Effect of transverse gap-junction channels on transverse propagation in an enlarged PSpice model of cardiac muscle

BACKGROUND: In previous PSpice modeling studies of simulated action potentials (APs) in parallel chains of cardiac muscle, it was found that transverse propagation could occur between adjacent chains in the absence of gap-junction (gj) channels, presumably by the electric field (EF) generated in the narrow interstitial space between the chains. Transverse propagation was sometimes erratic, the more distal chains firing out of order. METHODS: In the present study, the propagation of complete APs was studied in a 2-dimensional network of 100 cardiac muscle cells (10 × 10 model). Various numbers of gj-channels (assumed to be 100 pS each) were inserted across the junctions between the longitudinal cells of each chain and between adjacent chains (only at the end cells of each chain). The shunt resistance produced by the gj-channels (R(gj)) was varied from 100,000 MΩ (0 gj-channels) to 1,000 MΩ (10 channels), 100 MΩ (100 channels) and 10 MΩ (1,000 channels). Total propagation time (TPT) was measured as the difference between the times when the AP rising phase of the first cell (cell # A1) and the last cell (in the J chain) crossed 0 mV. When there were no gj-channels, the excitation was transmitted between cells by the EF, i.e., the negative potential generated in the narrow junctional clefts (e.g., 100 Å) when the prejunctional membrane fired an AP. For the EF mechanism to work, the prejunctional membrane must fire a fraction of a millisecond before the adjacent surface membrane. When there were many gj-channels (e.g., 100 or 1,000), the excitation was transmitted by local-circuit current flow from one cell to the next through these channels. RESULTS: TPT was measured as a function of four different numbers of transverse gj-channels, namely 0, 10, 100 and 1,000, and four different numbers of longitudinal gj-channels, namely 0, 10, 100 and 1,000. Thus, 16 different measurements were made. It was found that increasing the number of transverse channels had no effect on TPT when the number of longitudinal channels was low (i.e., 0 or 10). In contrast, when the number of longitudinal gj-channels was high (e.g., 100 or 1,000), then increasing the number of transverse channels decreased TPT markedly. CONCLUSION: Thus, complete APs could propagate along a network of 100 cardiac muscle cells even when no gj-channels were present between the cells. Insertion of transverse gj-channels greatly speeded propagation through the 10 × 10 network when there were also many longitudinal gj-channels

Cable properties and propagation velocity in a long single chain of simulated myocardial cells

<p>Abstract</p> <p>Background</p> <p>Propagation of simulated action potentials (APs) was previously studied in short single chains and in two-dimensional sheets of myocardial cells <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr></abbrgrp>. The present study was undertaken to examine propagation in a long single chain of cells of various lengths, and with varying numbers of gap-junction (g-j) channels, and to compare propagation velocity with the cable properties such as the length constant (<it>λ</it>).</p> <p>Methods and Results</p> <p>Simulations were carried out using the PSpice program as previously described. When the electric field (EF) mechanism was dominant (0, 1, and 10 gj-channels), the longer the chain length, the faster the overall velocity (<it>θ</it>_ov). There seems to be no simple explanation for this phenomenon. In contrast, when the local-circuit current mechanism was dominant (100 gj-channels or more), <it>θ</it>_ovwas slightly slowed with lengthening of the chain. Increasing the number of gj-channels produced an increase in <it>θ</it>_ovand caused the firing order to become more uniform. The end-effect was more pronounced at longer chain lengths and at greater number of gj-channels.</p> <p>When there were no or only few gj-channels (namely, 0, 10, or 30), the voltage change (ΔV_m) in the two contiguous cells (#50 & #52) to the cell injected with current (#51) was nearly zero, i.e., there was a sharp discontinuity in voltage between the adjacent cells. When there were many gj-channels (e.g., 300, 1000, 3000), there was an exponential decay of voltage on either side of the injected cell, with the length constant (<it>λ</it>) increasing at higher numbers of gj-channels. The effect of increasing the number of gj-channels on increasing <it>λ </it>was relatively small compared to the larger effect on <it>θ</it>_ov. <it>θ</it>_ovbecame very non-physiological at 300 gj-channels or higher.</p> <p>Conclusion</p> <p>Thus, when there were only 0, 1, or 10 gj-channels, <it>θ</it>_ovincreased with increase in chain length, whereas at 100 gj-channels or higher, <it>θ</it>_ovdid not increase with chain length. When there were only 0, 10, or 30 gj-channels, there was a very sharp decrease in ΔV_min the two contiguous cells on either side of the injected cell, whereas at 300, 1000, or 3000 gj-channels, the voltage decay was exponential along the length of the chain. The effect of increasing the number of gj-channels on spread of current was relatively small compared to the large effect on <it>θ</it>_ov.</p

