A key role for the subunit SUR2B in the preferential activation of vascular KATP channels by isoflurane.
OBJECTIVE
It has been postulated that isoflurane, a volatile anaesthetic, produces vasodilatation through activation of ATP-sensitive K+ (KATP) channels. However, there is no direct evidence for the activation of vascular KATP channels by isoflurane. This study was conducted to examine the effect of isoflurane on vascular KATP channels and compare it with that on cardiac KATP channels.


METHODS
Effects of isoflurane on KATP channels were examined in aortic smooth muscle cells and cardiomyocytes of the mouse using patch clamp techniques. Effects of the anaesthetic on the KATP channels with different combinations of the inward rectifier pore subunits (Kir6.1 and Kir6.2) and sulphonylurea receptor subunits (SUR2A and SUR2B) reconstituted in a heterologous expression system were also examined.


RESULTS
Isoflurane increased the coronary flow in Langendorff-perfused mouse hearts in a concentration-dependent manner, which was abolished by 10 microM glibenclamide. In enzymically-dissociated aortic smooth muscle cells, isoflurane evoked a glibenclamide-sensitive current (i.e. KATP current). In isolated mouse ventricular cells, however, isoflurane failed to evoke the KATP current unless the KATP current was preactivated by the K+ channel opener pinacidil. Although isoflurane readily activated the Kir6.1/SUR2B channels (vascular type), the volatile anesthetic could not activate the Kir6.2/SUR2A channels (cardiac type) expressed in HEK293 cells. Isoflurane activated a glibenclamide-sensitive current in HEK293 cells expressing Kir6.2/SUR2B channels.


CONCLUSIONS
Isoflurane activates KATP channels in vascular smooth muscle cells and produces coronary vasodilation in mouse hearts. SUR2B may be important for the activation of vascular-type KATP channels by isoflurane.
Fujita
H
H
Department of Pharmacology, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan.
Ogura
T
T
Tamagawa
M
M
Uemura
H
H
Sato
T
T
Ishida
A
A
Imamaki
M
M
Kimura
F
F
Miyazaki
M
M
Nakaya
H
H
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000502:physiology*; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000502:physiology*; D011955:Receptors, Drug / Q000235:genetics / Q000502:physiology*; D064233:Sulfonylurea Receptors; D013806:Theophylline / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D014664:Vasodilation / Q000187:drug effects
C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; C577511:Abcc9 protein, mouse; D018685:Anesthetics, Inhalation; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D020110:Pinacidil; D013806:Theophylline; D007530:Isoflurane; D005905:Glyburide