Ketamine inhibits contractile responses of intestinal smooth muscle by decreasing the influx of calcium through the L‐type calcium channel

During the inflammatory response, tissues release histamine (H), substance P, serotonin (5-HT) prostaglandins and kinins, agents that mediate manifestations of inflammation such as pain, vasodilatation, increased capillary permeability and smooth muscle contraction. In this study we investigated whether racemic (R[+]) ketamine (K) and its isomers are spasmolytic on intestinal smooth muscle contracted by inflammatory mediators, and whether the spasmolytic effect of K is related to changes in calcium influx through the L-type calcium channel or to an interaction of K with opioid receptors. We measured the contractions of guinea-pig ileum mounted in an organ bath containing Tyrode's solution gassed with 95% O 2 /5% CO 2 at 37°C. In the first protocol we determined the effect of K and its isomers on contractions induced by five mediators : 10 -7 M H, 10 -8 M substance P, 10 -8 M neurokinin A, 5 X 10 -9 M bradykinin and 5 X 10 -7 M 5-HT. For each of these mediators, we plotted concentration-response curves for the inhibitory effect of K, and from regression fitting of these curves we calculated the IC 50 (concentration of K that inhibited the contraction by 50%). In the second protocol we measured the contraction induced by the calcium ionophore A23187 (5.0X10 -6 M), both alone and after 1.8-7.2 X10 -4 M R(±)K. Then we examined how the inhibition caused by R(±)K was affected by increases in the concentration of extracellular calcium by adding calcium (1.8-7.2 X 10 -3 M). To study whether the L-type calcium channel opener Si(-)Bay K8644 or naloxone reverse the spasmolytic effect of K, we added 7.2X10 -4 M (R(±)K to the bath, followed by S(-)Bay K8644 (2.5X10 -8 -2 X 10 -7 M) or naloxone (10 -8 - 3X 10 -6 M), and the response to H was elicited again. R(±)K and its isomers inhibited the contraction of the ileum induced by all of the agents tested. No significant differences in the inhibitory potency were found among the three forms of K. Naloxone, on the contrary, did not affect the relaxant effect of K. The calcium ionophore A23187 produced ileum contractions that were effectively blocked by K. The calculated IC 50 of K on histamine-induced contractions was 4.7±0.7X10 -4 M with 1.8X10 -3 M calcium ; this IC 50 increased significantly to 6.8±0.8X10 -4 M when calcium rose to 7.2X10 -3 M, P<0.01. The L-type calcium channel opener S(-)Bay, K8644 given after K, effectively restored the response of the muscle to H again in a dose-dependent manner. K and its isomers have equipotent inhibitory effect on ileum contraction induced by all the inflammatory mediators tested. This relaxant effect of K is related not to an interaction of K with opioid receptors but to changes in calcium influx through the L-type calcium channel.