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Biomedical subjects

H J Duff

Publications and source records attributed to H J Duff.

At least 37 records · Page 2Linked to original sources
PubMed1997

Regulation of expression of the [3H]-dofetilide binding site associated with the delayed rectifier K+ channel by dexamethasone in neonatal mouse ventricle.

Developmental shortening of cardiac action potential duration in mouse appears to result, at least in part, from replacement of the rapid component of the delayed rectifying potassium current (IKr) with the transient outward current (ItO1). This developmental decrease in the IKr current density was paralleled by a loss of the high affinity [3H]-dofetilide binding site and loss of prolongation of action potential duration by dofetilide. Since glucocorticoid treatment prevented the developmental shortening of action potential duration in rats in the perinatal period, we hypothesized that chronic dexamethasone treatment would alter the developmental loss of IKr channel expression in mice. Accordingly, 10-day-old mice were randomly allocated to chronic in vivo dexamethasone treatment (1 mg/kg) or placebo treatment for 3-5 days. At 15 days of life, transmembrane action potentials were recorded in right ventricular endocardium and [3H]-dofetilide equilibrium binding studies were performed. The baseline action potential duration in the dexamethasone-treated animals was significantly greater than that in the control group (66+/-3 v 54+/-10 ms, respectively; P<0.01). Moreover, dofetilide significantly prolonged action potential duration in the dexamethasone-treated animals, but had no effect on the placebo-treated group (P<0.01). In addition, a high affinity [3H]-dofetilide binding site (Kd 96+/-21 nM and Bmax 69+/-13 fmoles/mg protein) was observed in the dexamethasone-treated group (n=5), whereas no specific [3H]-dofetilide binding was observed in the placebo-treated group. In conclusion, dexamethasone modulates developmental regulation of IKr channel expression in mouse ventricle.

Action Potentials↗
PubMed1997

Divergence of endocardial QT interval components during programmed electrical stimulation including observations during induction of sustained ventricular tachyarrhythmias.

Measurements were made in 12 normal subjects and during induction of sustained ventricular tachyarrhythmias in 31 patients with remote myocardial infarction. QT interval measurements were made semiautomatically with computer assistance and the total QT interval was divided into early (QT1) and late (QT2) components. QT intervals and QT interval dispersion between two right ventricular endocardial sites were plotted against the degree of prematurity of the last extrastimulus (S2, S3, or S4). In the control group, total QT and QT1 intervals shortened with increasing prematurity of the last extrastimulus (p < 0.001). Slopes (positive) were steeper with faster pacing rates (600, 500, or 400 ms) and more extrastimuli (1 to 3). The relationship between QT2 intervals and prematurity of the last extrastimulus was flat, but the slope was slightly negative (p = 0.05 to < 0.001) and did not vary with changes in pacing cycle length or number of extrastimuli. QT interval dispersion in the control group was minor (95% CI 0-40 ms). During induction of sustained ventricular tachyarrhythmias, total QT and QT1 intervals were longer (y intercepts) than in the control group (p < 0.05 at 400-ms pacing cycle length) and their dispersion was increased (p < 0.05). Generally, QT2 intervals were shorter (p < 0.05 at 600-ms pacing cycle length) during induction of ventricular arrhythmias in comparison with the control group but dispersion was increased (p < 0.05 at 400-ms pacing cycle length). QT intervals and QT interval dispersion show an orderly and predictable relationship with prematurity of the last extrastimulus in normal subjects. These patterns differ during induction of sustained ventricular tachyarrhythmias. Such differences may be exploited to derive clinically predictive and useful measurements.

Aged↗
PubMed1997

Developmental changes in transient outward current in mouse ventricle.

