The effects of Na movement on surgical myocardial protection: the role of the Na+-H+ exchange system and Na-channel in the development of ischemia and reperfusion injury.
OBJECTIVE
We investigated whether the Na+-H+ exchange inhibitor, HOE642 (Hoe), and/or the Na channel blocker, mexiletine (Mex), enhance a cardioprotective effect on St. Thomas' Hospital cardioplegic solution (STS) to clarify the mechanism by which intracellular Na+ is accumulated after cardioplegic arrest.


METHODS
Isolated working rat hearts were perfused with Krebs-Henseleit bicarbonate buffer (KHBB). The hearts were then arrested with STS and subjected to normothermic global ischemia (30 min). This was followed by Langendorff reperfusion (15 min) and then a working reperfusion (20 min). In study A, we added Hoe (5, 10, and 20 microM), Mex (70 microM), or a combination of Hoe (20 microM) and Mex (70 microM), to STS. In study B, we added Hoe (20 microM), Mex (70 microM), or a combination of Hoe (20 microM) and Mex (70 microM) to KHBB during the first 3 min of Langendorff reperfusion.


RESULTS
In study A, the addition of Hoe (10 and 20 microM) to STS showed a significantly greater postischemic recovery of cardiac output compared to the control group [63.1+/-5.7% (10 microM), 62.7+/-4.7% (20 microM), and 55.5+/-4.6% (control), respectively]. The postischemic recovery of cardiac output was significantly greater in the group of the combined addition (Hoe and Mex) to STS than that in the control, 20 microM Hoe, 70 microM Mex groups [70.3+/-3.7 (Hoe and Mex), 55.5+/-4.6% (control), 62.7+/-4.7% (Hoe 20 microM), and 60.2+/-4.7% (Mex 70 microM), respectively]. The myocardial water content in the postischemic period was 565.1+/-29.1, 525.8+/-2.9, 509.4+/-19.6, and 532.2+/-20.1; it was 497.3+/-9.1 mL/100 g dry weight in the control; and 10 microM Hoe, 20 microM Hoe, and 70 microM Mex in the combined use groups. In study B, there was no significant difference in the postischemic recovery of cardiac output in all experimental groups.


CONCLUSIONS
The combined use of the Na+-H+ exchange inhibitor and Na+ channel blocker during cardioplegia may achieve a superior cardioprotective effect on myocardial damage because of ischemia and reperfusion.
Liu
Ke-Xiang
KX
Department of Cardiovascular Surgery, The Second Clinical Hospital, Jilin University, Changchun, China.
Yamamoto
Fumio
F
Yamamoto
Hiroshi
H
Wang
Tiance
T
Zhu
Zhicheng
Z
Xu
Rihao
R
Zhang
Shudong
S
D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D002314:Cardioplegic Solutions / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006324:Heart Arrest, Induced / Q000379:methods; D008297:Male; D008801:Mexiletine / Q000494:pharmacology*; D017202:Myocardial Ischemia / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D012965:Sodium Chloride / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D002314:Cardioplegic Solutions; D006146:Guanidines; D015222:Sodium Channels; D013450:Sulfones; D008801:Mexiletine; D012965:Sodium Chloride; C093373:cariporide