Potentiation by nitric oxide of the ATP-sensitive K+ current induced by K+ channel openers in guinea-pig ventricular cells.
1. Modulation by nitric oxide (NO) of the ATP-sensitive K+ channel (KATP) current (IK(ATP)) was investigated in single ventricular cells dissociated from guinea-pig hearts. IK(ATP) was induced by 5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine+ ++ (KRN4884) and cromakalim. 2. In the whole-cell patch clamp configuration, KRN4884 (0.1 3 microM) increased the outward current in a concentration-dependent manner with an EC50 value of 0.48 microM. This current was completely antagonized by glibenclamide (1 microM). 3. IK(ATP) induced by either KRN4884 (0.3 microM) or cromakalim (10 microM) was significantly enhanced by the additional application of a NO donor (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (NOR3, 0.1 and 1 mM). 4. The potentiating effect was observed only when NOR3 solution was prepared just before experiments, when release of NO was considered to be on-going. The effect was significantly eliminated in the presence of the NO scavenger oxyhaemoglobin (3 10 microM). Also, oxidative metabolites of NO, such as NO2 or NO3, were without effect. 5. 8-Bromo-guanosine-3':5'-cyclic monophosphate (8-Br-cyclic GMP, 0.1 0.5 mM) significantly decreased IK(ATP) induced by KRN4884. 6. In cell-attached patches, NOR3 (1 mM) potentiated the KRN4884-induced IK(ATP) in a way similar to that seen in whole-cell recordings. By contrast, NOR3 (1 mM) did not enhance the current in either inside-out or outside-out patches. 7. These results indicate that NO potentiates the action of K+ channel openers on the KATP through a mechanism which remains to be determined.
Shinbo
A
A
Department of Pharmacology, Akita University School of Medicine, Japan.
Iijima
T
T
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D009569:Nitric Oxide / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*
C096484:KRN 4884; D015221:Potassium Channels; D011725:Pyridines; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D006152:Cyclic GMP