A specific activator of the ATP-inhibited K+ channels in guinea pig ventricular cells.
The specific activity of a pyridylcyanoguanidine, P-1075, on cardiac potassium current inhibited by internal ATP (KATP) was examined using whole-cell and single-channel recording techniques. At 10 microM, the compound markedly abbreviated ventricular cell action potentials. The effect was reversible by 1 microM glyburide. Whole-cell current experiments showed that the compound elicited a time-independent outward current which had a linear current-voltage relationship between -70 to 0 mV. This current was inhibited by glyburide. Elevation of intracellular ATP from 1 to 5 mM strongly reduced the effect of P-1075 (50 microM) on the current, from 25.5 +/- 1.8 to 3.4 +/- 0.6 pA/pF. Removal of internal ATP, which caused KATP channel to "rundown", markedly diminished the drug effect, suggesting phosphorylation of the channel may be necessary for drug action. Dose-response effect of P-1075 on KATP channel had a Kd of 34.5 microM and a Hill coefficient of 2.0 for the 1 mM ATP experiment and a corresponding 36.6 microM and 2.2 for the 5 mM ATP experiment, implying probably two drug receptor sites. Single-channel recordings indicated that P-1075 increased KATP channel open probability. The complex interaction of ATP and P-1075 with the whole-cell current can be explained by a scheme developed by other investigators based on single-channel results. The compound, at doses of up to 25 microM, did not affect the inwardly and outwardly rectifying K+ currents nor the L-type Ca++ current. We conclude that P-1075 is a specific activator of phosphorylated KATP channels.
Xu
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Cardiovascular Diseases Research, Upjohn Laboratories, Kalamazoo, Michigan.
Tsai
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Lee
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D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*
D015220:Calcium Channels; D006146:Guanidines; D015221:Potassium Channels; D011725:Pyridines; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D000255:Adenosine Triphosphate