background—Na+/H+ exchange inhibition with HOE642 (cariporide) improves postischemic recovery of cardiac function, but the mechanisms of action remain speculative. Because Na+/H+ exchange is activated on reperfusion, it was hypothesized that its inhibition delays realkalinization and decreases intracellular Na+ and, via Na+/Ca2+ exchange, Ca2+ overload. Attenuated Ca2+ overload and prolonged acidosis are known to be cardioprotective.
Methods and Results—Left ventricular developed and
end-diastolic pressures were measured in isolated
buffer-perfused rat hearts subjected to 30 minutes of no-flow
ischemia and 30 minutes of reperfusion (37°C) with or without
1 µmol/L HOE642 added to the perfusate 15 minutes before
ischemia. Intracellular Ca2+ concentration
([Ca2+]i) and pHi were measured
with aequorin (n=10 per group) and 31P NMR spectroscopy
(n=6 per group), respectively. HOE642 did not affect
preischemic mechanical function,
[Ca2+]i, or pHi. Mechanical
recovery after 30 minutes of reperfusion was substantially improved
with HOE642: left ventricular developed pressure (in
percent of preischemic values) was 92±3 versus
49±7 and left ventricular end-diastolic
pressure was 16±3 versus 46±5 mm Hg (P<0.05 for
HOE642-treated versus untreated hearts). End-ischemic
[Ca2+]i was significantly lower in
HOE642-treated than in untreated hearts (1.04±0.06 versus
1.84±0.02 µmol/L, P<0.05). Maximal
intracellular Ca2+ overload during the first 60 seconds of
reperfusion was attenuated with HOE642 compared with untreated hearts:
2.0±0.3 versus 3.2±0.3 µmol/L (P<0.05).
pHi was not different at end ischemia
(
5.9±0.05). Realkalinization was similar in the first 90 seconds of
reperfusion and significantly delayed in the next 3 minutes (eg,
6.8±0.07 in HOE642-treated hearts compared with 7.2±0.07 in untreated
hearts; P<0.05).
Conclusions—HOE642 improves postischemic recovery by reducing Ca2+ overload during ischemia and early reperfusion and by prolonging postischemic acidosis.
Key Words: stunning, myocardial • myocardium • calcium • reperfusion
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