This experimental study showed that AF is accompanied by spatial remodeling of gap junctions that might induce changes in the biophysical properties of the tissue.

Endothelin-1 (ET-1) and angiotensin-II (AT-II) participate in the pathophysiology of cardiovascular diseases. Regulation of gap junctional intercellular communication may influence heart function and its response to cardiac injury. In this study, we examined the effects of ET-1 and AT-II on connexin43 (Cx43) and connexin40 (Cx40) in cultured neonatal rat ventricular cardiomyocytes (NRCs) and the role of mitogen-activated protein kinase signaling in the ET-1- and AT-II-induced responses. NRCs were incubated for 24 h with either ET-1 or AT-II (each at concentrations ranging from 10 to 1000 nM), and Cx43 expression and phosphorylation increased with increasing concentrations of both. ET-1 effects were significantly blocked by ETA (BQ123), but not by ETB (BQ788), receptor antagonists. AT-II-induced Cx43 induction could be completely inhibited by the AT1 receptor antagonist losartan. In contrast to Cx43, Cx40 expression did not change in either ET-1- or in AT-II-treated NRCs. Thus, these two connexins were differentially regulated. ET-1 and AT-II increased the gap junctional conductance between the cardiomyocytes in culture as measured using a dual-cell voltage clamp. Mitogen-activated protein kinase inhibition revealed that ERK1/2 was critical for up-regulation of Cx43 in response to ET-1, whereas both ERK and p38 signal pathways were involved in the regulation of Cx43 by AT-II. Thus, stimulation of the ERK and p38 signal pathways via ETA and AT1 receptors may partcipate in the regulation of cardiac gap junctions under (patho)physiological conditions.