Developmental changes in the transient outward K+ current (Ito) in mouse ventricular myocytes were assessed by the whole-cell patch-clamp technique. The density of Ito in mouse ventricular myocytes was significantly increased from the day-1 neonate to the adult. At +50 mV, the density of Ito was 3 +/- 1 pA/pF in the day-1 neonate, 15 +/- 3 pA/pF in the day-14 neonate, and 19 +/- 4 pA/pF in the adult (P < .01). Unlike other species, the rate of Ito inactivation significantly slowed in mouse ventricular cells during development. Moreover, the time courses of inactivation and recovery from inactivation of Ito were well described by a monoexponential function in day-1 neonatal cells, whereas they were best fitted by a biexponential function in day-14 neonatal and adult cells. The characteristics of steady state inactivation were also significantly different in day-1 neonatal cells (half-inactivation potential [Vh] = -66 +/- 4 mV, slope factor [k] = 12 +/- 2 mV), in day-14 neonatal cells (Vh = -40 +/- 3 mV, k = 13 +/- 1 mV), and in adult cells (Vh = -34 +/- 4 mV, k = 6 +/- 1 mV). Microelectrode studies revealed that action potential duration progressively decreased in mouse ventricles during normal postnatal development. In addition, 4-aminopyridine (1 mmol/L) prolonged action potential duration more in adult than in neonatal mouse ventricles, suggesting that the developmental increase in the density of Ito contributes to the age-related shortening of action potential duration in mouse ventricles. In conclusion, Ito in adult mouse ventricular myocytes exhibits a higher density, slower inactivation kinetics, and a relatively more positive half-inactivation potential. All these characteristics result in Ito being a physiologically more important repolarizing K+ current in adult than in neonatal mouse hearts.

Action Potentials↗
PubMed1997

Electrophysiological characterization of an alternatively processed ERG K+ channel in mouse and human hearts.

Mutants of HERG, the human form of ERG (the ether-a-go-go-related K+ channel gene), are responsible for some forms of the long-QT syndrome, an abnormality of cardiac repolarization. HERG was cloned from brain and has properties similar but not identical to the rapidly activating component of the native cardiac K+ channel current (Ikr). We identified in the mouse an alternatively processed form of ERG (MERG B) that is expressed abundantly in heart but only in trace amounts in brain. MERG B has a unique 36-amino acid NH2-terminal domain that is strongly basic and considerably shorter than the 376-amino acid NH2-terminal domain of HERG. When expressed in Xenopus oocytes, the kinetics of activation and deactivation of the MERG B current were best fit by a biexponential function, with the fast components dominant over the slow components. The fast component of activation had a mean tau value of 163 +/- 16 ms at -20 mV and 8 +/- 4 ms at +20 mV (n = 4). The fast component of deactivation had a mean tau value of 145 +/- 29 ms at -20 mV and 12 +/- 4 ms at -90 mV (n = 4). The MERG B current was blocked by the selective IKr blocker, dofetilide, with an IC50 of 54 nmol/L. In addition, we isolated HERG B, the human homologue of MERG B, which has electrophysiological characteristics qualitatively similar to those of MERG B. We have identified ERG B, an alternatively processed isoform of the ERG gene, expressed selectively in heart and with electrophysiological characteristics similar to those of native cardiac IKr.

Amino Acid Sequence↗
PubMed1996

Increased precordial QTc dispersion predicts ventricular fibrillation during acute myocardial infarction.

Electrocardiograms of 19 consecutive patients with acute myocardial infarction complicated by early ventricular fibrillation were compared with those in 19 case-matched patients with acute myocardial infarction not complicated by ventricular fibrillation. The mean precordial QTc interval dispersion in patients with ventricular fibrillation was greater than that of patients without ventricular fibrillation (73 +/- 28 ms vs 30 +/- 12 ms, p < 0.001).

Electrocardiography↗
PubMed1996

[3H]dofetilide binding: biological models that manifest solely the high or the low affinity binding site.

