THE RELAXANT EFFECT OF KETAMINE ON GUINEA-PIG AIRWAY SMOOTH-MUSCLE ISEPITHELIUM-INDEPENDENT

Airway epithelial cells and vascular endothelial cells modulate the to ne of the underlying smooth muscle by releasing relaxing factors such as prostanoids and nitric oxide (NO). Ln the present study, we investi gated whether the relaxant effect of ketamine depends on any of the ep ithelium-derived relaxing factors. Tracheae of female guinea pigs were cut spirally into strips (15 x 3 nun) and mounted in water-jacketed o rgan baths filled with Krebs-bicarbonate buffer aerated with a mixture of 95% O-2 and 5% CO2 at 37 degrees C. Changes in the tension of the strips were measured isometrically with a force displacement transduce r and recorded with a polygraph. In the first set of experiments, we e xamined the effect of ketamine on the concentration-response curves fo r histamine and carbachol in strips in which the epithelium was kept i ntact and in strips with denuded epithelium. In the second and third s et of experiments, we studied the effect of indomethacin, a cyclooxyge nase inhibitor, and N-omega-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, on the relaxant activity of ketamine on trachea l strips contracted by histamine or carbachol. The following results w ere obtained: 1. Mechanical denudation of the tracheal epithelium shif ted the concentration-response curve for histamine to the left (the 50 % effective concentration [EC(50)] value of histamine decreased from 3 .5 +/- 0.02 x 10(-6) M in the intact strips to 0.98 +/- 0.01 x 10(-6) nr in denuded strips, P < 0.001). However, removal of the tracheal epi thelium did not change the response to carbachol (the EC(50) for carba chol was 1.1 +/- 0.02 x 10(-7) M in intact strips versus 0.88 +/- 0.01 x 10(-7) M after epithelial removal, P > 0.05). 2. Ketamine shifted t o the right the concentration-response curves for histamine and carbac hol in both intact and denuded tracheae. 3. Indomethacin did not alter the relaxant effect of ketamine on the tracheae contracted by either histamine (the concentration that inhibits 50% [IC50] of ketamine = 1. 5 +/- 0.01 x 10(-3) M in control strips and 1.3 +/- 0.04 x 10(-3) M in strips pretreated with indomethacin, P > 0.05) or carbachol (the IC50 of ketamine was 2.5 +/- 0.02 x 10(-4) M in control strips and 2.4 +/- 0.01 x 10(-4) M in strips pretreated with indomethacin, P > 0.05). 4. L-NAME did not influence the relaxant effect of ketamine on tracheae contracted by either histamine (the IC50 of ketamine = 1.6 +/- 0.05 x 10(-3) M in control strips and 1.6 +/- 0.05 x 10(-3) M in strips pretr eated with L-NAME, P > 0.05) or carbachol (the IC50 of ketamine = 2.6 +/- 0.04 x 10(-4) M in control strips and 2.3 +/- 0.01 x 10(-4) M in t rips pretreated with L-NAME, P > 0.05). These results indicate that ne ither the mechanical removal of the tracheal epithelium nor the blocka de of the release of potent mediators from tracheal epithelial cells i nfluence the relaxant effect of ketamine on guinea pig tracheal strips contracted by histamine or carbachol. We conclude that ketamine relax es the airway smooth muscle by an epithelium-independent mechanism.