Adrenergic deficiency leads to impaired electrical conduction and increased arrhythmic potential in the embryonic mouse heart

作者：Baker Candice; Taylor David G; Osuala Kingsley; Natarajan Anupama; Molnar Peter J; Hickman James; Alam Sabikha; Moscato Brittany; Weinshenker David; Ebert Steven N^*

来源：Biochemical and Biophysical Research Communications, 2012, 423(3): 536-541.

DOI：10.1016/j.bbrc.2012.05.163

• Adrenergic regulation
• Arrhythmia
• Cardiac development
• Cardiac gap junctions
• Conduction velocity

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 beta-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 x 8,200 mu m 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 %26lt; 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 beta-adrenergic receptor agonist, isoproterenol (0.5 mu M). On average, all hearts showed increased heart rate responses following isoproterenol challenge, but a significant (p %26lt; 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.

• 出版日期2012-7-6