Dofetilide is a Class III antiarrhythmic agent known to selectively block the rapid component of the delayed rectifier K+ current (IKr). [3H]Dofetilide binds to a low and a high affinity sites on guinea-pig myocytes. The purposes of this study were: (1) to find biological models which express solely the high or the low [3H]dofetilide binding sites; (2) to characterize the single binding site models; and (3) to establish which of the high or the low affinity binding sites is associated with IKr. We compared and characterized the [3H]dofetilide binding on guinea-pig myocytes, neonatal mouse ventricular homogenate and untransfected CHO cells. These tissue preparations were selected since the neonatal mouse tissue expresses IKr while this current is absent from CHO cells. We compared the IC50 concentrations of dofetilide and two other known IKr blockers E-4031 and sotalol, on [3H]dofetilide binding to these three preparations. Using steady-state and kinetic binding techniques, we characterized the interaction of E-4031 and sotalol with the high and the low [3H]dofetilide binding sites. We found that neonatal mouse ventricle manifest solely the high affinity site (Kd 20 +/- 4 nmol/l, Bmax 18 +/- 4 fmol/mg) while CHO cells manifest solely the low affinity binding site (Kd 1.6 +/- 0.1 mumol/l, Bmax 5.8 +/- 0.8 pmol/mg). We demonstrated that the high and low affinity binding sites present on guinea-pig myocytes show characteristics similar to the single high affinity site expressed on neonatal mouse homogenate and to the single low affinity site expressed on CHO cells, respectively. Class III antiarrhythmic drugs inhibited binding to the high affinity site at concentrations similar to those required to inhibit 50% of IKr current in electrophysiologic studies. In contrast, dofetilide and E-4031 inhibited [3H]dofetilide binding to the low affinity site only at supra-pharmacologic concentrations. We next demonstrated that Class III drugs interact in a competitive manner with the high affinity site on neonatal mouse tissue while they interact with a site allosterically coupled to the low binding site on CHO cells. These data suggest that dofetilide interacts with the high and low affinity sites in a fundamentally different manner. We defined biological models which express solely the high or low [3H]dofetilide binding sites. Only the high affinity site is related to IKr.

Animals↗
PubMed1996

Hypomagnesemia: characterization of a model of sudden cardiac death.

OBJECTIVES: We sought to compare the incidence of sudden death in rats treated with magnesium-deficient and control diets and to address the electrophysiologic characteristics associated with these end points. BACKGROUND: Although magnesium deficiency is associated with an increased incidence of sudden cardiac death in patients, there has been no clear cause and effect relation because of a number of covariables, including diuretic use, hypokalemia, digitalis use and left ventricular dysfunction. METHODS: Hypomagnesemic rats and their paired control rats underwent in vivo electrophysiologic studies and measurements of the total calcium and magnesium content of their cardiac ventricles RESULTS: Serum magnesium levels were 0.5 +/- 0.3 mEq/liter (mean +/- SD) in hypomagnesemic animals and 1.2 +/- 0.9 mEq/liter in control animals. A modest but significant prolongation of the repolarization time was seen at the apical epicardial site (83 +/- 8 ms in hypomagnesemic rats vs. 68 +/- 13 ms in control rats, p < 0.05), but not at the other sites studied. Bradyarrhythmias and tachyarrhythmias were observed in 82% of the hypomagnesemic rats during the in vivo electrophysiologic studies, compared with 0% in the control group. During these studies, sudden, unexpected asystolic deaths were observed in 4 of 11 hypomagnesemic rats and 0 of 8 control rats. Polymorphic nonsustained ventricular tachycardia was provoked by rapid pacing in 5 to 11 hypomagnesemic rats and 0 of 8 control rats. Three of six hypomagnesemic rats exposed to auditory stimuli developed seizures, followed immediately by sudden deaths-two due to asystole and one due to ventricular fibrillation-although no end points occurred in the control animals. CONCLUSIONS: In this model, magnesium deficiency results in sudden cardiac death. The presence of startle induction of sudden death preceded by seizures suggests that sudden cardiac death results from a neurologic trigger.

Animals↗
PubMed1996

Identification and characteristics of delayed rectifier K+ current in fetal mouse ventricular myocytes.

