Na(+)/H(+) exchange inhibition with HOE642 improves postischemic recovery due to attenuation of Ca(2+) overload and...

Area of Science:

• Cardiology
• Cardiovascular Physiology
• Biochemistry

Background:

• Na(+)/H(+) exchange inhibition using cariporide (HOE642) shows potential for improving postischemic cardiac recovery.
• Mechanisms are speculative, but inhibition may delay realkalinization and reduce intracellular Na(+) and Ca(2+) overload, leading to cardioprotection.

Purpose of the Study:

• To investigate the mechanisms by which Na(+)/H(+) exchange inhibition with HOE642 improves postischemic cardiac function.
• To determine if HOE642 attenuates Ca(2+) overload and prolongs acidosis during reperfusion.

Main Methods:

• Isolated buffer-perfused rat hearts underwent 30 minutes of ischemia and 30 minutes of reperfusion with or without 1 micromol/L HOE642.
• Intracellular Ca(2+) concentration ([Ca(2+)](i)) and pH(i) were measured using aequorin and (31)P NMR spectroscopy, respectively.

Main Results:

• HOE642 significantly improved mechanical recovery post-reperfusion (left ventricular developed pressure: 92% vs. 49%).
• End-ischemic [Ca(2+)](i) was lower in HOE642-treated hearts (1.04 vs. 1.84 µmol/L).
• Maximal Ca(2+) overload during early reperfusion was attenuated (2.0 vs. 3.2 µmol/L), and realkalinization was significantly delayed.

Conclusions:

• HOE642 improves postischemic cardiac recovery by reducing Ca(2+) overload during ischemia and early reperfusion.
• Prolonged postischemic acidosis, mediated by HOE642, contributes to its cardioprotective effects.