American Journal of Physiology-heart and Circulatory Physiology, Nov 1, 1994
The atrioventricular node (AVN) is vital to normal cardiac function. The present report describes... more The atrioventricular node (AVN) is vital to normal cardiac function. The present report describes the properties of L-type calcium current (ICa) in rod- and spindle-shaped myocytes isolated from the rabbit AVN. With depolarizing voltage clamps from a holding potential of -40 mV, a rapidly activating ICa was observed, which peaked at +10 mV in most cells and exhibited a "bell-shaped" current-voltage relation. ICa was abolished by nifedipine (2-20 microM) and cadmium (100-200 microM) and was greatly reduced by manganese (1 mM). At +10 mV, time to peak ICa was 3.3 +/- 0.15 (SE) ms (n = 12) and ICa current density was 9.3 +/- 1.2 pA/pF (n = 9). Steady-state activation and inactivation curves for ICa showed half-maximal activation at -3.6 mV [slope factor (k) = 6.6 mV] and half-maximal inactivation at -25.8 mV (k = 6.5 mV). The time course of decay of ICa during a depolarizing pulse was voltage dependent and biexponential. The time course of recovery of ICa from inactivation was also biexponential (with two time constants tau 1 = 194.7 and tau 2 = 907.4 ms). Under current clamp, spontaneous action potentials from AVN cells were blocked by nifedipine as well as by cadmium, suggesting that L-type ICa was largely responsible for the action potential upstroke.
The electrophysiological properties of pulmonary vein (PV)-cardiomyocytes, and their responses to... more The electrophysiological properties of pulmonary vein (PV)-cardiomyocytes, and their responses to the sympathetic neurotransmitter, noradrenaline (NA), are thought to differ from those of the left atrium (LA) and contribute to atrial ectopy. The aim of this study was to examine rat PV cardiomyocyte electrophysiology and responses to NA in comparison with LA cells. LA and PV cardiomyocytes were isolated from adult male Wistar rat hearts, and membrane potentials and ion currents recorded at 36°C using whole-cell patch-clamp techniques. PV and LA cardiomyocytes did not differ in size. In control, there were no differences between the two cell-types in zero-current potential or action potential duration (APD) at 1 Hz, although the incidence of early afterdepolarizations (EADs) was greater in PV than LA cardiomyocytes. The L-type Ca 2+ current (I CaL) was ~×1.5 smaller (p = .0029, Student's t test) and the steady-state K + current (I Kss) was ~×1.4 larger (p = .0028, Student's t test) in PV than in LA cardiomyocytes. PV cardiomyocyte inward-rectifier current (I K1) was slightly smaller than LA cardiomyocyte I K1. In LA cardiomyocytes, NA significantly prolonged APD 30. In PV cells, APD 30 responses to 1 μM NA were heterogeneous: while the mean percentage change in APD 30 was not different from 0 (16.5 ± 9.7%, n cells/N animals = 12/10, p = .1177, one-sample t test), three cells showed shortening (-18.8 ± 6.0%) whereas nine showed prolongation (28.3 ± 10.1%, p = .008, Student's t test). NA had no effect on I K1 in either cell-type but inhibited PV I Kss by 41.9 ± 4.1% (n/N = 23/11 p < .0001), similar to LA cells. NA increased I CaL in most PV cardiomyocytes (median × 2.2-increase, p < .0001, n/N = 32/14, Wilcoxonsigned-rank test), although in 7/32 PV cells I CaL was decreased following NA. PV cardiomyocytes differ from LA cells and respond heterogeneously to NA. K E Y W O R D S action potential, delayed afterdepolarization, early afterdepolarization, inward-rectifier K + current (I K1), L-type Ca 2+ current (I CaL), noradrenaline, pulmonary vein sleeves, steady-state K + current (I Kss), triggered activity How to cite this article: Bond RC, Choisy SC, Bryant SM, Hancox JC, James AF. Ion currents, action potentials, and noradrenergic responses in rat pulmonary vein and left atrial cardiomyocytes.
Small conductance calcium-activated potassium channel current, IKCa, has recently been characteri... more Small conductance calcium-activated potassium channel current, IKCa, has recently been characterized in atrial tissue and linked with atrial arrhythmogenesis. As IKCa does not contribute significantly to the ventricular action potential, there is great interest in developing pharmacological agents targeting these channels. However, experimental data so far have presented conflicting evidence as to whether IKCa inhibition is pro-or anti-arrhythmic. We have created a new formulation for IKCa, which we included in recently developed heterogeneous and anisotropic 3D canine atrial models. These were applied to investigate the effect of IKCa blockade compared to inhibition of other potassium currents: IKr and IKur. Blocking IKCa led to the termination of AF in the 3D atrial model, in contrast to blockades of IKur or IKr. Blocking IKCa prolonged action potential duration, APD, by at least 20 ms in all atrial cell types, whereas IKr or IKur blocks did not increase APD by more than 10 ms, thus explaining IKCa's effectiveness in terminating AF. Nevertheless, the blockade of IKCa also led to an increase in APD dispersion, which is expected to be proarrhythmic. In cases when the APD dispersion effects dominate over the APD prolongation, the blockade of IKCa is expected to be pro-arrhythmic, as seen in experimental models of non-remodelled canine atria.
The congenital short QT syndrome (SQTS) is a cardiac condition that leads to abbreviated ventricu... more The congenital short QT syndrome (SQTS) is a cardiac condition that leads to abbreviated ventricular repolarization and an increased susceptibility to arrhythmia and sudden death. The SQT3 form of the syndrome is due to mutations to the KCNJ2 gene that encodes Kir2.1, a critical component of channels underlying cardiac inwardly rectifying K+ current, IK1. The first reported SQT3 KCNJ2 mutation gives rise to the D172N Kir2.1 mutation, the consequences of which have been studied on recombinant channels in vitro and in ventricular cell and tissue simulations. The aim of this study was to establish the effects of the D172N mutation on ventricular repolarization through real-time replacement of IK1 using the dynamic clamp technique. Whole-cell patch-clamp recordings were made from adult guinea-pig left ventricular myocytes at physiological temperature. Action potentials (APs) were elicited at 1 Hz. Intrinsic IK1 was inhibited with a low concentration (50 µM) of Ba2+ ions, which led to AP...