Although the genetics of mammalian cardiac K+ channels have been most intensively investigated in mice, there are limited data available from the electrophysiological studies of the K+ currents in native mouse cardiac myocytes, especially in fetal mouse heart. The present study utilized whole cell patch-clamp techniques to assess the delayed rectifier K+ current (IK) in fetal (18th day of gestation) mouse ventricular myocytes. IK in fetal mouse ventricular myocytes activated rapidly, displayed a negative slope conductance of the current-voltage relationships at test potentials > 0 mV, satisfied the envelope of IK-tail test for a single component, and was very sensitive to dofetilide. These characteristics confirm that this current is the rapidly activating component of IK known as IK,r. In addition, dofetilide dramatically prolonged action potential duration in single ventricular myocytes as well as in ventricular myocardium, suggesting that IK,r plays a dominant role in action potential repolarization in fetal mouse heart. From these data we can conclude that fetal mouse cardiac myocytes express IK,r, which functions as a dominant repolarizing K+ current.

Animals↗
PubMed1996

Developmental changes in the delayed rectifier K+ channels in mouse heart.

Expression of cardiac transient outward current and inwardly rectifying K+ current is age dependent. However, little is known about age-related changes in cardiac delayed rectifier K+ current (IK, with rapidly and slowly activating components, IKr and IKs, respectively). Accordingly, the purpose of the present study was to assess developmental changes in IK channels in fetal, neonatal, and adult mouse ventricles. Three techniques were used: conventional microelectrode to measure the action potential, voltage clamp to record macroscopic currents of IK, and radioligand assay to examine [3H]dofetilide binding sites. The extent of prolongation of action potential duration at 95% repolarization (APD95) by a selective IKr blocker, dofetilide (1 mumol/L), dramatically decreased from fetal (137% +/- 18%) to day-1 (75% +/- 29%) and day-3 (20% +/- 15%) neonatal mouse ventricular tissues (P < .01). Dofetilide did not prolong APD95 in adult myocardium. IKr is the sole component of IK in day-18 fetal mouse ventricular myocytes. However, both IKr and IKs were observed in day-1 neonatal ventricular myocytes. With further development, IKs became the dominant component of IK in day-3 neonates. In adult mouse ventricular myocytes, neither IKr nor IKs was observed. Correspondingly, a high-affinity binding site for [3H]dofetilide was present in fetal mouse ventricles but was absent in adult ventricles. The complementary data from microelectrode, voltage-clamp, and [3H]dofetilide binding studies demonstrate that expression of the IK channel is developmentally regulated in the mouse heart.

Action Potentials↗
PubMed1995

Long-term reproducibility of ventricular tachycardia induction in patients with implantable cardioverter/defibrillators. Serial noninvasive studies.