Transverse propagation of action potentials between parallel chains of cardiac muscle and smooth muscle cells in PSpice simulations

BACKGROUND: We previously examined transverse propagation of action potentials between 2 and 3 parallel chain of cardiac muscle cells (CMC) simulated using the PSpice program. The present study was done to examine transverse propagation between 5 parallel chains in an expanded model of CMC and smooth muscle cells (SMC). METHODS: Excitation was transmitted from cell to cell along a strand of 5 cells not connected by low-resistance tunnels (gap-junction connexons). The entire surface membrane of each cell fired nearly simultaneously, and nearly all the propagation time was spent at the cell junctions, the junctional delay time being about 0.3 – 0.5 ms (CMC) or 0.8 – 1.6 ms (SMC). A negative cleft potential (V(jc)) develops in the narrow junctional clefts, whose magnitude depends on the radial cleft resistance (R(jc)), which depolarizes the postjunctional membrane (post-JM) to threshold. Propagation velocity (θ) increased with amplitude of V(jc). Therefore, one mechanism for the transfer of excitation from one cell to the next is by the electric field (EF) that is generated in the junctional cleft when the pre-JM fires. In the present study, 5 parallel stands of 5 cells each (5 × 5 model) were used. RESULTS: With electrical stimulation of the first cell of the first strand (cell A1), propagation rapidly spread down that chain and then jumped to the second strand (B chain), followed by jumping to the third, fourth, and fifth strands (C, D, E chains). The rapidity by which the parallel chains became activated depended on the longitudinal resistance of the narrow extracellular cleft between the parallel strands (R(ol2)); the higher the R(ol2 )resistance, the faster the θ. The transverse resistance of the cleft (R(or2)) had almost no effect. Increasing R(jc )decreases the total propagation time (TPT) over the 25-cell network. When the first cell of the third strand (cell C1) was stimulated, propagation spread down the C chain and jumped to the other two strands (B and D) nearly simultaneously. CONCLUSIONS: Transverse propagation of excitation occurred at multiple points along the chain as longitudinal propagation was occurring, causing the APs in the contiguous chains to become bunched up. Transverse propagation was more erratic and labile in SMC compared to CMC. Transverse transmission of excitation did not require low-resistance connections between the chains, but instead depended on the value of R(ol2). The tighter the packing of the chains facilitated transverse propagation

Chronic Nicotine Modifies Skeletal Muscle Na,K-ATPase Activity through Its Interaction with the Nicotinic Acetylcholine Receptor and Phospholemman

Our previous finding that the muscle nicotinic acetylcholine receptor (nAChR) and the Na,K-ATPase interact as a regulatory complex to modulate Na,K-ATPase activity suggested that chronic, circulating nicotine may alter this interaction, with long-term changes in the membrane potential. To test this hypothesis, we chronically exposed rats to nicotine delivered orally for 21–31 days. Chronic nicotine produced a steady membrane depolarization of ∼3 mV in the diaphragm muscle, which resulted from a net change in electrogenic transport by the Na,K-ATPase α2 and α1 isoforms. Electrogenic transport by the α2 isoform increased (+1.8 mV) while the activity of the α1 isoform decreased (−4.4 mV). Protein expression of Na,K-ATPase α1 or α2 isoforms and the nAChR did not change; however, the content of α2 subunit in the plasma membrane decreased by 25%, indicating that its stimulated electrogenic transport is due to an increase in specific activity. The physical association between the nAChR, the Na,K-ATPase α1 or α2 subunits, and the regulatory subunit of the Na,K-ATPase, phospholemman (PLM), measured by co-immuno precipitation, was stable and unchanged. Chronic nicotine treatment activated PKCα/β2 and PKCδ and was accompanied by parallel increases in PLM phosphorylation at Ser63 and Ser68. Collectively, these results demonstrate that nicotine at chronic doses, acting through the nAChR-Na,K-ATPase complex, is able to modulate Na,K-ATPase activity in an isoform-specific manner and that the regulatory range includes both stimulation and inhibition of enzyme activity. Cholinergic modulation of Na,K-ATPase activity is achieved, in part, through activation of PKC and phosphorylation of PLM