The atrioventricular node (AVN) can act as a subsidiary cardiac pacemaker if the sinoatrial node ... more The atrioventricular node (AVN) can act as a subsidiary cardiac pacemaker if the sinoatrial node fails. In this study, we investigated the effects of the Na–Ca exchange (NCX) inhibitor KB-R7943, and inhibition of the sarcoplasmic reticulum calcium ATPase (SERCA), using thapsigargin or cyclopiazonic acid (CPA), on spontaneous action potentials (APs) and [Ca]i transients from cells isolated from the rabbit AVN. Spontaneous [Ca]i transients were monitored from undialysed AVN cells at 37 ◦C using Fluo-4. In separate experiments, spontaneous APs and ionic currents were recorded using the whole-cell patch clamp technique. Rapid application of 5 M KB-R7943 slowed or stopped spontaneous APs and [Ca]i transients. However, in voltage clamp experiments in addition to blocking NCX current (I ) KB-R7943 trioventricular node (AVN)
Background: Some congenital heart conditions are very rare. In a climate of limited resources, a ... more Background: Some congenital heart conditions are very rare. In a climate of limited resources, a viewpoint could be advanced that identifying diagnostic criteria for such conditions and, through empiricism, effective treatments should suffice and that extensive mechanistic research is unnecessary. Taking the rare but dangerous short QT syndrome (SQTS) as an example, this article makes the case for the imperative to study such rare conditions, highlighting that this yields substantial and sometimes unanticipated benefits. Genetic forms of SQTS are rare, but the condition may be under-diagnosed and carries a risk of sudden death. Genotyping of SQTS patients has led to identification of clear ion channel/transporter culprits in < 30% of cases, highlighting a role for as yet unidentified modulators of repolarization. For example, recent exome sequencing in SQTS has identified SLC4A3 as a novel modifier of ventricular repolarization. The need to distinguish "healthy" from "unhealthy" short QT intervals has led to a search for additional markers of arrhythmia risk. Some overlap may exist between SQTS, Brugada Syndrome, early repolarization and sinus bradycardia. Genotype-phenotype studies have led to identification of arrhythmia substrates and both realistic and theoretical pharmacological approaches for particular forms of SQTS. In turn this has increased understanding of underlying cardiac ion channels. In silico and pharmacological data have highlighted risks with abbreviation of refractoriness accompanied by local dispersion of repolarization, and this urges caution with the deployment of K + channel activation as a novel antiarrhythmic approach. The association between abbreviated QT c intervals and primary carnitine deficiency, particularly in patients with concomitant cardiomyopathy illustrates a link between metabolism and electrogenesis, in which the correct identification of causation could, in some cases, lead to dietary intervention that may obviate the need for antiarrhythmic or heart failure drugs. Conclusions: As illustrated here for the SQTS, the detailed study of rare disorders is both directly beneficial for the treatment/management of affected patients and for increasing the understanding of associated underlying cardiac physiology and pharmacology. The pursuit of underlying gene mutations can lead to unanticipated new links between particular genes and cardiac electrophysiology, opening new avenues for research and potential therapeutic intervention.
Biochemical and Biophysical Research Communications, 2019
Inhibition of SK channel function is being pursued in animal models as a possible therapeutic app... more Inhibition of SK channel function is being pursued in animal models as a possible therapeutic approach to treat atrial fibrillation (AF). However, the pharmacology of SK channels in human atria is unclear. SK channel function is inhibited by both apamin and UCL1684, with the former discriminating between SK channel subtypes. In this proof-of-principle study, the effects of apamin and UCL1684 on right atrial myocytes freshly isolated from patients in sinus rhythm undergoing elective cardiac surgery were investigated. Outward current evoked from voltage clamped human atrial myocytes was reduced by these two inhibitors of SK channel function. In contrast, membrane current underlying the atrial action potential was affected significantly only by UCL1684 and not by apamin. This pharmacology mirrors that observed in mouse atria, suggesting that mammalian atria possess two populations of SK channels, with only one population contributing to the action potential waveform. Immunovisualization of the subcellular localization of SK2 and SK3 subunits showed a high degree of colocalization, consistent with the formation of heteromeric SK2/SK3 channels. These data reveal that human atrial myocytes express two SK channel subtypes, one exhibiting an unusual pharmacology. These channels contribute to the atrial action potential waveform and might be a target for novel therapeutic approaches to treat supraventricular arrhythmic conditions such as atrial fibrillation.
Highlights • The short QT syndrome (SQTS) is a rare condition associated with atrial and ventricu... more Highlights • The short QT syndrome (SQTS) is a rare condition associated with atrial and ventricular arrhythmias and a risk of sudden death. Implantable devices and antiarrhythmic pharmacology are used to treat the syndrome. • There are 8 successfully genotyped variants, involving gain-of-function mutations to K + ion channel genes (SQT1-3) or loss-of-function mutations to Ca 2+ channel subunit genes (SQT4-6), to a Na + channel gene (SQT7) and to an anion exchanger (SQT8). • Information from patients and in vitro and in silico experiments indicates important roles for abbreviated refractoriness, dispersion of repolarisation and a shortened wavelength for re-entry in arrhythmia substrates in the SQTS. • A combination K + current inhibition during the action potential plateau, with sodium
Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the shor... more Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysicallydetailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in I K1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on I K1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of I K1 and I Kr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas I Kr block alone may be a safer alternative for the E299V mutation. Combined inhibition of I Kr and I Kur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF.
