Published online before print May 1, 2003, doi: 10.1161/01.RES.0000074916.41221.EA
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© 2003 American Heart Association, Inc.
Cellular Biology |
Impulse Propagation in Synthetic Strands of Neonatal Cardiac Myocytes With Genetically Reduced Levels of Connexin43
From the Department of Physiology (S.P.T., L.B.-L., A.G.K.), University of Bern, Switzerland; the Center for Cardiovascular Research and the Department of Pathology (J.E.S.), Washington University, St. Louis, Miss; and the Department of Biomedical Engineering (J.P.K., Y.R.), Case Western Reserve University, Cleveland, Ohio.
Correspondence to André G. Kléber, MD, Department of Physiology, University of Bern, Bühlplatz5, CH-3012 Bern, Switzerland. E-mail kleber{at}pyl.unibe.ch
Connexin43 (Cx43) is a major determinant of the electrical properties of the myocardium. Closure of gap junctions causes rapid slowing of propagation velocity (
), but the precise effect of a reduction in Cx43 levels due to genetic manipulation has only partially been clarified. In this study, morphological and electrical properties of synthetic strands of cultured neonatal ventricular myocytes from Cx43+/+ (wild type, WT) and Cx+/- (heterozygote, HZ) mice were compared. Quantitative immunofluorescence analysis of Cx43 demonstrated a 43% reduction of Cx43 expression in the HZ versus WT mice. Cell dimensions, connectivity, and alignment were independent of genotype. Measurement of electrical properties by microelectrodes and optical mapping showed no differences in action potential amplitude or minimum diastolic potential between WT and HZ. However, maximal upstroke velocity of the transmembrane action potential, dV/dtmax, was increased and action potential duration was reduced in HZ versus WT. was similar in the two genotypes. Computer simulation of propagation and dV/dtmax showed a relatively small dependence of on gap junction coupling, thus explaining the lack of observed differences in between WT and HZ. Importantly, the simulations suggested that the difference in dV/dtmax is due to an upregulation of INa in HZ versus WT. Thus, heterozygote-null mutation of Cx43 produces a complex electrical phenotype in synthetic strands that is characterized by both changes in ion channel function and cell-to-cell coupling. The lack of changes in in this tissue is explained by the dominating role of myoplasmic resistance and the compensatory increase of dV/dtmax.
Key Words: synthetic cardiac strands • neonatal mouse cardiomyocytes • connexin43 expression • conduction velocity
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