Increased Short-Term Variability of the QT Interval in Professional Soccer Players: Possible Implications for Arrhythmia Prediction

BACKGROUND: Sudden cardiac death in competitive athletes is rare but it is significantly more frequent than in the normal population. The exact cause is seldom established and is mostly attributed to ventricular fibrillation. Myocardial hypertrophy and slow heart rate, both characteristic changes in top athletes in response to physical conditioning, could be associated with increased propensity for ventricular arrhythmias. We investigated conventional ECG parameters and temporal short-term beat-to-beat variability of repolarization (STV(QT)), a presumptive novel parameter for arrhythmia prediction, in professional soccer players. METHODS: Five-minute 12-lead electrocardiograms were recorded from professional soccer players (n = 76, all males, age 22.0±0.61 years) and age-matched healthy volunteers who do not participate in competitive sports (n = 76, all males, age 22.0±0.54 years). The ECGs were digitized and evaluated off-line. The temporal instability of beat-to-beat heart rate and repolarization were characterized by the calculation of short-term variability of the RR and QT intervals. RESULTS: Heart rate was significantly lower in professional soccer players at rest (61±1.2 vs. 72±1.5/min in controls). The QT interval was prolonged in players at rest (419±3.1 vs. 390±3.6 in controls, p<0.001). QTc was significantly longer in players compared to controls calculated with Fridericia and Hodges correction formulas. Importantly, STV(QT) was significantly higher in players both at rest and immediately after the game compared to controls (4.8±0.14 and 4.3±0.14 vs. 3.5±0.10 ms, both p<0.001, respectively). CONCLUSIONS: STV(QT) is significantly higher in professional soccer players compared to age-matched controls, however, further studies are needed to relate this finding to increased arrhythmia propensity in this population

Serotonin Augments Gut Pacemaker Activity via 5-HT3 Receptors

Serotonin (5-hydroxytryptamine: 5-HT) affects numerous functions in the gut, such as secretion, muscle contraction, and enteric nervous activity, and therefore to clarify details of 5-HT's actions leads to good therapeutic strategies for gut functional disorders. The role of interstitial cells of Cajal (ICC), as pacemaker cells, has been recognised relatively recently. We thus investigated 5-HT actions on ICC pacemaker activity. Muscle preparations with myenteric plexus were isolated from the murine ileum. Spatio-temporal measurements of intracellular Ca2+ and electric activities in ICC were performed by employing fluorescent Ca2+ imaging and microelectrode array (MEA) systems, respectively. Dihydropyridine (DHP) Ca2+ antagonists and tetrodotoxin (TTX) were applied to suppress smooth muscle and nerve activities, respectively. 5-HT significantly enhanced spontaneous Ca2+ oscillations that are considered to underlie electric pacemaker activity in ICC. LY-278584, a 5-HT3 receptor antagonist suppressed spontaneous Ca2+ activity in ICC, while 2-methylserotonin (2-Me-5-HT), a 5-HT3 receptor agonist, restored it. GR113808, a selective antagonist for 5-HT4, and O-methyl-5-HT (O-Me-5-HT), a non-selective 5-HT receptor agonist lacking affinity for 5-HT3 receptors, had little effect on ICC Ca2+ activity. In MEA measurements of ICC electric activity, 5-HT and 2-Me-5-HT caused excitatory effects. RT-PCR and immunostaining confirmed expression of 5-HT3 receptors in ICC. The results indicate that 5-HT augments ICC pacemaker activity via 5-HT3 receptors. ICC appear to be a promising target for treatment of functional motility disorders of the gut, for example, irritable bowel syndrome