Biomedical subjects

R S Sheldon

Publications and source records attributed to R S Sheldon.

At least 55 records · Page 3Linked to original sources

PubMed1992

Use-dependent electrophysiologic effects of amiodarone in coronary artery disease and inducible ventricular tachycardia.

Amiodarone produces use-dependent block of cardiac sodium channels in vitro. This study assessed whether similar use-dependent block occurred in 19 patients with coronary artery disease and inducible, sustained, monomorphic ventricular tachycardia treated with amiodarone. Beat-to-beat measurements of ventricular paced QRS durations during 12-beat trains at cycle lengths of 700, 600, 400 and 300 ms were analyzed at a baseline antiarrhythmic drug-free study and after 2 and 10 weeks of amiodarone therapy. At the drug-free study, there were no significant changes in paced QRS durations within the 12-beat trains at any pacing cycle lengths. After 2 and 10 weeks of amiodarone therapy, progressive prolongation of paced QRS durations occurred over the 12-beat trains at pacing cycle lengths of 600, 400 and 300 ms (p less than 0.05). Significant changes in QRS duration were not observed at a pacing cycle length of 700 ms. This progressive prolongation in QRS duration can be fitted as a function of beat number to a monoexponential equation and occurred with an onset time constant of 1.02 +/- 0.41 beats (306 +/- 122 ms) at a pacing cycle length of 300 ms. The magnitude of QRS prolongation increased as the pacing cycle length was shortened. The magnitudes of QRS prolongation were similar after 2 and 10 weeks of amiodarone therapy. In conclusion, use-dependent prolongation in QRS duration occurs at rapid pacing cycle lengths in humans receiving amiodarone.

Amiodarone↗

PubMed1991

Transcainide: biochemical evidence for state-dependent interaction with the class I antiarrhythmic drug receptor.

The mechanism of action of the lidocaine derivative transcainide was examined using [3H]batrachotoxinin 20 alpha-benzoate, which binds specifically to and stabilizes activated states of the sodium channel. Transcainide (IC50 0.3 microM) inhibited equilibrium [3H]batrachotoxinin binding to sodium channels present on freshly isolated rat cardiac myocytes. Scatchard analysis of [3H]batrachotoxinin binding showed that transcainide both reduced maximal binding and altered the KD for [3H]batrachotoxinin binding, indicating noncompetitive, allosteric inhibition. Inhibition by transcainide of [3H]batrachotoxinin binding was reversible within 60 min. We used state-dependent [3H]batrachotoxinin binding assays to examine whether transcainide preferentially binds to activated or nonactivated sodium channels. Transcainide had little effect on the k-1 of [3H]batrachotoxinin even at concentrations 1000-fold greater than its IC50, indicating low affinity of transcainide for activated channels. However, transcainide decreased the k + 1 of [3H]batrachotoxinin at a concentration very close to its IC50 concentration for inhibiting equilibrium [3H]batrachotoxinin binding. The results are discussed in terms of a model in which transcainide inhibits [3H]batrachotoxinin binding by binding specifically to and stabilizing a nonactivated state of the cardiac sodium channel.

Animals↗

PubMed1991

Cyclic AMP-dependent regulation of the number of [3H]batrachotoxinin benzoate binding sites on rat cardiac myocytes.

We sought to assess the effect of an increase in cAMP on sodium channels on adult rat cardiac ventricular myocytes. Sodium channels were studied with the use of the radiolabeled sodium channel-specific toxin [3H] batrachotoxinin benzoate ([3H]BTXB). Forskolin, isoproterenol, prostaglandin E1, cholera toxin, and pertussis toxin each increased cAMP levels and decreased the number of [3H]BTXB binding sites without changing the affinity of [3H]BTXB for the sodium channel. The cAMP analog 8-bromo-cyclic AMP (8-Br-cAMP) reduced the number of [3H]BTXB binding sites from 19 fmol/10(5) cells to 11 fmol/10(5) cells. [3H]BTXB binding site down-regulation was reversible, cAMP dose-dependent, and time-dependent. To test the hypothesis that the cAMP effect was mediated by cAMP-dependent phosphorylation, we determined the effect of 8-Br-cAMP on [3H]BTXB binding after preincubation of myocytes with N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide dihydrochloride (H8), a protein kinase A inhibitor. H8 inhibited 70% of the decrease in the number of [3H]BTXB binding sites induced by 8-Br-cAMP. Thus increases in intracellular cAMP in cardiac myocytes reversibly induced a decrease in the number of [3H]BTXB binding sites via cAMP-dependent protein phosphorylation, possibly of the sodium channel.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1991

