Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice.
-ATP-sensitive potassium (K(ATP)) channels were discovered in ventricular cells, but their roles in the heart remain mysterious. K(ATP) channels have also been found in numerous other tissues, including vascular smooth muscle. Two pore-forming subunits, Kir6.1 and Kir6.2, contribute to the diversity of K(ATP) channels. To determine which subunits are operative in the cardiovascular system and their functional roles, we characterized the effects of pharmacological K(+) channel openers (KCOs, ie, pinacidil, P-1075, and diazoxide) in Kir6.2-deficient mice. Sarcolemmal K(ATP) channels could be recorded electrophysiologically in ventricular cells from Kir6.2(+/+) (wild-type [WT]) but not from Kir6.2(-/-) (knockout [KO]) mice. In WT ventricular cells, pinacidil induced an outward current and action potential shortening, effects that were blocked by glibenclamide, a K(ATP) channel blocker. KO ventricular cells exhibited no response to KCOs, but gene transfer of Kir6.2 into neonatal ventricular cells rescued the electrophysiological response to P-1075. In terms of contractile function, pinacidil decreased force generation in WT but not KO hearts. Pinacidil and diazoxide produced concentration-dependent relaxation in both WT and KO aortas precontracted with norepinephrine. In addition, pinacidil induced a glibenclamide-sensitive current of similar magnitude in WT and KO aortic smooth muscle cells and comparable levels of hypotension in anesthetized WT and KO mice. In both WT and KO aortas, only Kir6.1 mRNA was expressed. These findings indicate that the Kir6.2 subunit mediates the depression of cardiac excitability and contractility induced by KCOs; in contrast, Kir6.2 plays no discernible role in the arterial tree.
Suzuki
M
M
Department of Pharmacology, Chiba University School of Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Li
R A
RA
Miki
T
T
Uemura
H
H
Sakamoto
N
N
Ohmoto-Sekine
Y
Y
Tamagawa
M
M
Ogura
T
T
Seino
S
S
Marbán
E
E
Nakaya
H
H
D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D015152:Blotting, Northern; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005822:Genetic Vectors / Q000235:genetics; D005838:Genotype; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D016276:Ventricular Function
D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D014665:Vasodilator Agents; D020110:Pinacidil; D000255:Adenosine Triphosphate; D003981:Diazoxide; D005905:Glyburide; D009638:Norepinephrine