Class 1 antiarrhythmic drugs are highly effective in restoring and maintaining sinus rhythm in at... more Class 1 antiarrhythmic drugs are highly effective in restoring and maintaining sinus rhythm in atrial fibrillation patients but carry a risk of ventricular tachyarrhythmia. The anti-anginal agent, ranolazine, is a prototypic atrial-selective voltage-gated Na(+) channel blocker but the mechanisms underlying its atrial-selective action remain unclear. The present study examined the mechanisms underlying the atrial-selective action of ranolazine. Whole-cell voltage-gated Na(+) currents (INa) were recorded at room temperature (∼22 °C) from rabbit isolated left atrial and right ventricular myocytes. INa conductance density was ∼1.8-fold greater in atrial than in ventricular cells. Atrial INa was activated at command potentials ∼7 mV more negative and inactivated at conditioning potentials ∼11 mV more negative than ventricular INa. The onset of inactivation of INa was faster in atrial cells than in ventricular myocytes. Ranolazine (30 μM) inhibited INa in atrial and ventricular myocytes i...
Transient outward potassium current (I to) in the heart underlies phase 1 repolarization of cardi... more Transient outward potassium current (I to) in the heart underlies phase 1 repolarization of cardiac action potentials and thereby affects excitation-contraction coupling. Small molecule activators of I to may therefore offer novel treatments for cardiac dysfunction, including heart failure and atrial fibrillation. NS5806 has been identified as a prototypic activator of canine I to. This study investigated, for the first time, actions of NS5806 on rabbit atrial and ventricular I to. Whole cell patch-clamp recordings of I to and action potentials were made at physiological temperature from rabbit ventricular and atrial myocytes. 10 lmol/L NS5806 increased ventricular I to with a leftward shift in I to activation and accelerated restitution. At higher concentrations, stimulation of I to was followed by inhibition. The EC 50 for stimulation was 1.6 lmol/L and inhibition had an IC 50 of 40.7 lmol/L. NS5806 only inhibited atrial I to (IC 50 of 18 lmol/L) and produced a modest leftward shifts in I to activation and inactivation, without an effect on restitution. 10 lmol/L NS5806 shortened ventricular action potential duration (APD) at APD 20-APD 90 but prolonged atrial APD. NS5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio-selective effect on Na + channels. In contrast to NS5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial I to. NS5806 discriminates between rabbit ventricular and atrial I to, with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac I to .
American journal of physiology. Heart and circulatory physiology, Jan 6, 2016
Atrial L-type Ca(2+) current (ICaL) downregulation in heart failure contributes to the pathogenes... more Atrial L-type Ca(2+) current (ICaL) downregulation in heart failure contributes to the pathogenesis of atrial fibrillation and is proposed to involve reduction in channel phosphorylation by PKA. The regulation of atrial ICaL was examined in heart failure. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, N=10) or equivalent sham-operation (Sham, N=12). Left atrial myocytes were isolated ~18 weeks post-surgery and whole-cell currents recorded (holding potential=-80 mV). ICaL activated by depolarizing pulses to voltages from -40 to +50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cells were larger than Sham (94.7±5.2 pF; n=63 vs 56.6±2.1 pF; n=47; P≤0.0001). Maximal ICaL conductance (Gmax) was downregulated in CAL (Gmax: 140.6±16.5 pS/pF, n/N=31/10; Sham 288.4±24.2 pS/pF, n/N=32/12; P<0.0001). Norepinephrine (NE; 1 μmol/L) increased Gmax >50% more effectively in CAL (2.72-fold) than in Sham (1.78-fo...
Journal of molecular and cellular cardiology, Aug 27, 2016
Background inward sodium current (IB,Na) that influences cardiac pacemaking has been comparativel... more Background inward sodium current (IB,Na) that influences cardiac pacemaking has been comparatively under-investigated. The aim of this study was to determine for the first time the properties and role of IB,Na in cells from the heart's secondary pacemaker, the atrioventricular node (AVN). Myocytes were isolated from the AVN of adult male rabbits and mice using mechanical and enzymatic dispersion. Background current was measured using whole-cell patch clamp and monovalent ion substitution with major voltage- and time-dependent conductances inhibited. In the absence of a selective pharmacological inhibitor of IB,Na, computer modelling was used to assess the physiological contribution of IB,Na. Net background current during voltage ramps was linear, reversing close to 0mV. Switching between Tris- and Na(+)-containing extracellular solution in rabbit and mouse AVN cells revealed an inward IB,Na, with an increase in slope conductance in rabbit cells at -50mV from 0.54±0.03 to 0.91±0....
Aims Atrial stunning, a loss of atrial mechanical contraction, can occur following a successful c... more Aims Atrial stunning, a loss of atrial mechanical contraction, can occur following a successful cardioversion. It is hypothesized that persistent atrial fibrillation-induced electrical remodeling (AFER) on atrial electrophysiology may be responsible for such impaired atrial mechanics. This simulation study aimed to investigate the effects of AFER on atrial electro-mechanics. Methods and Results A 3D electromechanical model of the human atria was developed to investigate the effects of AFER on atrial electro-mechanics. Simulations were carried out in 3 conditions for 4 states: (i) the control condition, representing the normal tissue (state 1) and the tissue 2-3 months after cardioversion (state 2) when the atrial tissue recovers its electrophysiological properties after completion of reverse electrophysiological remodelling; (ii) AFER-SR condition for AF-remodeled tissue with normal sinus rhythm (SR) (state 3); and (iii) AFER-AF condition for AF-remodeled tissue with re-entrant excitation waves (state 4). Our results indicate that at the cellular level, AFER (states 3 & 4) abbreviated action potentials and reduced the Ca 2+ content in the sarcoplasmic reticulum, resulting in a reduced amplitude of the intracellular Ca 2+ transient leading to decreased cell active force and cell shortening as compared to the control condition (states 1 & 2). Consequently at the whole organ level, atrial contraction in AFER-SR condition (state 3) was dramatically reduced. In the AFER-AF condition (state 4) atrial contraction was almost abolished.