Drug therapy for ventricular tachyarrhythmias: how many electropharmacologic trials are appropriate?

To determine how many electropharmacologic drug trials should be performed to select therapy for patients with ventricular tachyarrhythmias, the outcome of 150 consecutive patients with inducible ventricular tachyarrhythmias undergoing serial electropharmacologic testing was examined. The probability of identifying predicted effective therapy (inductive of fewer than five ventricular responses with three ventricular extrastimuli at three pacing cycle lengths) and the probability of that therapy preventing sustained ventricular tachyarrhythmia recurrences were determined as a function of the number of preceding trials. The probability ( +/- SE) of identifying predicted effective therapy by the first trial (0.23 +/- 0.03) was significantly higher than that of the second (0.09 +/- 0.04), third (0.08 +/- 0.04) and fourth (0.05 +/- 0.04) trials (p = 0.001). No patient had predicted effective therapy identified by subsequent trials. The 2 year actuarial probability of freedom from sustained ventricular tachyarrhythmias on predicted effective therapy was higher for the first (0.79 +/- 0.08), second (0.73 +/- 0.13) and third (0.86 +/- 0.13) trials than for the fourth (0.33 +/- 0.27) trial (p = 0.02). Thus, the probability of selecting therapy with long-term efficacy was highest for the first trial (0.18), intermediate for the second (0.07) and third (0.07) trials and lowest for the fourth (0.02) and subsequent (0.00) trials. Accordingly, the electropharmacologic approach to therapy selection should be abandoned after three unsuccessful trials.

Actuarial Analysis↗

PubMed1991

Reduction in defibrillator shocks with an implantable device combining antitachycardia pacing and shock therapy.

Implantable defibrillators reduce the risk of sudden death in patients with malignant ventricular arrhythmias, but significant restriction in quality of life can occur as a result of frequent device activation. To determine if a device that provides both antitachycardia pacing and shock therapy can safely reduce the frequency of shocks after implantation, 46 consecutive patients undergoing initial implantation of a defibrillator were studied. In all patients, the implanted device provided antitachycardia pacing and shock therapy. Detected tachycardia characteristics and the results of therapy were stored in the device's memory. There were 42 men and 4 women, aged 26 to 71 years (mean 58.7 +/- 13.5). Left ventricular ejection fraction ranged from 13% to 67% (mean 32.2 +/- 13.4%) and 31 patients had experienced one or more episodes of cardiac arrest. Induced arrhythmias included sustained monomorphic ventricular tachycardia in 38 patients, nonsustained polymorphic ventricular tachycardia in 2 and ventricular fibrillation in 4. Over a total follow-up period of 255 patient-months (range 1 to 13, mean 6.1), 25 patients experienced spontaneous arrhythmic events. In 22 patients, 909 episodes of tachycardia were treated by antitachycardia pacing, which was successful on 840 occasions (92.4%). Acceleration of ventricular tachycardia by pacing therapy was estimated to have occurred 39 times. Syncope occurred once during pacing-induced acceleration of ventricular tachycardia. Forty-four episodes of tachycardia in seven patients were treated directly by shocks because of short tachycardia cycle length; 88% of all detected tachycardias were treated without the need for shocks. Four patients died from cardiorespiratory failure and one patient died suddenly without any detected tachyarrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗

PubMed1991

Upregulation of the rat cardiac sodium channel by in vivo treatment with a class I antiarrhythmic drug.