BACKGROUND: Noninvasive electrophysiological studies (EPSs) can be performed in current implantable antitachycardia pacemaker/cardioverter/defibrillators (ICDs). Thus, these devices may be used as tools to study changes in the electrophysiological substrate and ventricular tachycardia characteristics over time. METHODS AND RESULTS: Fifty-five patients receiving an ICD for treatment of sustained ventricular tachyarrhythmias underwent serial EPSs after implantation of the ICD. Studies were performed before hospital discharge and 1, 3, 5, 9, 12, 18, 24, and 36 months after ICD implantation. Sustained monomorphic ventricular tachycardia (VT) was induced in 37 patients (group 1) at the predischarge EPS, whereas no sustained arrhythmia could be induced in 18 patients (group 2) at baseline. Group 1 patients underwent 165 noninvasive EPSs after discharge. Sustained monomorphic VT was induced during 72% of the follow-up EPSs, ventricular fibrillation (VF) was induced during 11% of follow-up EPSs, and no sustained VT or VF was induced during 17% of follow-up visits. Sustained VT was induced at every follow-up EPS in 23 patients (62%), whereas no sustained VT/VF could be induced at least once during follow-up in 14 patients (38%). Clinical or electrophysiological variables did not predict noninducibility during follow-up. However, the probability that a patient would experience spontaneous VT decreased significantly over time in patients in whom VT was not inducible during at least 1 follow-up EPS (P = .05). Group 2 patients underwent 86 noninvasive EPSs after discharge. Sustained monomorphic VT was induced during 22% of follow-up EPSs, VF was induced during 19% of follow-up EPSs, and no sustained VT/VF could be induced during 68% of follow-up EPSs. No sustained VT/VF could be induced during every follow-up EPS in 9 patients (50%), whereas sustained monomorphic VT was induced at least once during follow-up in 7 patients (34%). Persistent noninducibility of VT during follow-up was associated with low probability of occurrence of spontaneous VT (11%), whereas inducibility of VT at least once during follow-up was associated with the occurrence of spontaneous VT (89%, P = .003). CONCLUSIONS: Considerable variability of VT induction is observed over a lengthy period in patients presenting with sustained VT/VF. Persistent noninducibility of VT is associated with a reduced probability of spontaneous VT. These observations suggest that the substrates for inducible and spontaneous VT change in parallel over time.

Aged↗
PubMed1995

Effects of intracellular calcium on sodium current density in cultured neonatal rat cardiac myocytes.

1. Na+ channel mRNA levels in the heart can be modulated by changes in intracellular Ca2+ ([Ca2+]i). We have investigated whether this regulation of Na+ channel biosynthesis by cytosolic Ca2+ translates into functional Na+ channels that can be detected electrophysiologically. 2. Whole-cell Na+ currents (INa) were recorded using patch-clamp techniques from single ventricular myocytes isolated from neonatal rats and maintained in tissue culture for 24 h. Na+ current density, measured at a membrane potential of -10 mV, was significantly decreased in the cells which were exposed for 24 h to culture medium containing 10 mM of both external Ca2+ and K+ in order to raise [Ca2+]i compared with control cells which were maintained in culture medium containing 2 and 5 mM of Ca2+ and K+, respectively. In contrast, Na+ current density (at -10 mV) was significantly increased in cells exposed for 24 h to 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetraacetoxymethyl ester (BAPTA AM; a cell membrane-permeable Ca2+ chelator) which lowered the average [Ca2+]i compared with control. 3. Changes in current density were not associated with changes in the voltage dependence of activation and inactivation of INa. There were no changes in single-channel conductances. 4. It is concluded that Na+ current density in neonatal rat cardiac myocytes is modulated by [Ca2+]i. The findings suggest that the differences in current density are attributable to a change in Na+ channel numbers rather than to changes in single-channel conductance or gating. These changes are consistent with the previously documented modulation of Na+ channel biosynthesis by cytosolic Ca2+.

Animals↗
PubMed1995

Time to arrhythmic, ischemic, and heart failure events: exploratory analyses to elucidate mechanisms of adverse drug effects in the Cardiac Arrhythmia Suppression Trial.

In this study we investigated the time to the first arrhythmic, ischemic, or failure event for encainide-flecainide and moricizine versus their respective placebo comparison groups in the Cardiac Arrhythmia Suppression Trial. The purpose was to explore possible mechanisms for the excessive deaths associated with active therapy that have been previously reported. Differences were noted between the active drugs. In particular, encainide-flecainide appeared to convert an ischemic event into death in more cases and more promptly than moricizine. However, the excessive deaths noted on encainide-flecainide were as likely to occur subsequent to a failure event as an ischemic event; for both encainide-flecainide and moricizine, the vast majority of excess deaths appeared to be the result of an increase in arrhythmia events without any protective effect of the drug. We were unable to identify any specific mechanism to explain the adverse effect of encainide and flecainide.

Anti-Arrhythmia Agents↗
PubMed1995

Quinidine pharmacodynamics in patients with arrhythmia: effects of left ventricular function.