4-Aminopyridine (4-AP) is used extensively in the field of cardiac muscle electrophysiology to st... more 4-Aminopyridine (4-AP) is used extensively in the field of cardiac muscle electrophysiology to study the role (s) in cardiac tissue of transient outward K + current (I to). Although millimolar 4-AP is widely considered to be selective for I to , results of a previous study from this laboratory suggested that 4-AP might, in addition, exert an inhibitory effect on the rapid delayed rectifier K + current, I Kr (Mitcheson & Hancox, 1999). The aim of the present study was to investigate further this possibility, by characterising effects of 4-AP on heterologously expressed HERG channels, since HERG (human-ether-ago go related gene) encodes the pore-forming subunit of channels responsible for I Kr (Sanguinetti & Keating, 1997). Measurements of whole-cell HERG current (I HERG) were made at 37 ± 1°C from a mammalian cell line (HEK-293) stably expressing HERG (Zhou et al. 1998). I HERG 'tail' amplitude was monitored at _40 mV, following activating pulses to +30 mV. 4-AP was found to exert a concentration-dependent inhibitory effect on I HERG , with a half-maximal inhibitory concentration (IC 50) of 4.4 ± 0.5 mM (mean ± S.E.M.; n = minimum of 5 cells for each of seven 4-AP concentrations between 0.1 and 100 mM). Positive control experiments under similar conditions with the methanesulphonanilide HERG blocker E-4031 gave an IC 50 value near to 12 nM, which is close to an IC 50 value (7.7 nM) observed previously for E-4031 with this cell line (Zhou et al. 1998). Inhibition of I HERG by 5 mM 4-AP was observed to be voltage dependent; 4-AP also shifted voltage-dependent activation of I HERG towards more negative voltages, producing a mean shift in half-maximal activation of _7.4 ± 0.9 mV (n = 8 cells). In experiments utilising a ventricular AP waveform as the voltage command, 5 mM 4-AP suppressed the peak outward I HERG elicited during the AP repolarisation phase by 58.5 ± 4.1 % (n = 5 cells). We conclude that 4-AP is a low-affinity blocker of cardiac HERG potassium channels, blocking I HERG with a potency similar to that suggested for I Kr from previous experiments on rabbit native cardiomyocytes (Mitcheson & Hancox, 1999). Since 4-AP concentrations in the millimolar range are used in investigations of cardiac I to , our results confirm that an accessory inhibitory effect on I Kr may need to be taken into account in interpreting data that might otherwise be ascribed to selective inhibition of I to .
The atrioventricular node (AVN) is a key component of the cardiac pacemaker-conduction system. Th... more The atrioventricular node (AVN) is a key component of the cardiac pacemaker-conduction system. This study investigated the electrophysiology of cells isolated from the AVN region of adult mouse hearts, and compared murine ionic current magnitude with that of cells from the more extensively studied rabbit AVN. Whole-cell patch-clamp recordings of ionic currents, and perforated-patch recordings of action potentials (APs), were made at 35-37°C. Hyperpolarizing voltage commands from -40 mV elicited a Ba(2+)-sensitive inward rectifier current that was small at diastolic potentials. Some cells (Type 1; 33.4 ± 2.2 pF; n = 19) lacked the pacemaker current, If, whilst others (Type 2; 34.2 ± 1.5 pF; n = 21) exhibited a clear If, which was larger than in rabbit AVN cells. On depolarization from -40 mV L-type Ca(2+) current, IC a,L, was elicited with a half maximal activation voltage (V0.5) of -7.6 ± 1.2 mV (n = 24). IC a,L density was smaller than in rabbit AVN cells. Rapid delayed rectifier (...
Noradrenaline plays an important role in the modulation of atrial electrophysiology. However, the... more Noradrenaline plays an important role in the modulation of atrial electrophysiology. However, the identity of the modulated channels, their mechanisms of modulation, and their role in the action potential remain unclear. This study aimed to investigate the noradrenergic modulation of an atrial steady-state outward current (IKss). Rat atrial myocyte whole-cell currents were recorded at 36°C. Noradrenaline potently inhibited IKss (IC50 = 0.90 nM, 42.1 ± 4.3% at 1 µM, n = 7) and potentiated the L-type Ca(2+) current (ICaL, EC50 = 136 nM, 205 ± 40% at 1 µM, n = 6). Noradrenaline-sensitive IKss was weakly voltage-dependent, time-independent, and potentiated by the arachidonic acid analogue, 5,8,11,14-eicosatetraynoic acid (EYTA; 10 µM), or by osmotically induced membrane stretch. Noise analysis revealed a unitary conductance of 8.4 ± 0.42 pS (n = 8). The biophysical/pharmacological properties of IKss indicate a TREK-like K(+) channel. The effect of noradrenaline on IKss was abolished by ...
Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively lit... more Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively little is known about its effects on the function of the atrio-ventricular node (AVN). In this study, the electrical activity of the epicardial surface of the left ventricle of isolated Langendorff-perfused rabbit hearts was examined using optical methods. Perfusion with hypercapnic Tyrode's solution (20% CO 2 , pH 6.7) increased the time of earliest activation (T act) from 100.5 ± 7.9 to 166.1 ± 7.2 ms (n = 8) at a pacing cycle length (PCL) of 300 ms (37 • C). T act increased at shorter PCL, and the hypercapnic solution prolonged T act further: at 150 ms PCL, T act was prolonged from 131.0 ± 5.2 to 174.9 ± 16.3 ms. 2:1 AVN block was common at shorter cycle lengths. Atrial and ventricular conduction times were not significantly affected by the hypercapnic solution suggesting that the increased delay originated in the AVN. Isolated right atrial preparations were superfused with Tyrode's solutions at pH 7.4 (control), 6.8 and 6.3. Low pH prolonged the atrial-Hisian (AH) interval, the AVN effective and functional refractory periods and Wenckebach cycle length significantly. Complete AVN block occurred in 6 out of 9 preparations. Optical imaging of conduction at the AV junction revealed increased conduction delay in the region of the AVN, with less marked effects in atrial and ventricular tissue. Thus acidosis can dramatically prolong the AVN delay, and in combination with short cycle lengths, this can cause partial or complete AVN block and is therefore implicated in the development of brady-arrhythmias in conditions of local or systemic acidosis.
