Celikalim (WAY-120491) increases K+ outward flux in dog and human airway smooth muscle.
The ability of the potassium channel opener celikalim (WAY-120491) to increase potassium conductance in airway smooth muscle cells was investigated. The rate of 86Rb+ efflux was measured from dog trachealis muscle strips and human trachealis smooth muscle cells in culture. Whole-cell currents were recorded from dog trachealis smooth muscle cells freshly dissociated using the nystatin-perforated patch technique. Celikalim (1-10 microM) enhanced the rate of 86Rb+ efflux from dog airway smooth muscle in a concentration-dependent manner. At 1 microM, the rate of 86Rb+ efflux was enhanced by 25% in human airway smooth muscle cells. In current recordings, celikalim (1 microM) elicited a glyburide-sensitive outward current, increasing the steady-state current from 367 +/- 20 pA to 688 +/- 172 pA at +20 mV (n = 5). At -60 mV, a voltage closer to the resting potential, the holding current was increased by only +26 +/- 15 pA (n = 5). This smaller increase was sufficient to hyperpolarize the membrane by 8 mV. These results indicate that celikalim is a potent potassium channel opener in dog and human airway smooth muscles. The present data support the hypothesis that an increase in resting K+ conductance by potassium channel openers may account for their relaxing effect in airway smooth muscles.
de Lorenzi
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Wyeth-Ayerst Research, Cardiovascular and Metabolic Disorders Division, Princeton, New Jersey 08543.
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004285:Dogs; D004558:Electric Stimulation; D005071:Evoked Potentials; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D012414:Rubidium Radioisotopes; D014132:Trachea / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D000959:Antihypertensive Agents; D001578:Benzopyrans; D007211:Indoles; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; C067406:WAY 120491