Effects of Ketamine and Its Isomers on Ischemic Preconditioning.Molojavyi et al. and Mullenheim et al.(page 623) and (page 630)
Ischemic preconditioning, in which brief periods of myocardial ischemia followed by reperfusion provide protection from subsequent ischemic injury, has been shown to occur in animals as well as humans. Current evidence suggests that opening of the adenosine triphosphate–sensitive potassium channel is a key mechanism. Based on this evidence and the finding of a concentration-dependent inhibitory effect of ketamine on adenosine triphosphate–sensitive potassium channel activity, two research teams from the same institution investigated the effects of ketamine and its stereoisomers on preconditioning in animal models.
In the first study, Molojavyi et al. subjected 80 isolated rat hearts to 30 min of no-flow ischemia followed by 60 min of reperfusion. The hearts were assigned randomly to one of 10 groups: two groups of eight hearts received no preconditioning stimulus before undergoing the study protocol; in another group of eight hearts, preconditioning was elicited by two 5-min periods of ischemia before the 30-min ischemic period. In six treatment groups, ketamine, R (−)-ketamine, or S (+)-ketamine were administered at concentrations of 2 or 20 μg/ml before the preconditioning stimulus. A final group of eight hearts received 20 μg/ml R (−)-ketamine before ischemia. Left ventricular (LV) end-diastole pressure, LV developed pressure, and maximum and minimum dP/dt were obtained from digitized signals and later processed on a personal computer. LV end-diastole was determined as the point at which dP/dt started its rapid upstroke after crossing the zero line.
Baseline LV developed pressure was similar in all groups of hearts. Those hearts in the control groups showed the poorest recovery of LV developed pressure, as well as a high creatine kinase release (evidence of cellular injury) after ischemia. Preconditioning improved recovery of LV developed pressure and reduced creatine kinase release. Administration of 2 μg/ml ketamine or 2 or 20 μg/ml S (+)-ketamine did not influence recovery of LV developed pressure. After 20 μg/ml ketamine or 2 or 20 μg/ml R (−) ketamine, the protective effects of preconditioning were abolished.
In vivo , the pathophysiology of preconditioning and ischemia–reperfusion injury is more complex. Accordingly, Mullenheim et al. investigated the effects of ketamine and S (+)-ketamine on preconditioning in rabbit hearts in vivo . Forty-eight male New Zealand white rabbits were anesthetized with α-chloralose and instrumented for measurement of left ventricular pressure, cardiac output, and myocardial infarct size. Rabbits were assigned to one of five groups: a control group of 10 rabbits that received no pretreatment or conditioning before ischemia; a preconditioning group (n = 10) that underwent 30 min of coronary artery occlusion followed by 60 min of reperfusion; a group to which either 10 mg/kg ketamine (n = 9) or 10 mg/kg S (+)-ketamine (n = 8) was administered before preconditioning; and a final group of nine rabbits to which only 10 mg/kg−2ketamine was administered before ischemia. Two rabbits died during coronary artery occlusion, so the researchers were able to evaluate a total of 46 rabbits for analysis.
All rabbits underwent 30 min of coronary occlusion, during which left ventricular pressure was reduced to 83 ± 14% of baseline values, and cardiac output was reduced to 84 ± 19% of baseline values. Functional recovery after 2 h of reperfusion did not differ significantly among groups. Infarct size (assessed by triphenyltetrazolium staining) was reduced from 45 ± 16% of the area at risk in controls to 24 ± 17% in the preconditioning group. Administration of ketamine had no effect on infarct size in animals without preconditioning but abolished the cardioprotective effects of preconditioning. S (+)-ketamine, however, had no effect, so the researchers conclude that the influence of ketamine on ischemic preconditioning is most likely enantiomer specific.