Background ATP-sensitive K+ (KATP) channel activators produce relaxation of smooth muscle in many tissues. However, this wide range of effects restricts their clinical usefulness in bronchial asthma because of a reduction in systemic blood pressure.
Methods We have now examined the effects of JTV-506, a new benzopyran derivative, on airway smooth muscle contraction and systemic blood pressure and have compared this compound with cromakalim. We measured isometric tension records from guinea-pig isolated trachea, as well as the respiratory resistance (Rrs) and systemic blood pressure in anesthetized guinea-pigs.
Results JTV-506 caused a concentration-dependent inhibition of histamine-induced contraction in guinea-pig isolated tracheal smooth muscle, and was antagonized by glibenclamide. JTV-506 was 7.6-fold more potent than cromakalim. In anesthetized animals the intravenous injection of JTV-506 reduced the increase in Rrs induced by intravenous application of 5 μg/kg of histamine in a dose-dependent manner, 10μ/kg of JTV-506 resulted in 57.0 17.9% inhibition of the increase in Rrs at 10 min. The inhibitory action on Rrs disappeared after 60 min. 10μg/kg of cromakalim caused 25.4 ± 5.8% inhibition of the increase in Rrs induced by histamine at 1 min. The ED50 values for JTV-506 and cromakalim were 6.7 ± 3.5μg/kg and 60.1 ± 15.8μg/kg, respectively (P<0.05). Cromakalim was ± 9-fold less potent in inhibiting the increased Rrs by histamine. and the inhibitory action lasted less than 10 min. The reduction of systemic blood pressure by JTV-506 and cromakalim (each at a dose of 10μg/kg iv) was 11.3% and 21.5%, respectively
Conclusion JTV-506 inhibits histamine-induced contraction of tracheal smooth muscle by activation of KATP channels. This compound is more potent and longer-lasting in the suppression of histamine-induced increases in Rrs, and is less hypotensive than cromakalim. Our results suggest that this compound merits further investigation for utility as a bronchodilator in the clinic.
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