American Journal of Physiology-heart and Circulatory Physiology, Nov 1, 1994
The atrioventricular node (AVN) is vital to normal cardiac function. The present report describes... more The atrioventricular node (AVN) is vital to normal cardiac function. The present report describes the properties of L-type calcium current (ICa) in rod- and spindle-shaped myocytes isolated from the rabbit AVN. With depolarizing voltage clamps from a holding potential of -40 mV, a rapidly activating ICa was observed, which peaked at +10 mV in most cells and exhibited a &amp;amp;amp;amp;quot;bell-shaped&amp;amp;amp;amp;quot; current-voltage relation. ICa was abolished by nifedipine (2-20 microM) and cadmium (100-200 microM) and was greatly reduced by manganese (1 mM). At +10 mV, time to peak ICa was 3.3 +/- 0.15 (SE) ms (n = 12) and ICa current density was 9.3 +/- 1.2 pA/pF (n = 9). Steady-state activation and inactivation curves for ICa showed half-maximal activation at -3.6 mV [slope factor (k) = 6.6 mV] and half-maximal inactivation at -25.8 mV (k = 6.5 mV). The time course of decay of ICa during a depolarizing pulse was voltage dependent and biexponential. The time course of recovery of ICa from inactivation was also biexponential (with two time constants tau 1 = 194.7 and tau 2 = 907.4 ms). Under current clamp, spontaneous action potentials from AVN cells were blocked by nifedipine as well as by cadmium, suggesting that L-type ICa was largely responsible for the action potential upstroke.
The electrophysiological properties of pulmonary vein (PV)-cardiomyocytes, and their responses to... more The electrophysiological properties of pulmonary vein (PV)-cardiomyocytes, and their responses to the sympathetic neurotransmitter, noradrenaline (NA), are thought to differ from those of the left atrium (LA) and contribute to atrial ectopy. The aim of this study was to examine rat PV cardiomyocyte electrophysiology and responses to NA in comparison with LA cells. LA and PV cardiomyocytes were isolated from adult male Wistar rat hearts, and membrane potentials and ion currents recorded at 36°C using whole-cell patch-clamp techniques. PV and LA cardiomyocytes did not differ in size. In control, there were no differences between the two cell-types in zero-current potential or action potential duration (APD) at 1 Hz, although the incidence of early afterdepolarizations (EADs) was greater in PV than LA cardiomyocytes. The L-type Ca 2+ current (I CaL) was ~×1.5 smaller (p = .0029, Student's t test) and the steady-state K + current (I Kss) was ~×1.4 larger (p = .0028, Student's t test) in PV than in LA cardiomyocytes. PV cardiomyocyte inward-rectifier current (I K1) was slightly smaller than LA cardiomyocyte I K1. In LA cardiomyocytes, NA significantly prolonged APD 30. In PV cells, APD 30 responses to 1 μM NA were heterogeneous: while the mean percentage change in APD 30 was not different from 0 (16.5 ± 9.7%, n cells/N animals = 12/10, p = .1177, one-sample t test), three cells showed shortening (-18.8 ± 6.0%) whereas nine showed prolongation (28.3 ± 10.1%, p = .008, Student's t test). NA had no effect on I K1 in either cell-type but inhibited PV I Kss by 41.9 ± 4.1% (n/N = 23/11 p < .0001), similar to LA cells. NA increased I CaL in most PV cardiomyocytes (median × 2.2-increase, p < .0001, n/N = 32/14, Wilcoxonsigned-rank test), although in 7/32 PV cells I CaL was decreased following NA. PV cardiomyocytes differ from LA cells and respond heterogeneously to NA. K E Y W O R D S action potential, delayed afterdepolarization, early afterdepolarization, inward-rectifier K + current (I K1), L-type Ca 2+ current (I CaL), noradrenaline, pulmonary vein sleeves, steady-state K + current (I Kss), triggered activity How to cite this article: Bond RC, Choisy SC, Bryant SM, Hancox JC, James AF. Ion currents, action potentials, and noradrenergic responses in rat pulmonary vein and left atrial cardiomyocytes.
Small conductance calcium-activated potassium channel current, IKCa, has recently been characteri... more Small conductance calcium-activated potassium channel current, IKCa, has recently been characterized in atrial tissue and linked with atrial arrhythmogenesis. As IKCa does not contribute significantly to the ventricular action potential, there is great interest in developing pharmacological agents targeting these channels. However, experimental data so far have presented conflicting evidence as to whether IKCa inhibition is pro-or anti-arrhythmic. We have created a new formulation for IKCa, which we included in recently developed heterogeneous and anisotropic 3D canine atrial models. These were applied to investigate the effect of IKCa blockade compared to inhibition of other potassium currents: IKr and IKur. Blocking IKCa led to the termination of AF in the 3D atrial model, in contrast to blockades of IKur or IKr. Blocking IKCa prolonged action potential duration, APD, by at least 20 ms in all atrial cell types, whereas IKr or IKur blocks did not increase APD by more than 10 ms, thus explaining IKCa's effectiveness in terminating AF. Nevertheless, the blockade of IKCa also led to an increase in APD dispersion, which is expected to be proarrhythmic. In cases when the APD dispersion effects dominate over the APD prolongation, the blockade of IKCa is expected to be pro-arrhythmic, as seen in experimental models of non-remodelled canine atria.
The congenital short QT syndrome (SQTS) is a cardiac condition that leads to abbreviated ventricu... more The congenital short QT syndrome (SQTS) is a cardiac condition that leads to abbreviated ventricular repolarization and an increased susceptibility to arrhythmia and sudden death. The SQT3 form of the syndrome is due to mutations to the KCNJ2 gene that encodes Kir2.1, a critical component of channels underlying cardiac inwardly rectifying K+ current, IK1. The first reported SQT3 KCNJ2 mutation gives rise to the D172N Kir2.1 mutation, the consequences of which have been studied on recombinant channels in vitro and in ventricular cell and tissue simulations. The aim of this study was to establish the effects of the D172N mutation on ventricular repolarization through real-time replacement of IK1 using the dynamic clamp technique. Whole-cell patch-clamp recordings were made from adult guinea-pig left ventricular myocytes at physiological temperature. Action potentials (APs) were elicited at 1 Hz. Intrinsic IK1 was inhibited with a low concentration (50 µM) of Ba2+ ions, which led to AP...
