Glyburide actions on the dihydropyridine-sensitive Ca2+ channel in rat vascular muscle.
The effects of glyburide, a purportedly selective ATP-sensitive K+ channel antagonist, were studied on dihydropyridine (DHP)-sensitive (L-type) Ca2+ channel currents in rat aortic muscle cells. Whole-cell voltage-clamp Ba2+ currents (IBa) were recorded at a series of test potentials (VT) from -30 to +60 mV during 300-ms voltage steps from a holding potential of -80 mV. Bay k8644 (1 microM) increased peak divalent cation currents from 47.2 +/- 15.1 to 102.6 +/- 13.4 pA, and the current-voltage relationship curve was shifted 10 mV to the left (n = 5). The combination of 10 microM glyburide with 1 microM Bay k8644 further increased Bay k8644-enhanced IBa in each cell (average of 223.7 +/- 26.4 pA, n = 5), and caused a further 10 mV hyperpolarizing (leftward) shift of the activation curve. The kinetics of IBa were also changed (more rapid inactivation) by glyburide. These stimulatory actions of glyburide were reversed on washout. In contrast to this apparent synergism with Bay k8644, 10 microM glyburide alone inhibited (rather than potentiated) IBa by about 20% at VT of 0, +10, and +30 mV. Increasing glyburide concentration to 30 microM further inhibited the IBa to about 40-50% of controls. With the pure agonist isomer, 0.5 microM Bay R5417, at theoretically the same concentration of the minus enantiomer as is present in Bay k8644, IBa increased from 137 +/- 18.3 pA to 354.2 +/- 12.4 pA (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)
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Earle A. Chiles Research Insitute, Oregon Health Sciences University, Portland.
Hermsmeyer
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D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D002120:Calcium Channel Agonists / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009553:Nimodipine / Q000494:pharmacology; D015737:Nisoldipine / Q000494:pharmacology; D051381:Rats
D002120:Calcium Channel Agonists; D015220:Calcium Channels; D004095:Dihydropyridines; D015737:Nisoldipine; D009553:Nimodipine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C038806:1,4-dihydropyridine; D005905:Glyburide