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.
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd, Orlando, FL 32827, USA.
Candice
C
Baker
David G
DG
Taylor
Kingsley
K
Osuala
Anupama
A
Natarajan
Peter J
PJ
Molnar
James
J
Hickman
Sabikha
S
Alam
Brittany
B
Moscato
David
D
Weinshenker
Steven N
SN
Ebert
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000196:embryology* / Q000235:genetics*; D018031:Connexin 43 / Q000096:biosynthesis; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D004553:Electric Conductivity; D004622:Embryo, Mammalian / Q000201:enzymology / Q000503:physiopathology; D006321:Heart / Q000196:embryology* / Q000503:physiopathology*; D006340:Heart Rate, Fetal / Q000235:genetics / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D051379:Mice; D018345:Mice, Knockout
D018031:Connexin 43; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D004299:Dopamine beta-Hydroxylase