The atrioventricular node (AVN) can act as a subsidiary cardiac pacemaker if the sinoatrial node ... more The atrioventricular node (AVN) can act as a subsidiary cardiac pacemaker if the sinoatrial node fails. In this study, we investigated the effects of the Na–Ca exchange (NCX) inhibitor KB-R7943, and inhibition of the sarcoplasmic reticulum calcium ATPase (SERCA), using thapsigargin or cyclopiazonic acid (CPA), on spontaneous action potentials (APs) and [Ca]i transients from cells isolated from the rabbit AVN. Spontaneous [Ca]i transients were monitored from undialysed AVN cells at 37 ◦C using Fluo-4. In separate experiments, spontaneous APs and ionic currents were recorded using the whole-cell patch clamp technique. Rapid application of 5 M KB-R7943 slowed or stopped spontaneous APs and [Ca]i transients. However, in voltage clamp experiments in addition to blocking NCX current (I ) KB-R7943 trioventricular node (AVN)
Background: Some congenital heart conditions are very rare. In a climate of limited resources, a ... more Background: Some congenital heart conditions are very rare. In a climate of limited resources, a viewpoint could be advanced that identifying diagnostic criteria for such conditions and, through empiricism, effective treatments should suffice and that extensive mechanistic research is unnecessary. Taking the rare but dangerous short QT syndrome (SQTS) as an example, this article makes the case for the imperative to study such rare conditions, highlighting that this yields substantial and sometimes unanticipated benefits. Genetic forms of SQTS are rare, but the condition may be under-diagnosed and carries a risk of sudden death. Genotyping of SQTS patients has led to identification of clear ion channel/transporter culprits in < 30% of cases, highlighting a role for as yet unidentified modulators of repolarization. For example, recent exome sequencing in SQTS has identified SLC4A3 as a novel modifier of ventricular repolarization. The need to distinguish "healthy" from "unhealthy" short QT intervals has led to a search for additional markers of arrhythmia risk. Some overlap may exist between SQTS, Brugada Syndrome, early repolarization and sinus bradycardia. Genotype-phenotype studies have led to identification of arrhythmia substrates and both realistic and theoretical pharmacological approaches for particular forms of SQTS. In turn this has increased understanding of underlying cardiac ion channels. In silico and pharmacological data have highlighted risks with abbreviation of refractoriness accompanied by local dispersion of repolarization, and this urges caution with the deployment of K + channel activation as a novel antiarrhythmic approach. The association between abbreviated QT c intervals and primary carnitine deficiency, particularly in patients with concomitant cardiomyopathy illustrates a link between metabolism and electrogenesis, in which the correct identification of causation could, in some cases, lead to dietary intervention that may obviate the need for antiarrhythmic or heart failure drugs. Conclusions: As illustrated here for the SQTS, the detailed study of rare disorders is both directly beneficial for the treatment/management of affected patients and for increasing the understanding of associated underlying cardiac physiology and pharmacology. The pursuit of underlying gene mutations can lead to unanticipated new links between particular genes and cardiac electrophysiology, opening new avenues for research and potential therapeutic intervention.
Biochemical and Biophysical Research Communications, 2019
Inhibition of SK channel function is being pursued in animal models as a possible therapeutic app... more Inhibition of SK channel function is being pursued in animal models as a possible therapeutic approach to treat atrial fibrillation (AF). However, the pharmacology of SK channels in human atria is unclear. SK channel function is inhibited by both apamin and UCL1684, with the former discriminating between SK channel subtypes. In this proof-of-principle study, the effects of apamin and UCL1684 on right atrial myocytes freshly isolated from patients in sinus rhythm undergoing elective cardiac surgery were investigated. Outward current evoked from voltage clamped human atrial myocytes was reduced by these two inhibitors of SK channel function. In contrast, membrane current underlying the atrial action potential was affected significantly only by UCL1684 and not by apamin. This pharmacology mirrors that observed in mouse atria, suggesting that mammalian atria possess two populations of SK channels, with only one population contributing to the action potential waveform. Immunovisualization of the subcellular localization of SK2 and SK3 subunits showed a high degree of colocalization, consistent with the formation of heteromeric SK2/SK3 channels. These data reveal that human atrial myocytes express two SK channel subtypes, one exhibiting an unusual pharmacology. These channels contribute to the atrial action potential waveform and might be a target for novel therapeutic approaches to treat supraventricular arrhythmic conditions such as atrial fibrillation.
Highlights • The short QT syndrome (SQTS) is a rare condition associated with atrial and ventricu... more Highlights • The short QT syndrome (SQTS) is a rare condition associated with atrial and ventricular arrhythmias and a risk of sudden death. Implantable devices and antiarrhythmic pharmacology are used to treat the syndrome. • There are 8 successfully genotyped variants, involving gain-of-function mutations to K + ion channel genes (SQT1-3) or loss-of-function mutations to Ca 2+ channel subunit genes (SQT4-6), to a Na + channel gene (SQT7) and to an anion exchanger (SQT8). • Information from patients and in vitro and in silico experiments indicates important roles for abbreviated refractoriness, dispersion of repolarisation and a shortened wavelength for re-entry in arrhythmia substrates in the SQTS. • A combination K + current inhibition during the action potential plateau, with sodium
Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the shor... more Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysicallydetailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in I K1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on I K1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of I K1 and I Kr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas I Kr block alone may be a safer alternative for the E299V mutation. Combined inhibition of I Kr and I Kur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF.
