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Cardioprotective Effects of KB-R7943, a Na+/Ca2+ Exchanger Inhibitor, on Stunned Myocardium in Dogs
Osamu Yoshitomi, M.D.; Tetsuya Hara, M.D.; Sungsam Cho, M.D.; Shiro Tomiyasu, M.D.; Koji Sumikawa, M.D.
Anesthesiology, Nagasaki University School of Medicine, Nagasaki, Japan
The Na+/Ca2+ exchanger (NCX) is one of the essential regulators of Ca2+ homeostasis in cardiomyocytes and an important modulator of the cardiac contractile function. The primary function of forward mode of NCX in the heart is extrusion of Ca2+ from myocytes during cardiac relaxation and diastole, whereas activation of the reverse mode of NCX induces Ca2+ overload during ischemia-reperfusion. Intracellular Ca2+ overload is thought to be one of the major causes of ischemia-reperfusion injury. KB-R7943 (KBR) has been reported to selectively inhibit the reverse mode of NCX. However, the effects on the contractile function of stunned myocardium in vivo have not been clarified. We investigated the cardioprotective effects of KBR on stunned myocardium in dogs.

Methods: All experimental procedures used in this investigation were approved by Institutional Animal Care Committee. Fifteen mongrel dogs were anesthetized with alpha-chloralose and fentanyl, and acutely instrumented for measurements of systemic and coronary hemodynamics. The dogs were allocated to one of three groups (n=5 for each group). Each group received drug vehicle (group C), high-dose KBR (10 mg/kg; group H) or low-dose KBR (5 mg/kg; group L). Stunned myocardium was produced by 15-min occlusion of left anterior descending coronary artery (LAD) and 90-min reperfusion in all dogs. KBR was administered by an intravenous injection at 15 min before LAD occlusion. Regional myocardial contractility was evaluated with segment shortening (%SS). Measurements were made before and during LAD occlusion and after LAD reperfusion. Statistical analysis was made by ANOVA followed by Scheffe's test. P < 0.05 was considered significant.

Results: There were no significant differences in demographic data among groups. In group C, %SS 90 min after reperfusion was 32.4 ± 2.4 % of baseline value. In group H, %SS showed an improved recovery compared to group C and the value 90 min after reperfusion was 70.3 ± 4.1 % of baseline value. In group L, %SS was similar to group C and the value 90 min after reperfusion was 35.6 ± 10.2 %. There were no significant differences in coronary blood flow among groups.

Conclusions: Preischemic administration of KBR improves myocardial contractile dysfunction after ischemia-reperfusion in a dose-dependent manner, and has no effect on coronary and systemic hemodynamics in dogs.

Anesthesiology 2002; 96: A600