Stereospecific effects of ketamine enantiomers on canine tracheal smooth muscle

Abstract

1. Ketamine is a potent bronchodilator which relaxes airway smooth muscle (ASM). Clinically, ketamine is used as a 1:1 racemic mixture of enantiomers that differ in their analgesic and anaesthetic effects. The aim of this study was to determine whether there was a difference between the enantiomers in their ability to relax isolated ASM and to explore mechanisms responsible for any observed differences.

2. Canine tracheal smooth muscle strips were loaded with fura-2 and mounted in a photometric system to measure simultaneously force and [Ca²⁺]_i. Calcium influx was estimated by use of a manganese quenching technique.

3. In strips stimulated with 0.1 μM ACh (EC₅₀) R(−)-ketamine (1–100 μM) caused a significantly greater concentration-dependent decrease in force (P<0.0001) and [Ca²⁺]_i than S(+)-ketamine (1–100 μM) (P<0.0005). In contrast, there was no significant difference between the enantiomers in their ability to inhibit calcium influx (45% decrease in influx rate for R(−)-ketamine and 44% for S(+)-ketamine, P=0.782). In strips contracted with 24 mM isotonic KCl (which activates voltage-operated calcium channels), the enantiomers modestly decreased force and [Ca²⁺]_i; there was no significant difference between the enantiomers in their effects on force (P=0.425) or [Ca²⁺]_i (P=0.604).

4. The R(−)-enantiomer of ketamine is a more potent relaxant of ACh-induced ASM contraction than the S(+)-enantiomer. This difference appears to be caused by differential actions on receptor-operated calcium channels.

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