KETAMINE RELAXES AIRWAY SMOOTH-MUSCLE CONTRACTED BY ENDOTHELIN

Endothelins (ETs) are synthesized not only in vascular endothelial cel ls but also in airway epithelial cells. Increased ET-1 has been demons trated in bronchial epithelium of asthmatic patients, and, in severe a sthma attacks, ET-1 increases in plasma and bronchoalveolar lavage flu id. In this study, we investigated whether ketamine (KET) relaxes ET-i nduced tracheal contractions. Female guinea pigs were killed with an o verdose of pentobarbital. The trachea was removed and cut spirally int o two strips that were mounted in an organ bath filled with Krebs-bica rbonate buffer. The response of each strip to 10(-7) M carbachol was t aken as 100% contraction to which the response to ET was referred. The contribution of the epithelium to the relaxant effect of KET was stud ied in denuded tracheae or in the presence of 5 x 10(-5) M indomethaci n. ET-1 (3 x 10(-8) M) induced contractions that were 76 +/- 3% of tho se induced by carbachol. KET reversed the response to ET-1 in a dose-d ependent fashion. Similarly, ET-2 (3 x 10(-8) M) induced contractions that were 74 +/- 5% of those induced by carbachol, and KET also revers ed this response in a dose-dependent manner. In epithelium-denuded str ips, ET-1 induced contractions that were 104 +/- 3% of those induced b y carbachol, and KET still reversed this response. The tonic phase of the response to ET-1 was equal (100 +/- 6%) to the response to carbach ol, and KET did not affect it significantly. In the presence of ryanod ine, KET reduced the ET-1-induced contraction from 67 +/- 2% to 36 +/- 3.%, P < 0.01. In the presence of nicardipine, KET also inhibited the ET-1-induced contraction. We conclude that KET relaxes the tracheal s mooth muscle contracted by ETs via a mechanism that is independent of the tracheal epithelium. The relaxant effect of KET on the ET-induced contraction of the trachealis muscle is not dependent upon blockade of 1) sarcolemma influx of Ca2+ through the dihydropyridine Ca2+ channel or 2) the release of intracellular Ca2+ through the ryanodine-sensiti ve intracellular Ca2+ channel. It is likely that the action of KET rel axing ET-induced tracheal contractions is at some point of the inosito l 1,4,5-trisphosphate signaling pathway.