Characterization of sulfonylurea receptors and the action of potassium channel openers on cholinergic neurotransmission in guinea pig isolated small intestine

S. Zini, Y. Ben-Ari, M. L. Ashford

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    38 Citations (Scopus)


    Specific binding sites for [3H]glibenclamide, a potent ATP-sensitive K+ channel blocker, have been characterized in the isolated guinea pig longitudinal muscle-myenteric plexus preparation. The Scatchard plot of the saturation isotherm was curvilinear and revealed two binding sites, one of high affinity (Kd = 0.42 nM; maximum binding site = 156 fmol/mg of protein), the other of low affinity (Kd = 83 nM; maximum binding site = 3100 fmol/mg of protein). Displacement experiments in the presence of various sulfonylureas showed the same order of potency for the two binding sites (glibenclamide greater than gliquidone greater than glipizide glibornuride greater than chlorpropamide greater than tolbutamide). The K+ channel opener RP 49356 (but not diazoxide or cromakalim) displaced the [3H] glibenclamide with an IC50 of 4.8 microM. The effects of the K+ channel openers diazoxide, RP 49356, cromakalim and its two optical isomers BRL 38226 and BRL 38227 were also studied on the electrically induced contractions of isolated guinea pig small intestine. These compounds produce an inhibition of neurally evoked twitch height with pD2 values of 4.5 to 6.2 (BRL 38227 greater than cromakalim greater than RP 49356 greater than diazoxide, whereas BRL 38226 was practically ineffective). The effects of cromakalim and RP 49356 were antagonized competitively by glibenclamide (pA2 = 7.2) and other sulfonylureas, suggesting they act on ATP-sensitive K+ channels. Affinities of the sulfonylureas obtained from concentration-response curves to cromakalim on electrically induced contractions are better correlated with the IC50 value corresponding to the low affinity binding site than to the high affinity.(ABSTRACT TRUNCATED AT 250 WORDS)
    Original languageEnglish
    Pages (from-to)566-573
    Number of pages8
    JournalJournal of Pharmacology and Experimental Therapeutics
    Issue number2
    Publication statusPublished - 1991


    • Glyburide
    • Animals
    • Choline
    • Benzopyrans
    • Guinea Pigs
    • Cromakalim
    • Pyrroles
    • Electric Stimulation
    • Potassium Channels
    • Myenteric Plexus
    • Receptors, Drug
    • Pyrans
    • Muscle, Smooth
    • Tritium
    • Kinetics
    • Potassium Channels, Inwardly Rectifying
    • Picolines
    • Intestine, Small
    • ATP-Binding Cassette Transporters
    • Adenosine Triphosphate
    • Muscle Contraction
    • Synaptic Transmission
    • Male


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