ACTION OF A NOVEL POTASSIUM CHANNEL OPENER, SR-47063, ON HUMAN BRONCHI AND ON GUINEA-PIG TRACHEA INVITRO - COMPARISON WITH CROMAKALIM

Potassium channels are present on airway smooth muscle cells and their activation results in hyperpolarization and relaxation. Because these effects may have therapeutic relevance to asthma, the aim of our stud y was to examine the activity of SR 47063, a potassium channel opener (KCO), against a variety of spasmogens or against electrical field sti mulation in guinea-pig isolated trachea and in human isolated bronchi in vitro; the effects of SR 47063 were compared with those of cromakal im, isoprenaline, and theophylline. Like cromakalim, SR 47063 reduced the contractility of guinea-pig isolated trachea and the human isolate d bronchus in basal tone with pD2 of 7.79 +/-0.01 and 7.83 +/- 0.09, r espectively, or during precontractions induced by acetylcholine 10(-4) M, histamine 10(-5) M, or low concentrations of KCl (<30 mM), but not by high KCl concentrations (greater-than-or-equal-to 30 mM); these ef fects were antagonized by glibenclamide 10(-5) M. This spectrum of act ion is typical of the compounds known as potassium channel openers. El ectrical field stimulation (EFS: 16 Hz, 1 ms, 320 mA for 10 sec in the presence of indomethacin 10(-6) M and propranolol 10(-6) M) of guinea -pig isolated main bronchi induced 2 successive contractile responses. Both contractions were reduced significantly by SR 47063 and cromakal im. Although we have not studied the effects of KCOs on exogenous neur okinin A- or substance P-induced contractions, it might be suggested a s a hypothesis that this inhibition seems to take place presynapticall y and to affect the release of neuromediators produced by electrical f ield stimulation. In conclusion, SR 47063 exerts in vitro on the bronc hial smooth muscle an inhibitory effect which seems to be due to the o pening of glibenclamide-sensitive potassium channels. SR 47063 is 3- t o 10-fold more potent than cromakalim.