Class I antiarrhythmic drugs inhibit the sodium channel by binding to a drug receptor associated with the channel. In this report we show that in vivo administration of the class I antiarrhythmic drug mexiletine to rats induces sodium channel upregulation in isolated cardiac myocytes. The number of sodium channels was assessed with a radioligand assay using the sodium channel-specific toxin [3H]batrachotoxinin benzoate ([3H]BTXB). The administration of mexiletine to rats induced a dose-dependent increase in [3H]BTXB total specific binding (Bmax) on isolated cardiac myocytes. Sodium channel numbers were 15 +/- 5, 29 +/- 9, and 54 +/- 4 fmol/10(5) cells after 3 d treatment with 0, 50 mg/kg per d, and 150 mg/kg per d mexiletine (P less than 0.001, analysis of variance). Sodium channel number increased monoexponentially to a steady-state value within 3 d with a half-time of increase of 1.0 d. After cessation of treatment with mexiletine the number of sodium channels returned to normal within 12 d. Finally, treatment with mexiletine altered only sodium channel number; the Kd for [3H]BTXB and the IC50 for mexiletine were not different for myocytes prepared from control and mexiletine-treated rats.

Animals↗

PubMed1991

Class I anti-arrhythmic drugs: structure and function at the cardiac sodium channel.

The major electrophysiologic effect of Class I anti-arrhythmic drugs is blockade of the cardiac sodium channel thereby reducing the initial depolarization of the action potential and slowing impulse propagation. Despite the widespread use of these drugs, our understanding of their mechanism of action is incomplete. Models based on electrophysiologic studies predict that a receptor for Class I drugs is associated with the sodium channel, and that occupancy of this receptor causes sodium channel blockade. Recent radioligand studies with [3H]batrachotoxin A benzoate have identified a binding site for Class I drugs associated with rat cardiac myocyte sodium channels which may be the predicted receptor. Binding of drugs to this site is saturable, reversible, stereospecific, and occurs at pharmacologically relevant concentrations with similar rank order of potency in vivo and in vitro. Drugs appear to bind preferentially to a closed state of the channel, thereby preventing channel opening and subsequent sodium influx.

Animals↗

PubMed1991

Mexiletine/quinidine combination therapy: electrophysiologic correlates of anti-arrhythmic efficacy.

This article reviews the data which support the use of selected drug combinations to enhance anti-arrhythmic activity. Specifically, we have focused on the mexiletine-quinidine interaction and the relation between anti-arrhythmic efficacy and electrophysiologic effects. In an initial clinical study, we found that combination therapy with mexiletine-quinidine produced enhanced efficacy in suppressing spontaneous ventricular tachycardia with fewer side-effects than high dose monotherapy. This enhanced efficacy has been confirmed in other laboratories. Combination therapy also enhanced suppression of inducible ventricular tachycardia in patients and in animal models. Animal models were used to assess the relation between electrophysiologic effects and anti-arrhythmic efficacy. In the animal studies, combination therapy produced selective prolongation of refractoriness and conduction in the infarct and peri-infarct zones without significant changes in the normal zone. Subsequent studies focused on the relative contribution of sodium channel and potassium channel blocking properties of these drugs to the enhanced activity seen with the combination. Studies using the selective sodium channel blocker tetrodotoxin confirmed that sodium channel blockade was necessary for this interaction. To assess the contribution of prolongation of action potential duration by quinidine to the combined effect we compared the anti-arrhythmic and electrophysiologic effects of the stereoisomers quinidine and quinine given alone and in combination with mexiletine. These experimental data confirm that the property of prolongation of action potential duration by quinidine is essential to the interaction. When comparing quinidine and quinine it is apparent that prolongation of refractoriness in the peri-infarct zone is essential for anti-arrhythmic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Aminoalkyl structural requirements for interaction of lidocaine with the class I antiarrhythmic drug receptor on rat cardiac myocytes.

