Ketamine Has Stereospecific Effects in the Isolated Perfused Guinea Pig Heart

Abstract

S(+)-Ketamine is judged to produce more potent anesthesia than either the racemate or the R(-) ketamine isomer because of differential activation of specific cerebral receptors. Other than central nervous system effects, the most important side effects of ketamine occur in the cardiovascular system. We examined the direct cardiac effects of the isomers and the racemate of ketamine in the isolated perfused guinea pig heart. Twenty-three guinea pig hearts were perfused by the Langendorff technique with modified 37 degrees C Krebs-Ringer's solution (97% oxygen and 3% carbon dioxide) at a constant perfusion pressure. Eight animals were pretreated with reserpine to deplete hearts of catecholamines. These pretreated hearts were also perfused with Krebs-Ringer's solution containing propranolol, phenoxybenzamine, and atropine to block any remaining effects of catecholamines and of acetylcholine. Five additional hearts were perfused with naloxone to block cardiac opioid receptors. Ten hearts were not treated. All 23 hearts were then exposed to four increasing equimolar concentrations of each isomer and the racemate of ketamine for 10 min. Heart rate, atrioventricular conduction time (AVCT), left ventricular pressure, coronary flow, and inflow and outflow oxygen tensions were measured. Percentage oxygen extraction, oxygen delivery, and oxygen consumption were calculated. Both isomers and the racemate caused a concentration-dependent depression of systolic left ventricular pressure and an increase in AVCT. In the untreated hearts, S(+)-ketamine decreased heart rate and left ventricular pressure and, at higher concentrations, oxygen consumption and percentage oxygen extraction significantly less than R(-)-ketamine independent of blocked or unblocked opioid receptors. Racemic ketamine depressed cardiac function to a degree intermediate to that produced by the isomers. Coronary flow and AVCT were equally affected by the isomers and by the racemic mixture. In the catecholamine-depleted hearts both isomers and the racemate caused equipotent depression of all variables. In these hearts cardiac depression was greater, and AVCT, coronary flow, and oxygen delivery were significantly greater than in untreated and opioid receptor-blocked hearts. Lesser cardiac depression by the S(+) isomer is attributable to an increased availability of catecholamines, because previous depletion of catecholamine stores and autonomic blockade completely inhibited these differences. The inability of cardiac tissue to reuptake released catecholamines into neuronal or extraneuronal sites during exposure to ketamine is stereoselective and caused predominantly by the S(+) isomer. Cardiac opioid receptors are apparently not involved in this phenomenon.