Atrioventricular conduction and arrhythmias at the initiation of beating in embryonic mouse hearts

Abstract

To investigate cardiac physiology at the onset of heart beating in embryonic mouse hearts, we performed optical imaging of membrane potential (Vm) and/or intracellular calcium (Ca i ). Action potentials and Ca i transients were detected in~50% of mouse embryo hearts at E8.5, but in all hearts at E9.0, indicating that beating typically starts between E8-E9. Beating was eliminated by Ca channel blocker nifedipine and the I f blocker ZD7288, unaffected by tetrodotoxin and only mildly depressed by disabling sarcoplasmic (SR) and endoplasmic (ER) reticulum Ca cycling. From E8.5 to E10, conduction velocity increased from 0.2-1 mm/s to >5 mm/s in first ventricular and then atrial tissue, while remaining slow in other areas. Arrhythmias included atrioventricular reentry induced by adenosine. In summary, at the onset of beating, I f -dependent pacemaking drives both AP propagation and Ca i transient generation through activation of voltage-dependent Ca channels. Na channels and intracellular Ca cycling have minor roles. Developmental Dynamics 239:1941-1949,

Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors

“…When the embryonic mouse heart develops from a "primitive heart tube" at E8.5 to a well-defined tubular shape expanded at the ventricular end at E9, Ca 2+ activity increases from 50% to almost 100% of the nascent myocytes (35) and electrophysiological maturation of human ES-derived cardiomyocytes involves the development of more rapid spontaneous Ca 2+ transients (36). In comparison, the ETS2/MESP1 reprogrammed cells appear to be at the early to intermediate stages of cardiomyocyte maturation.…”

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

“…Several studies showed that a blockade of I f by ZD7288 or ivabradine was associated with a reduction in the intracellular calcium sparks. These observations were made in mouse embryonic (E8-E9) cardiomyocytes [180] , in cardiomyocytes isolated from the rabbit pulmonary vein [181] , and in rabbit SAN cells [182] . One can assume that the decreased Figure 5.…”

A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance

“…Since ADO represents an important regulator of the embryonic cardiovascular function (35), the present study focuses on the modulation of the adenosinergic system by hypoxia and its functional consequences in the developing heart. Generally ADO has negative chrono-, dromo-, and inotropic actions (28, 55, 62) and can be anti-or proarrhythmic both in adult and developing hearts (3,5,22,25,40,51). We have recently shown in the embryonic chick heart model that ADO metabolism mainly relies on ectonucleoside triphosphate diphosphohydrolase (eNTPDase, apyrase, CD39), ecto-5=-nucleotidase (eNT, CD73), adenosine kinase (AdK), and adenosine deaminase (ADA).…”

“…CD39 and CD73 sequentially convert ATP to ADO and ADA mediates conversion of ADO to inosine (INO). ADO is transported across cell membrane by equilibrative (ENT1, 3,4) or concentrative (CNT3) transporters and interacts with the four subtypes of ADO receptors (AR), i.e., A 1 AR, A 2A AR, A 2B AR, and A 3 AR (5,22,40,41,51). Pharmacological disturbances of nucleosides metabolism and transport in the embryonic heart can rapidly lead to interstitial accumulation of ADO and INO and provoke arrhythmias in an autocrine/paracrine manner through A 1 AR and A 2A AR stimulation and ERK2 activation (41).…”