The structural and physicochemical determinants of binding of lidocaine and several of its aminoalkyl homologs to specific sites associated with the sodium channel were assessed using a radioligand assay and freshly isolated rat cardiac myocytes. The two series of closely related lidocaine homologs that were studied were composed, first, of homologs differing in the length of the link between the arylamide and amine domains of the molecule and, second, of homologs differing in the number of carbons attached to the terminal amine. Drug affinity was measured with a radioligand binding assay, using [3H]batrachotoxinin A 20 alpha-benzoate and freshly isolated cardiac myocytes. The affinities of the homologs were then compared with the pKa values, partition coefficients, distribution coefficients, and molecular structure of the homologs, to determine the relationship between the affinity for the receptor and the physicochemical and structural properties of the drug. Optimal binding was obtained with a link between the arylamide and amine domains that was two carbons in length. The affinity of the drug for the receptor was optimal with four or more amino-terminal carbons, and the precise arrangement of the carbons was not important. Each of the amino-terminal carbons independently contributed 0.3 kcal of free energy of binding, suggesting that the carbons dissolve in a hydrophobic pocket. The evolving picture of a drug structure that is optimal for receptor binding is one of a compound with a two-carbon arylamide-amine link and four or more amino-terminal carbons.

Amides↗

PubMed1990

Role of quinidine in the mexiletine-quinidine interaction: electrophysiologic correlates of enhanced antiarrhythmic efficacy.

Quinidine has multiple electrophysiologic effects, including prolongation of ventricular conduction time, repolarization, and refractoriness. The purpose of this study was to address the relative contributions of these electrophysiologic effects to the enhanced anti-arrhythmic activity observed when quinidine is combined with mexiletine. We compared antiarrhythmic and electrophysiologic effects observed when quinidine or its stereoisomer quinine were combined with mexiletine. Quinine and quinidine both prolong conduction time; however, these agents have divergent effects on ventricular repolarization time and refractoriness. The modest prolongation of conduction time observed with quinine and mexiletine-quinine in the absence of change of ventricular refractoriness was not associated with antiarrhythmic efficacy. The antiarrhythmic efficacy of mexiletine-quinidine exceeds that of mexiletine-quinine, suggesting that the ability of quinidine to prolong refractoriness and repolarization contributes to the antiarrhythmic efficacy of mexiletine-quinidine. Although, both the mexiletine-quinidine combination and quinidine monotherapy prolonged refractoriness to a similar extent, the mexiletine-quinidine combination produced greater antiarrhythmic efficacy and prolonged interventricular conduction within the periinfarct zone to an extent greater than did quinidine alone. We concluded that the role of quinidine in producing enhanced antiarrhythmic activity when combined with mexiletine includes both prolongation of refractoriness and conduction time in the periinfarct zone.

Action Potentials↗

PubMed1990

Quinidine/quinine: stereospecific electrophysiologic and antiarrhythmic effects in a canine model of ventricular tachycardia.

The two major electrophysiologic effects of quinidine are prolongation of refractoriness and prolongation of conduction time. To determine which of these effects contributes to its antiarrhythmic effect, we compared the electrophysiologic effects of quinidine and its stereoisomer quinine (which was expected to prolong conduction time but not refractoriness) in 24 dogs with inducible sustained ventricular tachyarrhythmia late after ischemic injury. Conscious but sedated animals were randomly assigned to receive infusions of saline, quinidine, or quinine. Serum concentrations of quinidine and quinine were 18 +/- 9 and 23 +/- 8 microM, respectively. Both drugs prolonged conduction times to a similar extent, but quinidine prolonged local repolarization times and refractoriness much more than quinine. Sustained ventricular tachyarrhythmia was consistently inducible during placebo (saline) studies. Antiarrhythmic efficacy was observed with quinidine (3 of 12) but not quinine (0 of 15) or saline (0 of 13) (p less than 0.05, Chi-square test). Quinidine also significantly prolonged monomorphic ventricular tachycardia (VT) cycle length (157 +/- 33 ms on quinidine vs. 129 +/- 26 ms at baseline, p less than 0.001) whereas quinine had no significant effect. Thus, prolonging refractoriness is important in preventing the induction of ventricular tachyarrhythmias and in prolonging VT cycle length.

