Decreased and heterogeneous expression of connexin 43 (Cx43) are common features in animal heart failure models. Ephpatic coupling, which relies on the presence of junctional cleft space between the ends of adjacent cells, has been suggested to play a more active role in mediating intercellular electrical communication when gap junctions are reduced. To better understand the interplay of Cx43 expression and ephaptic coupling on cardiac conduction during heart failure, we performed numerical simulations on our model when Cx43 expression is reduced and heterogeneous. Under severely reduced Cx43 expression, we identified three new phenomena in the presence of ephaptic coupling: alternating conduction, in which ephaptic and gap junction-mediated mechanisms alternate; instability of planar fronts; and small amplitude action potential (SAP), which has a smaller potential amplitude than the normal action potential. In the presence of heterogeneous Cx43 expression, ephaptic coupling can either prevent or promote conduction block (CB) depending on the Cx43 knockout (Cx43KO) content. When Cx43KO content is relatively high, ephaptic coupling reduces the probabilities of CB. However, ephaptic coupling promotes CB when Cx43KO and wild type cells are mixed in roughly equal proportion, which can be attributed to an increase in current-to-load mismatch.
Major renal functions such as renal blood flow, glomerular filtration rate, and urinary excretion are known to exhibit circadian oscillations. However, the underlying mechanisms that govern these variations have yet to be fully elucidated. To better understand the impact of the circadian clock on renal solute and water transport, we have developed a computational model of the renal circadian clock and coupled that model to an epithelial transport model of the proximal convoluted cell of the rat kidney. The activity of the Na-H exchanger 3 (NHE3) is assumed to be regulated by changes in transcription of the NHE3 mRNA due to regulation by circadian clock proteins. The model predicts the rhythmic oscillations in NHE3 activity, which gives rise to significant daily fluctuations in Na and water transport of the proximal tubule cell. Additionally, the model predicts that 1) mutation in period 2 (Per2) or cryptochrome 1 (Cry1) preserves the circadian rhythm and modestly raises Na reabsorption; 2) mutation in Bmal1 or CLOCK eliminates the circadian rhythm and modestly lowers Na reabsorption; 3) mutation in Rev-Erb or ROR-related orphan receptor (Ror) has minimal impact on the circadian oscillations. The model represents the first step in building a tool set aimed at increasing our understanding of how the molecular clock affects renal ion transport and renal function, which likely has important implications for kidney disease.
Acute myocardial ischemia is an imbalance between myocardial blood supply and demand, which is caused by the cessation of blood flow within the heart resulting from an obstruction in one of the major coronary arteries. A severe blockage may result in a region of nonperfused tissue known as ischemic core (IC). As a result, a border zone (BZ) between perfused and nonperfused regions is created due to differences in blood and oxygen supplies. Recent experimental findings reveal a complex “finger-like” geometry in BZ; however, its effect on arrhythmogenicity is not clear. Ephaptic coupling, which relies on the intercalated disk between cell ends, has been suggested to play an active role in mediating intercellular electrical communication when gap junctions are impaired. In this paper, we explored the interplay between ephaptic coupling and the geometry of BZ on action potential propagation across the ischemic region. Our study shows that ephaptic coupling can greatly suppress the occurrence of a conduction block, which points to its beneficial effect. The beneficial effect of ephaptic coupling is more evident in BZ with the “finger-like” geometry. In addition, the complex geometry of BZ, i.e., more frequent, deeper, and wider “fingers,” promotes the conduction through the ischemic region. In contrast, the larger size of IC impedes the cardiac conduction across the ischemic region. Our results also show that ephaptic coupling promotes the impact of the complex geometry of BZ on signal propagation; however, it inhibits the impact of IC size.
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