Effects of JTV‐506, a new K+ channel activator, on airway smooth muscle contraction and systemic blood pressure

Abstract

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. 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. 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 micrograms/kg of histamine in a dose-dependent manner. 10 micrograms/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. 10 micrograms/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 +/- 3.5 micrograms/kg and 60.1 +/- 15.8 micrograms/kg, respectively (P < 0.05). Cromakalim was approximately 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 10 micrograms/kg iv) was 11.3% and 21.5%, respectively (P < 0.05). 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.