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Aging Reduces the Cardioprotective Effect of Isoflurane-Induced Preconditioning in the Isolated Rat Hearts
Takeshi Oguchi, M.D., Ph.D., Satoshi Kashimoto, M.D., Ph.D., Kenichi Masui, M.D., Tadahiko Ishiyama, M.D., Ph.D., Teruo Kumazawa, M.D., Ph.D.
Anesthesiology, University of Yamanashi, Faculty of Medicine, Tamaho-cho, Yamanashi, Japan.
Introduction: Aging has been reported to reduce the effectiveness of ischemic preconditioning in providing cardioprotection against ischemic-induced myocardial necrosis (1). Isoflurane mimics ischemic preconditioning and protect ischemic myocardium against stunning and infarction. Therefore, we have hypothesized that aging reduces the efficacy of isoflurane-induced preconditioning in the ischemic isolated rat hearts. This study was also designed to assess intracellular calcium ([Ca2+]i) dynamics and oxygen free radical production during reperfusion.

Methods: After Animal Investigation Committee approval, hearts were excised from young (6 weeks), adult (9 weeks), and aged (>60 weeks) rats under pentobarbital anesthesia (each: n=16). The hearts were perfused with a Langendorff system at constant pressure (55 mmHg) and loaded with Fura-2/AM, as a [Ca2+]i marker. Surface fluorescence of the heart was recorded with an intracellular ion analyzer (CAF-110, Japan Spectroscopic Co.Ltd.). The [Ca2+]i was estimated by determining the ratio of the emission at 500 nm during excitation at 340 nm to the emission at 500 nm during excitation at 380 nm (the Fura-2/AM-dependent fluorescent ratio). After loading and washout of Fura-2/AM, young, adult, and aged hearts were randomly assigned to control or isoflurane-preconditioning groups (each group: n=8). In the isoflurane groups, isoflurane was administered for 8 min, followed by washout for 5 min. Afterwards, no-flow ischemia was induced for 10 min, followed by reperfusion for 20 min. The formation of hydroxyl radicals in the coronary effluent was measured with high performance liquid chromatography using salicylic acid. Data were presented as mean±S.D.

Results: All hearts presented ventricular arrhythmia (ventricular fibrillation and/or ventricular tachycardia) during reperfusion. Preconditioning with isoflurane reduced the duration of ventricular arrhythmia in young hearts. However, in adult and aged hearts, the preconditioning did not shorten arrhythmia. During reperfusion, increases in myocardial [Ca2+]i were observed in all groups. In the absence of preconditioning, diastolic [Ca2+]i at 20 min of reperfusion in young, adult, aged hearts were 1.07±0.35, 1.14±0.22, and 0.80±0.20, respectively. Preconditioning with isoflurane significantly reduced the increase in diastolic [Ca2+]i only in young hearts (0.79±0.19 at 20 min of reperfusion). Total DHBAs in the coronary effluent that indicated oxygen free radical production increased significantly 5 min after reperfusion in all groups. However, the preconditioning with isoflurane did not depress the increases in total DHBAs in all group.

Conclusions: The present data suggest that aging reduces the effectiveness of anesthetic preconditioning in providing cardioprotection against ventricular arrhythmia during reperfusion, which may be associated with myocardial [Ca2+]i dynamics during reperfusion. The administration of isoflurane prior to ischemia did not affect hydroxyl radicals production.


1. J Mol Cell 32, 7 : 1371-5, 2000

Anesthesiology 2003; 99: A688