Ionic mechanism of minoxidil sulfate-induced shortening of action potential durations in guinea pig ventricular myocytes.
Patch-clamp techniques were used to study pharmacological effects of minoxidil sulfate (MNXS) on the membrane currents of enzymatically isolated guinea pig ventricular myocytes. In the whole-cell current-clamp mode, MNXS (100 microM) shortened the action potential duration without affecting the resting membrane potential. This action was antagonized in part by 1 microM glibenclamide, a specific blocker of ATP-sensitive K+ channel. Under the whole-cell voltage-clamp condition, MNXS increased the time-independent outward current, in a dose-dependent manner, at voltages more positive to -73.5 mV. This MNXS-induced outward current was inhibited completely by 1 microM glibenclamide. In inside-out patch membranes, MNXS (100 microM) applied to the cytosolic side produced a reversible activation of ATP-sensitive K+ channels. This MNXS-dependent increase in the single-channel activity was abolished by increasing the ATP concentration to 3 mM or by adding 1 microM glibenclamide. Even after complete rundown of the channel activity in inside-out patches, MNXS could reactivate in part the channel in 22 of 35 patches. In addition, MNXS was found to suppress whole-cell L-type Ca++ channel currents in a dose-dependent manner. This MNXS effect on Ca++ currents was not antagonized by 1-3 microM glibenclamide. We conclude that MNXS shortens the cardiac action potential duration by both increasing ATP-sensitive K+ channel currents and decreasing L-type Ca++ channel currents.
Department of Physiology, Kyoto University Faculty of Medicine, Japan.
S
S
Hayashi
M
M
Horie
Y
Y
Okada
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects*; D006801:Humans; D008297:Male; D008914:Minoxidil / Q000031:analogs & derivatives* / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D016276:Ventricular Function
D015220:Calcium Channels; D015221:Potassium Channels; C039516:minoxidil sulfate ester; D008914:Minoxidil; D011188:Potassium; D005905:Glyburide; D002118:Calcium