TY - JOUR
T1 - Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice
AU - Suzuki, Masashi
AU - Li, Ronald A.
AU - Miki, Takashi
AU - Uemura, Hiroko
AU - Sakamoto, Naoya
AU - Ohmoto-Sekine, Yuki
AU - Tamagawa, Masaji
AU - Ogura, Takehiko
AU - Seino, Susumu
AU - Marbán, Eduardo
AU - Nakaya, Haruaki
PY - 2001/3/30
Y1 - 2001/3/30
N2 - ATP-sensitive potassium (KATP) channels were discovered in ventricular cells, but their roles in the heart remain mysterious. KATP 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 KATP 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 KATP 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 KATP 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.
AB - ATP-sensitive potassium (KATP) channels were discovered in ventricular cells, but their roles in the heart remain mysterious. KATP 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 KATP 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 KATP 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 KATP 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.
KW - Action potential
KW - ATP-sensitive K current
KW - Gene targeting
KW - Heart
KW - Vascular smooth muscle
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M3 - Article
C2 - 11282890
AN - SCOPUS:0035970590
SN - 0009-7330
VL - 88
SP - 570
EP - 577
JO - Circulation Research
JF - Circulation Research
IS - 6
ER -