RELAXANT EFFECT OF KETAMINE AND ITS ISOMERS ON HISTAMINE-INDUCED CONTRACTION OF TRACHEAL SMOOTH-MUSCLE

The mechanism by which racemic (R(+/-)) ketamine relaxes airway smooth muscle is unclear and there is no information on the differential eff ects of ketamine and its isomers. In this study, we have examined the spasmolytic effect of R(+/-) ketamine and its isomers S(+/-) and R(-) ketamine and the role of intracellular calcium and opioid receptors in R(+/-) ketamine-induced relaxation. The tension of isolated guinea pi g tracheal strips was measured isometrically with a force displacement transducer and contraction elicited with histamine 10(-5) mol litre(- 1). In histamine-preconstricted strips, the two ketamine isomers (4.5- 18.0 x 10(-4) mol litre(-1)) produced equipotent relaxation. A subthre shold dose of each isomer of ketamine (10(-4) mol litre(-1)) which alo ne did not relax histamine-induced contraction (S(+), P < 0.01; R(+/-) , P < 0.01; R(-), P < 0.05) significantly potentiated adrenaline 1.25- 5.0 x 10(-9) mot litre(-1)-induced relaxation (potency: S(+) > R(+/-)> R(-)). Increase in extracellular Ca2+ (1.8-14.4 x 10(-3) mol litre(-1 )) significantly reduced R(+/-) ketamine-induced relaxation. S(-) Bay K 8644, at concentrations up to 2.0 x 10(-6) mol litre(-1), partially antagonized R(+/-) ketamine-induced relaxation whereas at 10(-5) mot l itre(-1) or higher it potentiated the response. Naloxone 1.5-6.0 x 10( -6) mot litre(-1) did not affect the relaxation caused by R(+/-) ketam ine. We conclude that although both ketamine isomers produced equipote nt spasmolytic effects on airway smooth muscle precontracted with hist amine, they differed in their ability to potentiate the relaxing effec t of adrenaline. S(+) ketamine produced the greatest potentiation. Cha nges in intracellular Ca2+ level secondary to a reduction in the L-typ e Ca2+ current may partially mediate the spasmolytic effect of R(+/-) ketamine.