S(+)-ketamine, but not R(-)-ketamine, reduces postischemic adherence of neutrophils in the coronary system of isolated guinea pig hearts

Polymorphonuclear neutrophils (PMN) play a crucial role in the initiation o f reperfusion injury. In a previous study, we found that ketamine reduced t he postischemic adherence of PMN to the intact coronary system of isolated guinea pig hearts. Because ketamine is a racemic mixture (1:1) of two optic al enantiomers, we looked for possible differences in action between the st ereoisomers. Seventy-six guinea pig hearts were perfused in the "Langendorf f" mode under conditions of constant flow (5 mL/min) using modified Krebs-H enseleit buffer. After 15 min of global warm ischemia, freshly isolated hum an PMN (10(6)) were infused as a bolus into the coronary system during the second minute of reperfusion. PMN adhesion was expressed as the numeric dif ference between PMN recovered in the effluent and those applied. Series A h earts received 5 mu MS(+), 5 mu M R(-), or 10 mu M racemic ketamine startin g 20 min before ischemia and during reperfusion. in Series B hearts, 10 mu M nitro-L-arginine, an inhibitor of NO synthase, was added to the perfusate . Ln Series C, PMN were preincubated for 15 min with 5 mu M S(+)- or R(-)ke tamine. Coronary vascular leak was assessed by measuring the rate of format ion of transudate on the epicardial surface. Ischemia/reperfusion without a nesthetics increased coronary PMN adherence from 25.5% +/- 2.3% (basal) to 35.3% +/- 1.5% of the number applied. S(+)-ketamine reduced postischemic ad herence in each series (A, 25.5% +/- 5.1%; B, 22.5% +/- 1.7%; C, 25.3% +/- 7.7%), as did racemate (A, 26.4% +/- 3.7%). Although 5 mu M R(-)-ketamine h ad no effect on adhesion (A, 30.5% +/- 6.7%; B, 34.3% +/- 5.1%; C, 34.3% +/ - 4.3%), it significantly increased vascular leak in the presence of NOLAG. These findings indicate stereoselective differences in biological action b etween the two ketamine isomers: S(+)-ketamine inhibited PMN adherence, R(- )-ketamine worsened coronary vascular leak in reperfused isolated hearts. I mplications: Ln this study, we demonstrated stereoselective differences in the biologic action of the two ketamine isomers in an animal model of myoca rdial ischemia. Polymorphonuclear neutrophil adherence to the coronary vasc ulature after ischemia was inhibited by S(+)-ketamine, whereas R(-)-ketamin e increased coronary vascular fluid leak.