OBJECTIVES: This study was undertaken to determine whether quinidine pharmacodynamics are altered in the presence of left ventricular dysfunction. BACKGROUND: Left ventricular function is an independent predictor of antiarrhythmic drug efficacy. However, the effects of left ventricular dysfunction on the pharmacodynamics of antiarrhythmic drugs have not been studied extensively. METHODS: Signal-averaged electrocardiograms were obtained and quinidine plasma concentrations measured during 24-h quinidine washout in 22 patients. RESULTS: Linear quinidine concentration-effect relations were observed for QRS and QT intervals corrected for heart rate. The slopes of the concentration-effect relation describing changes in the corrected QT (QTc) interval were significantly higher in the group with left ventricular ejection fraction > or = 0.35 ([mean +/- SD] 29.5 +/- 11.2 ms/micrograms per ml) than in the group with a low left ventricular ejection fraction (15.7 +/- 9.7 ms/micrograms per ml, p = 0.001). The QRS concentration-effect relations were not different in the two groups. A significant linear correlation was observed between the slopes of the concentration-effect relations describing changes in QTc intervals and left ventricular ejection fraction (r = 0.7, p < 0.001). Nineteen patients with inducible ventricular tachycardia underwent serial electrophysiologic studies for evaluation of quinidine efficacy. Ventricular tachycardia could not be induced during quinidine therapy in eight patients. The slopes of the quinidine concentration-effect relations for QTc intervals were significantly higher in quinidine responders than in nonresponders (p < 0.05). CONCLUSIONS: The effects of quinidine on ventricular repolarization are linearly related to left ventricular ejection fraction. Quinidine concentration-effect relations describing ventricular repolarization are associated with antiarrhythmic efficacy in patients with ventricular tachycardia.

Cardiac Pacing, Artificial↗
PubMed1995

Quinidine-induced open channel block of K+ current in rat ventricle.

1. The effects of quinidine on calcium-independent outward K+ currents in rat ventricular myocytes were studied using whole-cell patch clamp techniques. 2. Quinidine sulphate (6 microM) significantly prolonged repolarization of the ventricular action potential. This effect was larger during early repolarization (25% level) than at later times (90% level). 3. Quinidine reduced the amplitude of a transient outward current, and accelerated its rate of decay by approximately 4 fold at membrane potentials between 0 to +50 mV. Quinidine also reduced the amplitude of a slowly inactivating, tetraethylammonium-sensitive 'pedestal' component of the outward current. 4. The quinidine-induced block of the transient outward current was dependent on time and membrane potential. Maximal block occurred with depolarizations of about 100 ms duration, and longer depolarizations (up to 1.5 s) produced little additional block. The membrane potential dependence of quinidine-induced block was very similar to the membrane potential dependence of activation of the transient outward current. The membrane potential dependence of steady-state inactivation of the transient outward current was not significantly affected by quinidine. 5. These results show that quinidine blocks outward K+ currents in rat ventricular cells. The time and potential dependence of this block suggests that quinidine blocks the transient outward K+ current by acting primarily on the open state of these channels.

Action Potentials↗
PubMed1995

High- and low-affinity sites for [3H]dofetilide binding to guinea pig myocytes.

