Dispersion of
Cell-To-Cell Uncoupling Precedes Low
K+-Induced
Ventricular Fibrillation
N. TRIBULOVÁ, M. MANOACH1, D. VARON1, L.
OKRUHLICOVÁ,
T. ZINMAN2 , A. SHAINBERG2
Institute
for Heart Research, Slovak Academy of Sciences,
Bratislava, Slovak Republic, 1Department
of Physiology, Sackler School of
Medicine, Tel Aviv, Israel and 2Department
of Life Sciences, Bar Ilan University, Ramat Gan,
Israel
Received
December 22, 1999
Accepted July 18, 2000
Summary
We
hypothesize that hypokalemia-related electrolyte
imbalance linked with abnormal elevation of
intracellular free Ca2+ concentration
can cause metabolic disturbances and subcellular
alterations resulting in intercellular
uncoupling, which favor the occurrence of
malignant arrhythmias. Langendorff-perfused
guinea pig heart (n = 44) was subjected to a
standard Tyrode solution (2.8 mmol/l K+) followed
by a K+-deficient solution (1.4 mmol/l K+).
Bipolar ECG of the left atria and ventricle was
continuously monitored and the incidence of
ventricular fibrillation was evaluated.
Myocardial tissue sampling was performed during
stabilization, hypokalemia and at the onset of
fibrillation. Enzyme activities of succinic
dehydrogenase, glycogen phosphorylase and
5-nucleotidase were determined using in situ
catalytic histochemistry. The main gap junction
protein, connexin-43, was labeled using mouse
monoclonal antibody and FITC conjugated goat
antimouse antibody. Ultrastructure was examined
by transmission electron microscopy. The free Ca2+
concentration was measured by the indo-1 method
in ventricular cell cultures exposed to a K+-free
medium. The results showed that sustained
ventricular fibrillation appeared within 15-30
min of low K+ perfusion. This was
preceded by ectopic activity, episodes of
bigeminy and tachycardia. Hypokalemia induced
moderate reversible and sporadically irreversible
subcellular alterations of cardiomyocytes and
impairment of intercellular junctions, which were
heterogeneously distributed throughout
myocardium. Patchy areas with decreased enzyme
activities and diminished immunoreactivity of
connexin-43 were found. Furthermore, lack of
external K+ was accompanied by an
increase of intracellular Ca2+. The prevention of
Ca2+ overload by either 1 mmol/l Ni2+
(Na+/Ca2+ inhibitor), 2.5
mmol/l verapamil, 10 mmol/l d-sotalol or 10
mmol/l tedisamil was associated with the
protection against fibrillation. The results
indicate that hypokalemia induces Ca2+ overload
injury and disturbances in intercellular
coupling. Dispersion of these changes throughout
the myocardium may serve as the basis for
microreentry circuits and thus favor fibrillation
occurrence.
Key
words
Hypokalemia
· Ventricular fibrillation · Ca2+ ·
Connexin-43 · Intercellular junctions
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requests
N.
Tribulová, PhD., Institute for Heart Research,
Slovak Academy of Sciences, Dubravska cesta 9,
842 33 Bratislava, Slovak Republic. Fax: +421 7
5477 6637, e-mail: usrdtri@savba.sk
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