title: Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs.
abstract: The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used. Selective IKr block (50-100 nmol l(-1) dofetilide) lengthened AP duration at 90% of repolarization (APD90) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective IK1 block (10 μmol l(-1) BaCl2) and IKs block (1 μmol l(-1) HMR-1556) increased APD90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that IK1 and IKs densities were 3- and 4.5-fold larger in dogs than humans, respectively. IKr density and kinetics were similar in human versus dog. ICa and Ito were respectively ~30% larger and ~29% smaller in human, and Na(+)-Ca(2+) exchange current was comparable. Cardiac mRNA levels for the main IK1 ion channel subunit Kir2.1 and the IKs accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (IKr and IKs α-subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human versus canine cardiomyocytes. IK1 and IKs inhibition increased the APD-prolonging effect of IKr block more in dog (by 56% and 49%, respectively) than human (34 and 16%), indicating that both currents contribute to increased repolarization reserve in the dog. A mathematical model incorporating observed human-canine ion current differences confirmed the role of IK1 and IKs in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of IKr block than dogs, because of lower repolarization reserve contributions from IK1 and IKs, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease.
authors.affiliation: A. Varró: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Dóm tér 12, PO Box 427, Hungary. varro.andras@med.u-szeged.hu.
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Philippe
authors.initials: P
authors.lastname: Comtois
authors.forename: Balázs
authors.initials: B
authors.lastname: Ordög
authors.forename: Viktória
authors.initials: V
authors.lastname: Szuts
authors.forename: György
authors.initials: G
authors.lastname: Seprényi
authors.forename: Miklós
authors.initials: M
authors.lastname: Bitay
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Kohajda
authors.forename: István
authors.initials: I
authors.lastname: Koncz
authors.forename: Norbert
authors.initials: N
authors.lastname: Nagy
authors.forename: Tamás
authors.initials: T
authors.lastname: Szél
authors.forename: János
authors.initials: J
authors.lastname: Magyar
authors.forename: Mária
authors.initials: M
authors.lastname: Kovács
authors.forename: László G
authors.initials: LG
authors.lastname: Puskás
authors.forename: Csaba
authors.initials: C
authors.lastname: Lengyel
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Péter P
authors.initials: PP
authors.lastname: Nánási
authors.forename: Julius Gy
authors.initials: JG
authors.lastname: Papp
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000200:Action Potentials; D000328:Adult; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004285:Dogs; D005260:Female; D006321:Heart / Q000502:physiology*; D006801:Humans; D017136:Ion Transport; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013045:Species Specificity
chemical_list: D015221:Potassium Channels; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D011188:Potassium; D002118:Calcium