Effects of Ketamine and Its Isomers on Ischemic Preconditioning in the Isolated Rat Heart

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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 microg/ml before preconditioning. Eight hearts received 20 microg/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 microg/ml) and 2 or 20 microg/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 microg/ml ketamine and 2 or 20 microg/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.