title: Characterization of a hyperpolarization-activated time-dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium.
abstract: Cardiomyocytes from the pulmonary vein sleeves (PVs) are known to play an important role in atrial fibrillation. PVs have been shown to exhibit time-dependent hyperpolarization-induced inward currents of uncertain nature. We observed a time-dependent K(+) current upon hyperpolarization of PV and left atrial (LA) cardiomyocytes (I(KH)) and characterized its biophysical and pharmacological properties. The activation time constant was weakly voltage dependent, ranging from 386 +/- 14 to 427 +/- 37 ms between -120 and -90 mV, and the half-activation voltage averaged -93 +/- 4 mV. I(KH) was larger in PV than LA cells (e.g. at -120 mV: -2.8 +/- 0.3 versus-1.9 +/- 0.2 pA pF(-1), respectively, P < 0.01). The reversal potential was approximately -84 mV with 5.4 mm[K(+)](o) and changed by 55.7 +/- 2.4 mV per decade [K(+)](o) change. I(KH) was exquisitely Ba(2+) sensitive, with a 50% inhibitory concentration (IC(50)) of 2.0 +/- 0.3 microm (versus 76.0 +/- 17.9 microm for instantaneous inward-rectifier current, P < 0.01), and showed similar Cs(+) sensitivity to instantaneous current. I(KH) was potently blocked by tertiapin-Q, a selective Kir3-subunit channel blocker (IC(50) 10.0 +/- 2.1 nm), was unaffected by atropine and was significantly increased by isoproterenol (isoprenaline), carbachol and the non-hydrolysable guanosine triphosphate analogue GTPgammaS. I(KH) activation by carbachol required GTP in the pipette and was prevented by pertussis toxin pretreatment. Tertiapin-Q delayed repolarization in atropine-exposed multicellular atrial preparations studied with standard microelectrodes (action potential duration pre- versus post-tertiapin-Q: 190.4 +/- 4.3 versus 234.2 +/- 9.9 ms, PV; 202.6 +/- 2.6 versus 242.7 +/- 6.2 ms, LA; 2 Hz, P < 0.05 each). Seven-day atrial tachypacing significantly increased I(KH) (e.g. at -120 mV in PV: from -2.8 +/- 0.3 to -4.5 +/- 0.5 pA pF(-1), P < 0.01). We conclude that I(KH) is a time-dependent, hyperpolarization-activated K(+) current that likely involves Kir3 subunits and appears to play a significant role in atrial physiology.
authors.affiliation: Department of Medicine, University of Montral, Montreal, Quebec, Canada.
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Ehrlich
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cha
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Denis
authors.initials: D
authors.lastname: Chartier
authors.forename: Louis
authors.initials: L
authors.lastname: Villeneuve
authors.forename: Terence E
authors.initials: TE
authors.lastname: Hébert
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001464:Barium / Q000494:pharmacology; D001514:Bee Venoms / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002586:Cesium / Q000494:pharmacology; D004285:Dogs; D004553:Electric Conductivity; D005260:Female; D005455:Fluorescent Antibody Technique; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019204:GTP-Binding Proteins / Q000378:metabolism; D006325:Heart Atria; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010805:Physical Conditioning, Animal; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D011667:Pulmonary Veins; D013612:Tachycardia, Ectopic Atrial / Q000503:physiopathology; D013997:Time Factors
chemical_list: D001514:Bee Venoms; D002316:Cardiotonic Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D002586:Cesium; D001464:Barium; C029738:tertiapin; D001285:Atropine; D019204:GTP-Binding Proteins; D007545:Isoproterenol