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Characterization of K ATP channels in intact mammalian skeletal muscle fibres
Author(s) -
BarrettJolley Richard,
McPherson Grant A.
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701727
Subject(s) - glibenclamide , pinacidil , tolbutamide , skeletal muscle , diazoxide , chemistry , biophysics , glipizide , potassium channel , biochemistry , medicine , endocrinology , biology , diabetes mellitus , insulin
1 The aim of this study was to characterize the K ATP channel of intact rat skeletal muscle (rat flexor digitorum brevis muscle). Changes in membrane currents were recorded with two‐electrode voltage‐clamp of whole fibres. 2 The K ATP channel openers, levcromakalim and pinacidil (10–400 μ M ), caused a concentration‐dependent increase in whole‐cell chord conductance (up to approximately 1.5 mScm −2 ). The activated current had a weak inwardly rectifying current‐voltage relation, a reversal potential near E K and nanomolar sensitivity to glibenclamide – characteristic of a K ATP channel current. Concentration‐effect analysis revealed that levcromakalim and pinacidil were not particularly potent (EC 50 ∼186 μ M , ∼30 μ M , respectively), but diazoxide was completely inactive. 3 The ability of both classical K ATP channel inhibitors (glibenclamide, tolbutamide, glipizide and 5‐hydroxydecanoic acid) and a number of structurally related glibenclamide analogues to antagonize the levcromakalim‐induced current was determined. Glibenclamide was the most potent compound with an IC 50 of approximately 5 n M . However, the non‐sulphonylurea (but cardioactive) compound 5‐hydroxydecanoic acid was inactive in this preparation. 4 Regression analysis showed that the glibenclamide analogues used have a similar rank order of potency to that observed previously in vascular smooth muscle and cerebral tissue. However, two compounds (glipizide and DK13) were found to have unexpectedly low potency in skeletal muscle. 5 These experiments revealed K ATP channels of skeletal muscle to be at least 10× more sensitive to glibenclamide than previously found; this may be because of the requirement for an intact intracellular environment for the full effect of sulphonylureas to be realised. Pharmacologically, K ATP channels of mammalian skeletal muscle appear to resemble most closely K ATP channels of cardiac myocytes.British Journal of Pharmacology (1998) 123 , 1103–1110; doi: 10.1038/sj.bjp.0701727