Animals↗

PubMed1989

Mexiletine-quinidine in isolated hearts: an interaction involving the sodium channel.

Combination therapy with mexiletine and quinidine has been shown to be more effective than either monotherapy in treating patients with ventricular tachycardia. This enhanced efficacy was associated with prolongation of ventricular refractoriness and conduction time in the infarct zone. As sodium channel activity is a determinant of both conduction time and refractoriness we formed the hypothesis that the mexiletine-quinidine interaction was due at least in part to interactions involving the sodium channel. To assess the role of sodium channel blockade in the enhanced anti-arrhythmic activity of mexiletine-quinidine combination we determined whether the electrophysiological and anti-arrhythmic effects of tetrodotoxin combined with mexiletine or quinidine mimicked the effect seen with mexiletine combined with quinidine. Eighty isolated perfused rabbit hearts were treated with mexiletine, quinidine and tetrodotoxin either alone or in combination before and after circumflex occlusion-reperfusion. Ventricular fibrillation occurred in response to single extrastimuli in all 24 hearts treated with a saline control infusion. Combinations of mexiletine and quinidine at concentrations which alone had little electrophysiological activity produced anti-arrhythmic activity greater than that seen with high concentrations of mexiletine or quinidine alone. The combination of similarly low concentrations of tetrodotoxin and quinidine also produced enhanced anti-arrhythmic efficacy and enhanced prolongation of ventricular refractoriness and conduction which mimicked the effect of mexiletine and quinidine in combination. In contrast, the combination of mexiletine and tetrodotoxin did not produce enhanced anti-arrhythmic and electrophysiological activity. Since tetrodotoxin is a highly specific sodium channel blocker, these data suggest that the enhanced antiarrhythmic activity of mexiletine-quinidine combination therapy involves, at least in part, blockade of the cardiac sodium channel.

Action Potentials↗

PubMed1989

Amiodarone: biochemical evidence for binding to a receptor for class I drugs associated with the rat cardiac sodium channel.

Amiodarone has multiple pharmacological effects in heart. Electrophysiological data suggest that among its other effects, amiodarone is a sodium channel blocker. Using a radioligand assay, we determined whether amiodarone interacted with a previously described receptor for type I agents associated with the cardiac sodium channel. The radioligand was [3H]batrachotoxinin A 20 alpha-benzoate ([ 3H]BTXB), a toxin that binds to the activated state of the sodium channel. We have previously shown that class I antiarrhythmic drugs inhibit [3H]BTXB binding. The purpose of this study was to assess whether amiodarone and other class III agents interact with this receptor. Amiodarone inhibited [3H]BTXB binding in a dose-dependent fashion, with an estimated IC50 value of 3.6 microM. This IC50 value is similar to reported clinically effective serum concentrations of amiodarone. In contrast to amiodarone, the IC50 values for other class III drugs (bretylium, sotalol, bethanidine, N-acetylprocainamide) were much higher than their therapeutic concentrations and bore no relation to them. Scatchard analysis of [3H]BTXB binding showed that amiodarone reduced the maximal binding for [3H]BTXB; this finding indicates irreversible inhibition or (more likely) allosteric inhibition by amiodarone. The latter agrees with electrophysiological data suggesting that amiodarone binds to inactivated sodium channels. Sodium channel blockade by amiodarone may contribute to its overall electrophysiological effect.

Allosteric Site↗

PubMed1989

Antiarrhythmic drugs and the cardiac sodium channel: current models.

