Effects of ketamine and its isomers on ischemic preconditioning in the isolated rat heart

Abstract

Background: Ischemic preconditioning protects the heart against subsequent ischemia. Opening of the adenosine triphosphate-sensitive potassium (KATP) channel is a key mechanism of preconditioning. Ketamine blocks KATP channels of isolated cardiomyocytes. The authors investigated the effects of ketamine and its stereoisomers on preconditioning. Methods: Isolated rat hearts (n = 80) underwent 30 min of no-flow ischemia and 60 min of reperfusion. Two groups with eight hearts each underwent the protocol without intervention (control-1 and control-2), and, in eight hearts, preconditioning was elicited by two 5-min periods of ischemia before the 30 min ischemia. In the six treatment groups (each n = 8), ketamine, R(-)- or S(+)-ketamine were administered at concentrations of 2 or 20 μg/ml before preconditioning. Eight hearts received 20 μg/ml R(-)-ketamine before ischemia. Left ventricular (LV) developed pressure and creatine kinase (CK) release during reperfusion were determined as variables of ventricular function and cellular injury. Results: Baseline LV developed pressure was similar in all groups: 104 ± 28 mmHg (mean ± SD). Controls showed a poor recovery of LV developed pressure (17 ± 8% of baseline) and a high CK release (70 ± 17 IU/g). Ischemic preconditioning improved recovery of LV developed pressure (46 ± 14%) and reduced CK release (47 ± 17 IU/g, both P < 0.05 vs. control-1). Ketamine (2 μg/ml) and 2 or 20 μg/ml S(+)-ketamine had no influence on recovery of LV developed pressure compared with preconditioning (47 ± 18, 43 ± 8, 49 ± 36%) and CK release (39 ± 8, 30 ± 14, 41 ± 25 IU/g). After administration of 20 μg/ml ketamine and 2 or 20 μg/ml R(-)-ketamine, the protective effects of preconditioning were abolished (LV developed pressure-recovery, 16 ± 14, 22 ± 21, 18 ± 11%; CK release, 67 ± 11, 80 ± 21, 82 ± 41 IU/g; each P < 0.05 vs. preconditioning). Preischemic treatment with R(-)-ketamine had no effect on CK release (74 ± 8 vs. 69 ± 9 IU/g in control-2, P = 0.6) and functional recovery (LV developed pressure 12 ± 4 vs. 9 ± 2 mmHg in control-2, P = 0.5). Conclusion: Ketamine can block the cardioprotective effects of ischemic preconditioning. This effect is caused by the R(-)-isomer.