Class 1 antiarrhythmic drugs are highly effective in restoring and maintaining sinus rhythm in at... more Class 1 antiarrhythmic drugs are highly effective in restoring and maintaining sinus rhythm in atrial fibrillation patients but carry a risk of ventricular tachyarrhythmia. The anti-anginal agent, ranolazine, is a prototypic atrial-selective voltage-gated Na(+) channel blocker but the mechanisms underlying its atrial-selective action remain unclear. The present study examined the mechanisms underlying the atrial-selective action of ranolazine. Whole-cell voltage-gated Na(+) currents (INa) were recorded at room temperature (∼22 °C) from rabbit isolated left atrial and right ventricular myocytes. INa conductance density was ∼1.8-fold greater in atrial than in ventricular cells. Atrial INa was activated at command potentials ∼7 mV more negative and inactivated at conditioning potentials ∼11 mV more negative than ventricular INa. The onset of inactivation of INa was faster in atrial cells than in ventricular myocytes. Ranolazine (30 μM) inhibited INa in atrial and ventricular myocytes i...
Transient outward potassium current (I to) in the heart underlies phase 1 repolarization of cardi... more Transient outward potassium current (I to) in the heart underlies phase 1 repolarization of cardiac action potentials and thereby affects excitation-contraction coupling. Small molecule activators of I to may therefore offer novel treatments for cardiac dysfunction, including heart failure and atrial fibrillation. NS5806 has been identified as a prototypic activator of canine I to. This study investigated, for the first time, actions of NS5806 on rabbit atrial and ventricular I to. Whole cell patch-clamp recordings of I to and action potentials were made at physiological temperature from rabbit ventricular and atrial myocytes. 10 lmol/L NS5806 increased ventricular I to with a leftward shift in I to activation and accelerated restitution. At higher concentrations, stimulation of I to was followed by inhibition. The EC 50 for stimulation was 1.6 lmol/L and inhibition had an IC 50 of 40.7 lmol/L. NS5806 only inhibited atrial I to (IC 50 of 18 lmol/L) and produced a modest leftward shifts in I to activation and inactivation, without an effect on restitution. 10 lmol/L NS5806 shortened ventricular action potential duration (APD) at APD 20-APD 90 but prolonged atrial APD. NS5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio-selective effect on Na + channels. In contrast to NS5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial I to. NS5806 discriminates between rabbit ventricular and atrial I to, with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac I to .
American journal of physiology. Heart and circulatory physiology, Jan 6, 2016
Atrial L-type Ca(2+) current (ICaL) downregulation in heart failure contributes to the pathogenes... more Atrial L-type Ca(2+) current (ICaL) downregulation in heart failure contributes to the pathogenesis of atrial fibrillation and is proposed to involve reduction in channel phosphorylation by PKA. The regulation of atrial ICaL was examined in heart failure. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, N=10) or equivalent sham-operation (Sham, N=12). Left atrial myocytes were isolated ~18 weeks post-surgery and whole-cell currents recorded (holding potential=-80 mV). ICaL activated by depolarizing pulses to voltages from -40 to +50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cells were larger than Sham (94.7±5.2 pF; n=63 vs 56.6±2.1 pF; n=47; P≤0.0001). Maximal ICaL conductance (Gmax) was downregulated in CAL (Gmax: 140.6±16.5 pS/pF, n/N=31/10; Sham 288.4±24.2 pS/pF, n/N=32/12; P<0.0001). Norepinephrine (NE; 1 μmol/L) increased Gmax >50% more effectively in CAL (2.72-fold) than in Sham (1.78-fo...
Journal of molecular and cellular cardiology, Aug 27, 2016
Background inward sodium current (IB,Na) that influences cardiac pacemaking has been comparativel... more Background inward sodium current (IB,Na) that influences cardiac pacemaking has been comparatively under-investigated. The aim of this study was to determine for the first time the properties and role of IB,Na in cells from the heart's secondary pacemaker, the atrioventricular node (AVN). Myocytes were isolated from the AVN of adult male rabbits and mice using mechanical and enzymatic dispersion. Background current was measured using whole-cell patch clamp and monovalent ion substitution with major voltage- and time-dependent conductances inhibited. In the absence of a selective pharmacological inhibitor of IB,Na, computer modelling was used to assess the physiological contribution of IB,Na. Net background current during voltage ramps was linear, reversing close to 0mV. Switching between Tris- and Na(+)-containing extracellular solution in rabbit and mouse AVN cells revealed an inward IB,Na, with an increase in slope conductance in rabbit cells at -50mV from 0.54±0.03 to 0.91±0....
Aims Atrial stunning, a loss of atrial mechanical contraction, can occur following a successful c... more Aims Atrial stunning, a loss of atrial mechanical contraction, can occur following a successful cardioversion. It is hypothesized that persistent atrial fibrillation-induced electrical remodeling (AFER) on atrial electrophysiology may be responsible for such impaired atrial mechanics. This simulation study aimed to investigate the effects of AFER on atrial electro-mechanics. Methods and Results A 3D electromechanical model of the human atria was developed to investigate the effects of AFER on atrial electro-mechanics. Simulations were carried out in 3 conditions for 4 states: (i) the control condition, representing the normal tissue (state 1) and the tissue 2-3 months after cardioversion (state 2) when the atrial tissue recovers its electrophysiological properties after completion of reverse electrophysiological remodelling; (ii) AFER-SR condition for AF-remodeled tissue with normal sinus rhythm (SR) (state 3); and (iii) AFER-AF condition for AF-remodeled tissue with re-entrant excitation waves (state 4). Our results indicate that at the cellular level, AFER (states 3 & 4) abbreviated action potentials and reduced the Ca 2+ content in the sarcoplasmic reticulum, resulting in a reduced amplitude of the intracellular Ca 2+ transient leading to decreased cell active force and cell shortening as compared to the control condition (states 1 & 2). Consequently at the whole organ level, atrial contraction in AFER-SR condition (state 3) was dramatically reduced. In the AFER-AF condition (state 4) atrial contraction was almost abolished.
