ATP-sensitive potassium channels and skeletal muscle function in vitro.
Compounds that act at ATP-modulated potassium channels (KATP) were tested in an in vitro model of skeletal muscle ischemia. The extensor digitorum longus muscles were removed from anesthetized rats and placed in tissue baths, and contractions were elicited by electrical field stimulation at 0.2 Hz. During normoxia, the force of contraction gradually decayed to about 55% of the peak over 85 min. None of the KATP openers tested, cromakalim (300 microM), P-1075 (10 microM) and pinacidil (100 microM), affected twitch force during normoxia. However, when the muscles were made anoxic, all three compounds greatly accelerated the loss of function in a concentration-related manner. For example, the cromakalim/vehicle ratios of the area under the force-time curve during anoxia were 0.98 +/- 0.03, 0.77* +/- 0.03 and 0.72* +/- 0.04 for cromakalim at 30, 100 and 300 microM, respectively (*P < .05). Upon reoxygenation, muscles treated with the KATP openers recovered twitch force to a greater extent than those treated with vehicle. Glyburide (1 or 10 microM) had no effect on its own, but it was able to prevent fully the effects of KATP openers during both anoxia and reoxygenation, indicating that the effects of the KATP openers were mediated by KATP. These results suggest that KATP openers would not be beneficial in the treatment of skeletal muscle ischemia in vivo but that they may be useful in preserving skeletal muscle function in cases of ischemia followed by reperfusion.
Weselcouch
E O
EO
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
Sargent
C
C
Wilde
M W
MW
Smith
M A
MA
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D004558:Electric Stimulation; D004734:Energy Metabolism / Q000187:drug effects; D005703:Gallamine Triethiodide / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D066298:In Vitro Techniques; D007511:Ischemia / Q000188:drug therapy; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000098:blood supply / Q000187:drug effects*; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011725:Pyridines; D011758:Pyrroles; D019806:Cromakalim; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D020110:Pinacidil; D005703:Gallamine Triethiodide; D005905:Glyburide