Biomedical Engineering Reference
In-Depth Information
Inhibition of Cardiomyocyte Automaticity by
Electrotonic Application of Inward Rectifier Current
from Kir2.1 Expressing Cells
Teun P. de Boer
1,4
, Toon A.B. van Veen
1
, Marien J.C. Houtman
1
, John A. Jansen
1
,
Shirley C.M. van Amersfoorth
2,4
, Pieter A. Doevendans
3
, Marc A. Vos
1
,
and Marcel A.G. van der Heyden
1,4
1
Department of Medical Physiology, Heart Lung Center Utrecht,
University Medical Center Utrecht, Yalelaan 50, 3584 Utrecht, The Netherlands
m.a.g.vanderheyden@umcutrecht.nl
2
Experimental and Molecular Cardiology Group, Academic Medical Center,
Amsterdam, The Netherlands
3
Department of Cardiology, University Medical Center Utrecht, Utrecht,
The Netherlands
4
Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
Abstract.
A biological pacemaker might be created by generation of a cellular construct
consisting of cardiac cells that display spontaneous membrane depolarization, and that
are electrotonically coupled to surrounding myocardial cells by means of gap junctions.
Depending on the frequency of the spontaneously beating cells, frequency regulation
might be required. We hypothesized that application of Kir2.1 expressing non-cardiac
cells, which provide
I
K1
to spontaneously active neonatal cardiomyocytes (NCMs) by
electrotonic coupling in such a cellular construct, would generate an opportunity for
pacemaker frequency control. Non-cardiac Kir2.1 expressing cells were co-cultured with
spontaneously active rat NCMs. Electrotonic coupling between the two cell types
resulted in hyperpolarization of the cardiomyocyte membrane potential and silencing of
spontaneous activity. Either blocking of gap-junctional communication by halothane or
inhibition of
I
K1
by BaCl
2
restored the original membrane potential and spontaneous
activity of the NCMs. Our results demonstrate the power of electrotonic coupling for
the application of specific ion currents into an engineered cellular construct such as a
biological pacemaker.
Keywords:
Kir2.1, Inward rectifier, Cardiomyocyte, Pacemaker, Electrotonic coupling.
1 Introduction
Genetically engineered cell based pacemakers may become a valuable alternative
for the current electronic pacemakers. The dominant endogenous pacemakers in
the mammalian heart, such as the sinoatrial (SA) and atrioventricular nodes,
constitute a specific spatially organized population of cardiac myocytes that have
no primary contractile function. These cardiomyocytes are characterized by the
