Adrenergic deficiency leads to impaired electrical conduction and increased arrhythmic potential in the embryonic mouse heart
Copyright policy )Adrenergic deficiency leads to impaired electrical conduction and increased arrhythmic potential in the embryonic mouse heart
To determine if adrenergic hormones play a critical role in the functional development of the cardiac pacemaking and conduction system, we employed a mouse model where adrenergic hormone production was blocked due to targeted disruption of the dopamine β-hydroxylase (Dbh) gene. Immunofluorescent histochemical evaluation of the major gap junction protein, connexin 43, revealed that its expression was substantially decreased in adrenergic-deficient (Dbh-/-) relative to adrenergic-competent (Dbh+/+ and Dbh+/-) mouse hearts at embryonic day 10.5 (E10.5), whereas pacemaker and structural protein staining appeared similar. To evaluate cardiac electrical conduction in these hearts, we cultured them on microelectrode arrays (8×8, 200 μm apart). Our results show a significant slowing of atrioventricular conduction in adrenergic-deficient hearts compared to controls (31.4±6.4 vs. 15.4±1.7 ms, respectively, p<0.05). To determine if the absence of adrenergic hormones affected heart rate and rhythm, mouse hearts from adrenergic-competent and deficient embryos were cultured ex vivo at E10.5, and heart rates were measured before and after challenge with the β-adrenergic receptor agonist, isoproterenol (0.5 μM). On average, all hearts showed increased heart rate responses following isoproterenol challenge, but a significant (p<0.05) 225% increase in the arrhythmic index (AI) was observed only in adrenergic-deficient hearts. These results show that adrenergic hormones may influence heart development by stimulating connexin 43 expression, facilitating atrioventricular conduction, and helping to maintain cardiac rhythm during a critical phase of embryonic development.
- University of Central Florida United States
- Emory University United States
CONNEXIN43, EXPRESSION, Biochemistry & Molecular Biology, RAT-HEART, Conduction velocity, Biophysics, Cyclic Nucleotide-Gated Cation Channels, Dopamine beta-Hydroxylase, Mice, Cardiac development, junctions, CARDIAC CONDUCTION, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Animals, Mice, Knockout, Cardiac gap, GAP-JUNCTIONS, Adrenergic regulation, Electric Conductivity, Arrhythmias, Cardiac, Heart, Heart Rate, Fetal, Embryo, Mammalian, GENE, CATECHOLAMINES, MICE, Cardiac gap junctions, PHENYLETHANOLAMINE N-METHYLTRANSFERASE, Connexin 43, Arrhythmia, SYSTEM
CONNEXIN43, EXPRESSION, Biochemistry & Molecular Biology, RAT-HEART, Conduction velocity, Biophysics, Cyclic Nucleotide-Gated Cation Channels, Dopamine beta-Hydroxylase, Mice, Cardiac development, junctions, CARDIAC CONDUCTION, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Animals, Mice, Knockout, Cardiac gap, GAP-JUNCTIONS, Adrenergic regulation, Electric Conductivity, Arrhythmias, Cardiac, Heart, Heart Rate, Fetal, Embryo, Mammalian, GENE, CATECHOLAMINES, MICE, Cardiac gap junctions, PHENYLETHANOLAMINE N-METHYLTRANSFERASE, Connexin 43, Arrhythmia, SYSTEM
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