Dofetilide specifically blocks the rapid component of the delayed rectifier current (IKr) at nanomolar concentrations in a saturable manner, suggesting the presence of a receptor. We characterized two [3H]dofetilide binding sites to ventricular myocytes from adult guinea pigs by using a conventional filter assay. Scatchard analysis revealed two binding sites with different affinities: a high-affinity site (Kd, 2.8 +/- 0.3 x 10(-8) mol/L; Bmax, 76 +/- 15 fmol/10(6) myocytes) and a low-affinity site (Kd, 1.64 +/- 0.4 x 10(-6) mol/L; Bmax, 1620 +/- 260 fmol/10(6) myocytes) (n = 11). Kinetic studies showed that there were two dissociation rate constants for [3H]dofetilide (0.02 +/- 0.005 min-1 [high-affinity site] and 0.22 +/- 0.064 min-1 [low-affinity site], n = 4), although the observed association rate constant is equally well fit to a single- or two-site model. The ability of known IKr blockers to compete with [3H]dofetilide binding to both sites was assessed. E4031, clofilium, quinidine, and sotalol competed for binding at both sites. Disopyramide and NAPA only competed for a single binding site. The mean IC50 values for inhibition of binding to both the high- and low-affinity binding sites correlated with their concentrations required to inhibit IKr in electrophysiological studies. However, inhibition of [3H]dofetilide binding to the high-affinity site by class III antiarrhythmic drugs occurred at pharmacological concentrations, whereas suprapharmacological concentrations were required to inhibit binding to the low-affinity site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Proarrhythmia of a class Ic drug: suppression by combination with a drug prolonging repolarization in the dog late after infarction.

Encainide treatment in patients after myocardial infarction is associated with increased risk of sudden cardiac death. This may relate to drug-induced changes in the electrophysiologic milieu, thus predisposing the patient to sustained ventricular tachyarrhythmias. The goals of this study were to first develop a model of class Ic-induced ventricular tachycardia (VT) and then to design treatments to oppose this prodysrhythmic activity. Dogs with time-dependent loss of inducible sustained VT in the antiarrhythmic drug-free state were studied late after infarction. These dogs received a series of three loading and maintenance infusions of O-demethyl encainide (ODME) to achieve concentrations of 60 +/- 31, 136 +/- 46 and 339 +/- 171 ng/ml. Drug maintenance continued until programmed stimulation induced monomorphic sustained VT. When ODME infusion allowed this induction, barium chloride infusions were added. ODME treatment allowed induction of monomorphic sustained VT in 9 of 10 dogs studied. Prodysrhythmic monomorphic VT was significantly related (P < .01) to prolongation of conduction velocity in the peri-infarct zone. ODME modestly increased ventricular refractoriness at some but not all peri-infarct sites. Infusion of barium chloride in the above nine dogs caused their hearts to return to the noninducible state. Prolongation of refractoriness in the peri-infarct zone was correlated to this suppression of prodysrhythmia. Prolongation of conduction velocity in the absence of substantial prolongation of refractoriness may underlie ODME-facilitated induction of monomorphic VT. Prolongation of refractoriness in the peri-infarct zone by combination treatment with barium chloride reversed prodysrhythmic VT in all of the dogs.

Animals↗
PubMed1995

Clinical and in vivo antiarrhythmic potential of sodium-hydrogen exchange inhibitors.

Intracellular acidification may be the initial stimulus for a cascade of events contributing to intracellular calcium overload. Ischaemia results in the accumulation of lactate and other proton donors causing intracellular acidification. During reperfusion the activity of the Na+/H+ exchanger recovers, allowing extrusion of protons at the expense of increases in intracellular sodium. The rise in intracellular sodium decreases the gradient required for sodium calcium exchange, resulting in accumulation of intracellular calcium. These data are in keeping with the pathophysiological model that the Na+/H+ exchanger is an important part of a cascade leading from intracellular acidosis to intracellular sodium loading followed by calcium overload. From this model we predicted that amiloride would be antiarrhythmic. In 1988, we reported that low concentration of amiloride (0.1-0.3 microM) suppresses the induction of sustained ventricular tachyarrhythmias in dogs late following infarction. Amiloride suppressed inducible ventricular tachycardia in approximately 50% of the animals. In an extension of this work we assessed the efficacy of amiloride in suppressing inducible ventricular tachycardia in humans who presented with symptomatic ventricular tachycardia. In that study, amiloride manifested antiarrhythmic activity, but not to the degree that was observed in our dog model. Six of 31 patients (19%) had complete suppression of induced ventricular tachycardia. In an extension of this work, we assessed in our in vivo dog model which of the pharmacological effects of amiloride were associated with antiarrhythmic efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