The major electrophysiological effect of Class I antiarrhythmic drugs is blockade of the cardiac sodium channel, thereby reducing the initial depolarization of the action potential and slowing impulse propagation. Despite the widespread use of these drugs our understanding of their mechanism of action is incomplete. Models based on electrophysiological studies predict that a receptor for Class I drugs is associated with the sodium channel, and that occupancy of this receptor causes blockade of the sodium channel. Recent radioligand studies with [3H]batrachotoxinin-A benzoate have identified a binding site for Class I drugs associated with rat cardiac myocyte sodium channels, which may be the predicted receptor. Binding of drugs to this site is saturable, reversible, stereospecific, and occurs at pharmacologically relevant concentrations with similar rank order of potency in vivo and in vitro. Drugs appear to bind preferentially to a closed state of the channel, thereby preventing channel opening and subsequent sodium influx.

Anti-Arrhythmia Agents↗

PubMed1989

Class I antiarrhythmic drug receptor: biochemical evidence for state-dependent interaction with quinidine and lidocaine.

The state-dependent binding of class I antiarrhythmic drugs to a receptor associated with the cardiac sodium channel was assessed using [3H]batrachotoxinin A 20-alpha-benzoate [( 3H]BTXB) binding. [3H]BTXB binds specifically to and stabilizes activated states of the sodium channel. Quinidine (IC50 = 40 microM) and lidocaine [IC50 = 61 microM) inhibited equilibrium [3H]BTXB binding to sodium channels present on freshly isolated rat cardiac myocytes. Scatchard analysis of [3H]BTXB binding in the presence of quinidine and lidocaine revealed two apparent patterns of inhibition. Quinidine (33 microM) increased the KD but had no significant effect on the Bmax, whereas lidocaine (91 microM) reduced the Bmax but had no significant effect on the KD. To address drug binding to activated and nonactivated states, we exploited the state-specific binding of [3H]BTXB. Drugs that increase the rate of dissociation (k-1) of [3H]BTXB must bind to sodium channels to which [3H]BTXB is already bound (i.e., activated channels). Therefore, drug-mediated increases in k-1 measure drug binding to activated states. Both quinidine and lidocaine increased the k-1 of [3H]BTXB, indicating drug binding to and destablization of activated sodium channels. However, the minimal affinities of quinidine and lidocaine for activated channels (KDact) were estimated to be 433 and 455 microM, respectively, concentrations much higher than the equilibrium IC50 values. Drugs that allosterically decrease the rate of association (k+1) of [3H]BTXB must bind to sodium channels to which [3H]BTXB is not already bound (i.e., nonactivated channels). Therefore, drug-mediated decreases in k+1 measures drug binding to nonactivated states. Quinidine and lidocaine decreased the k+1 of [3H]BTXB, indicating drug binding to and stablization of nonactivated sodium channels. The affinity of quinidine and lidocaine for nonactivated channels (KDnon) was estimated to be 10 and 35 microM, respectively, concentrations close to the equilibrium IC50 values. The markedly different KDact and KDnon values for both quinidine and lidocaine indicate state-dependent binding of quinidine and lidocaine to the class I receptor on the cardiac sodium channel. Both drugs destabilize activated channels and stabilize nonactivated channels. The Scatchard results suggest that quinidine and lidocaine may have different mechanisms of allosteric inhibition of [3H]BTXB binding.

Allosteric Regulation↗

PubMed1988

Right and left ventricular function during chronic amiodarone therapy.

Although chronic therapy with amiodarone is an effective means of suppressing ventricular tachycardia, its long-term effects on ventricular function have not been evaluated. Therefore, left ventricular (LV) and right ventricular (RV) ejection fraction (EF) as well as wall motion score were assessed in 21 patients with ventricular tachycardia before therapy and after 2, 6, 10 and 20 weeks of amiodarone therapy. Serum amiodarone levels after 2, 6, 10 and 20 weeks were 1.9 +/- 0.7, 1.7 +/- 0.6, 1.5 +/- 0.6 and 1.5 +/- 0.7 micrograms/ml, respectively. Drug therapy did not significantly affect the mean LVEF (0 weeks 38 +/- 17, 2 weeks 40 +/- 17, 6 weeks 40 +/- 17, 10 weeks 41 +/- 18 and 20 weeks 40 +/- 18%) or the mean RVEF. Neither LV wall motion score nor RV wall motion score were changed significantly during amiodarone therapy. Fourteen patients had a drug-free LVEF less than 40% (mean 28 +/- 7%). Ventricular function in this subgroup was not impaired after 20 weeks of amiodarone therapy (drug-free LVEF 28 +/- 7%, 20 weeks LVEF 29 +/- 9%; drug-free RVEF 42 +/- 13%, 20 weeks RVEF 41 +/- 12%). Ten patients who were evaluated 34 +/- 6 months after initiation of amiodarone therapy had no significant change in LVEF (drug-free 37 +/- 20%, 34 months 43 +/- 20%). Ventricular functional reserve was assessed after 20 weeks of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1988

