Hyperpolarization of denervated skeletal muscle by lemakalim and its antagonism by glybenclamide and tolbutamide.
Innervated skeletal muscles are endowed with K+ channels activatable by K+ channel openers. It is of interest to know whether the denervation-induced depolarization is due to a deficiency of such a K+ channel. In denervated mouse diaphragm, lemakalim, a K+ channel opener, effectively hyperpolarizes membrane and reduces membrane resistance, spontaneous activity as well as twitch force reversibly. Reductions of transmembrane K+ gradient diminish the lemakalim-induced hyperpolarization. In voltage-clamped fiber, lemakalim induces a long-lasting outward current. A current clamp experiment suggests a reversal potential of around -90 mV. On innervated diaphragm, lemakalim hyperpolarizes membrane and increases conductance if the muscle is predepolarized by anodal current. Lemakalim, however, is much less effective in overcoming the depolarization caused by crotamine, which activates Na+ channel. The effects of lemakalim are not attenuated by blockades of membrane Na+, Ca++ and Cl- permeabilities. Glybenclamide and tolbutamide, blockers of ATP-regulated K+ channel, antagonize the effects of lemakalim at low concentrations and produce slight membrane hyperpolarizations in denervated muscle, but marked membrane depolarizations in innervated muscle at higher concentrations. Cs+ depolarizes both innervated and denervated diaphragms and reduces the hyperpolarizing effect of lemakalim. The results suggest that lemakalim hyperpolarizes denervated muscle via glybenclamide sensitive K+ channels. It is inferred that a reduction of membrane K+ conductance rather than an increase of Na+ or Ca++ conductance contributes to the denervation-induced depolarization.
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei.
S J
SJ
Hong
C C
CC
Chang
D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002586:Cesium / Q000494:pharmacology; D019806:Cromakalim; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009121:Muscle Denervation; D009132:Muscles / Q000187:drug effects / Q000294:innervation* / Q000502:physiology; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology*
D001578:Benzopyrans; D002121:Calcium Channel Blockers; D011758:Pyrroles; D019806:Cromakalim; D002586:Cesium; D014044:Tolbutamide; D005905:Glyburide