4-Aminopyridine (4-AP) is used extensively in the field of cardiac muscle electrophysiology to st... more 4-Aminopyridine (4-AP) is used extensively in the field of cardiac muscle electrophysiology to study the role (s) in cardiac tissue of transient outward K + current (I to). Although millimolar 4-AP is widely considered to be selective for I to , results of a previous study from this laboratory suggested that 4-AP might, in addition, exert an inhibitory effect on the rapid delayed rectifier K + current, I Kr (Mitcheson & Hancox, 1999). The aim of the present study was to investigate further this possibility, by characterising effects of 4-AP on heterologously expressed HERG channels, since HERG (human-ether-ago go related gene) encodes the pore-forming subunit of channels responsible for I Kr (Sanguinetti & Keating, 1997). Measurements of whole-cell HERG current (I HERG) were made at 37 ± 1°C from a mammalian cell line (HEK-293) stably expressing HERG (Zhou et al. 1998). I HERG 'tail' amplitude was monitored at _40 mV, following activating pulses to +30 mV. 4-AP was found to exert a concentration-dependent inhibitory effect on I HERG , with a half-maximal inhibitory concentration (IC 50) of 4.4 ± 0.5 mM (mean ± S.E.M.; n = minimum of 5 cells for each of seven 4-AP concentrations between 0.1 and 100 mM). Positive control experiments under similar conditions with the methanesulphonanilide HERG blocker E-4031 gave an IC 50 value near to 12 nM, which is close to an IC 50 value (7.7 nM) observed previously for E-4031 with this cell line (Zhou et al. 1998). Inhibition of I HERG by 5 mM 4-AP was observed to be voltage dependent; 4-AP also shifted voltage-dependent activation of I HERG towards more negative voltages, producing a mean shift in half-maximal activation of _7.4 ± 0.9 mV (n = 8 cells). In experiments utilising a ventricular AP waveform as the voltage command, 5 mM 4-AP suppressed the peak outward I HERG elicited during the AP repolarisation phase by 58.5 ± 4.1 % (n = 5 cells). We conclude that 4-AP is a low-affinity blocker of cardiac HERG potassium channels, blocking I HERG with a potency similar to that suggested for I Kr from previous experiments on rabbit native cardiomyocytes (Mitcheson & Hancox, 1999). Since 4-AP concentrations in the millimolar range are used in investigations of cardiac I to , our results confirm that an accessory inhibitory effect on I Kr may need to be taken into account in interpreting data that might otherwise be ascribed to selective inhibition of I to .
The atrioventricular node (AVN) is a key component of the cardiac pacemaker-conduction system. Th... more The atrioventricular node (AVN) is a key component of the cardiac pacemaker-conduction system. This study investigated the electrophysiology of cells isolated from the AVN region of adult mouse hearts, and compared murine ionic current magnitude with that of cells from the more extensively studied rabbit AVN. Whole-cell patch-clamp recordings of ionic currents, and perforated-patch recordings of action potentials (APs), were made at 35-37°C. Hyperpolarizing voltage commands from -40 mV elicited a Ba(2+)-sensitive inward rectifier current that was small at diastolic potentials. Some cells (Type 1; 33.4 ± 2.2 pF; n = 19) lacked the pacemaker current, If, whilst others (Type 2; 34.2 ± 1.5 pF; n = 21) exhibited a clear If, which was larger than in rabbit AVN cells. On depolarization from -40 mV L-type Ca(2+) current, IC a,L, was elicited with a half maximal activation voltage (V0.5) of -7.6 ± 1.2 mV (n = 24). IC a,L density was smaller than in rabbit AVN cells. Rapid delayed rectifier (...
Noradrenaline plays an important role in the modulation of atrial electrophysiology. However, the... more Noradrenaline plays an important role in the modulation of atrial electrophysiology. However, the identity of the modulated channels, their mechanisms of modulation, and their role in the action potential remain unclear. This study aimed to investigate the noradrenergic modulation of an atrial steady-state outward current (IKss). Rat atrial myocyte whole-cell currents were recorded at 36°C. Noradrenaline potently inhibited IKss (IC50 = 0.90 nM, 42.1 ± 4.3% at 1 µM, n = 7) and potentiated the L-type Ca(2+) current (ICaL, EC50 = 136 nM, 205 ± 40% at 1 µM, n = 6). Noradrenaline-sensitive IKss was weakly voltage-dependent, time-independent, and potentiated by the arachidonic acid analogue, 5,8,11,14-eicosatetraynoic acid (EYTA; 10 µM), or by osmotically induced membrane stretch. Noise analysis revealed a unitary conductance of 8.4 ± 0.42 pS (n = 8). The biophysical/pharmacological properties of IKss indicate a TREK-like K(+) channel. The effect of noradrenaline on IKss was abolished by ...
Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively lit... more Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively little is known about its effects on the function of the atrio-ventricular node (AVN). In this study, the electrical activity of the epicardial surface of the left ventricle of isolated Langendorff-perfused rabbit hearts was examined using optical methods. Perfusion with hypercapnic Tyrode's solution (20% CO 2 , pH 6.7) increased the time of earliest activation (T act) from 100.5 ± 7.9 to 166.1 ± 7.2 ms (n = 8) at a pacing cycle length (PCL) of 300 ms (37 • C). T act increased at shorter PCL, and the hypercapnic solution prolonged T act further: at 150 ms PCL, T act was prolonged from 131.0 ± 5.2 to 174.9 ± 16.3 ms. 2:1 AVN block was common at shorter cycle lengths. Atrial and ventricular conduction times were not significantly affected by the hypercapnic solution suggesting that the increased delay originated in the AVN. Isolated right atrial preparations were superfused with Tyrode's solutions at pH 7.4 (control), 6.8 and 6.3. Low pH prolonged the atrial-Hisian (AH) interval, the AVN effective and functional refractory periods and Wenckebach cycle length significantly. Complete AVN block occurred in 6 out of 9 preparations. Optical imaging of conduction at the AV junction revealed increased conduction delay in the region of the AVN, with less marked effects in atrial and ventricular tissue. Thus acidosis can dramatically prolong the AVN delay, and in combination with short cycle lengths, this can cause partial or complete AVN block and is therefore implicated in the development of brady-arrhythmias in conditions of local or systemic acidosis.
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Papers by Jules Hancox