Effect of oral combination therapy with mexiletine and quinidine on left and right ventricular function.

Combination therapy with mexiletine (MEX) and quinidine (Q) may be more efficacious than monotherapy with either drug in suppressing ventricular arrhythmias, but its effects on ventricular performance are not known. Thus, right ventricular ejection fraction (RVEF) and left ventricular ejection fraction (LVEF) and wall motion score (WMS) were assessed in 14 patients with ventricular tachycardia before antiarrhythmic therapy, during MEX and Q monotherapies, and during combination therapy. During monotherapy, the daily doses and serum drug levels were: MEX, 621 mg/day and 3.4 microM/L; Q, 1573 mg/day and 8.3 microM/L, respectively. With combination therapy, the daily doses and serum drug levels were: MEX, 636 mg/day and 3.3 microM/L; Q, 1643 mg/day and 9.5 microM/L, respectively. Drug therapy did not affect group LVEF (drug free = 36 +/- 19%, MEX = 34 +/- 18%, Q = 36 +/- 19%, and combination MEX-Q = 35 +/- 19%), RVEF (drug free = 34 +/- 11%, MEX = 35 +/- 11%, Q = 36 +/- 13%, and combination MEX-Q = 36 +/- 12%), or WMS. Ventricular function reserve was assessed in five patients. Drug therapy did not affect group exercise LVEF (drug free = 44 +/- 14%, MEX = 42 +/- 12%, Q = 43 +/- 13%, and MEX-Q = 45 +/- 12%), RVEF (drug free = 38 +/- 10%, MEX = 40 +/- 11%, Q = 39 +/- 12%, and MEX-Q = 40 +/- 12%), WMS, or exercise duration. Combination MEX-Q therapy did not have a significant effect on exercise performance or ventricular function in seven additional patients in whom no exercise studies were done during monotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Pacing, Artificial↗

PubMed1988

Tetrodotoxin: sodium channel specific anti-arrhythmic activity.

Many Class I anti-arrhythmic drugs not only block the cardiac sodium channel but also block the calcium and/or potassium channels. The hypothesis tested in this study was that sodium channel blockade without blockade of calcium or potassium channels produced anti-arrhythmic activity in the treatment of malignant ventricular arrhythmias. The arrhythmia model consists of ventricular fibrillation induced by critically timed single extrastimuli at twice diastolic pacing threshold following 15 minutes of ischaemic injury in a rabbit heart perfused in vitro. Preparations were randomly assigned to either tetrodotoxin (a selective sodium channel blocking toxin) or vehicle. Ventricular fibrillation occurred in all vehicle treated preparations in response to single extrastimuli following ischaemic injury. Treatment with tetrodotoxin at concentrations of 0.1 to 1.0 micromolar protected some hearts from fibrillation, while at concentrations above 3 micromolar ventricular fibrillation was not inducible. Tetrodotoxin produced concentration dependent increases in ventricular effective refractory period and conduction time in the infarct zone which were associated with anti-arrhythmic activity. No concentration dependent change in action potential duration was seen with tetrodotoxin. Thus the electrophysiological and anti-arrhythmic activities of tetrodotoxin in this model demonstrate that the property of selective sodium channel blockade is sufficient to produce anti-arrhythmic activity.

Action Potentials↗