Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice

Masashi Suzuki, Ronald A. Li, Takashi Miki, Hiroko Uemura, Naoya Sakamoto, Yuki Ohmoto-Sekine, Masaji Tamagawa, Takehiko Ogura, Susumu Seino, Eduardo Marbán, Haruaki Nakaya

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)570-577
Number of pages8
JournalCirculation Research
Volume88
Issue number6
StatePublished - Mar 30 2001

Keywords

  • Action potential
  • ATP-sensitive K current
  • Gene targeting
  • Heart
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Suzuki, M., Li, R. A., Miki, T., Uemura, H., Sakamoto, N., Ohmoto-Sekine, Y., Tamagawa, M., Ogura, T., Seino, S., Marbán, E., & Nakaya, H. (2001). Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Circulation Research, 88(6), 570-577.