Effect of isosorbiddinitrate on exogenously expressed slowly activating K+ channels and endogenous K+ channels in Xenopus oocytes.
1. The effects of isosorbiddinitrate (ISDN) were tested on membrane currents and resting potential in Xenopus laevis oocytes which were either uninjected or injected with cRNA encoding for K+ channels from three distinct families (slowly activating IsK channels, delayed-rectifying Kv1.1 or inwardly rectifying IRK1 K+ channels). 2. In uninjected oocytes ISDN (1 mM) resulted in a decrease of the holding current at potentials more positive than -100 mV and in an increase at potentials below -100 mV. Increasing extracellular K+ to 100 mM shifted the reversal potential for ISDN-mediated effects to approximately -12 mV, suggesting an inhibition of a K+ conductance by ISDN. 3. In current clamp studies ISDN (1 mM) and Ba2+ (3 mM) depolarized cell membrane. ISDN and Ba2+ had no additive effects on membrane potential when applied simultaneously. In voltage clamp studies, corresponding results were observed for the effects of ISDN and Ba2+ on the holding current with an apparent K(m) of 0.21 and 0.08 mM, respectively. 4. In contrast to ISDN, the nitric oxide (NO) donors isosorbidmononitrate (ISMN) and S-nitrosocysteine (SNOC) had no effects on the holding currents in Xenopus oocytes. Moreover, the guanylate inhibitor LY 83583 did not affect ISDN-mediated holding current alterations, suggesting that ISDN acts independently of the second messenger NO. 5. ISDN inhibited exogenously expressed IsK channels with an apparent K(m) of 0.15 mM, but at 1 mM only weakly inhibited Kv1.1 and IRK1 channels. 6. It is concluded that ISDN inhibits an endogenous K+ conductance in Xenopus oocytes with a similar potency to that shown by expressed IsK channels. These effects are independent of the second messenger NO.
Busch
A E
AE
Institute of Physiology, Eberhard-Karls-Universität Tübingen, Germany.
Kopp
H G
HG
Waldegger
S
S
Samarzija
I
I
Süssbrich
H
H
Raber
G
G
Kunzelmann
K
K
Ruppersberg
J P
JP
Lang
F
F
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives / Q000494:pharmacology*; D007700:Kinetics; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018075:RNA, Complementary / Q000096:biosynthesis; D051381:Rats; D026403:S-Nitrosothiols; D014665:Vasodilator Agents / Q000494:pharmacology*; D014982:Xenopus laevis
D000634:Aminoquinolines; D004791:Enzyme Inhibitors; D015221:Potassium Channels; D018075:RNA, Complementary; D026403:S-Nitrosothiols; D014665:Vasodilator Agents; D001464:Barium; C041715:6-anilino-5,8-quinolinedione; C021315:S-nitrosocysteine; D006162:Guanylate Cyclase; D007548:Isosorbide Dinitrate; D003545:Cysteine; C030397:isosorbide-5-mononitrate