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Biomedical subjects

S Nattel

Publications and source records attributed to S Nattel.

At least 199 records · Page 11Linked to original sources
PubMed1985

Age-dependent lidocaine disposition in patients with acute myocardial infarction.

To evaluate age-dependent changes in lidocaine disposition in patients with acute myocardial infarction, we measured plasma concentrations of lidocaine and its metabolites monoethylglycinexylidide and glycinexylidide after discontinuation of a maintenance lidocaine infusion. Plasma lidocaine clearance was calculated by dividing the lidocaine concentration at the end of the infusion into the maintenance infusion rate. Lidocaine clearance in 35 patients was related to body weight and was reduced by heart failure. Heart failure was more common in the elderly, occurring in 15 of 27 (56%) patients over 65 years old and seven of 29 (24%) patients under 65 years old. There was a reduction in lidocaine clearance with age due, in part, to lower body weight and a higher prevalence of heart failure in the elderly. Multilinear regression analysis showed that age and weight contributed to the prediction of lidocaine plasma clearance in patients with and without heart failure. Age was a particularly important predictor of lidocaine clearance in patients with heart failure. Adjustment of lidocaine maintenance doses based on age, weight, and heart failure may help control the frequency of lidocaine adverse reactions in the elderly.

Adult↗
PubMed1985

Effect of sympathetic tone on ventricular arrhythmias during circumflex coronary occlusion.

To determine if the sympathetic nervous system exerts an arrhythmogenic effect on the ischemic myocardium independent of heart rate, the proximal circumflex coronary artery was occluded for 1 h in 62 open-chest, anesthetized dogs. The atrial rate was maintained at 200/min, and the vagosympathetic trunks were transected in all dogs. The total incidence of ventricular fibrillation was 35% in 20 dogs with intact stellates and not significantly different from the incidence of ventricular fibrillation (15%) in another 20 dogs in which both stellate ganglia had been decentralized. Electrical stimulation of the left ansae subclavia (3 Hz, 2 ms, 6-8 V) in the remaining 22 dogs significantly increased the incidence of ventricular fibrillation to 73% (P less than 0.05). The magnitude of S-T segment elevation in the lead II electrocardiogram 90 s after occlusion was 0.69 +/- 0.08 mV in the group with left ansae stimulation and significantly elevated (P less than 0.01) compared with dogs with intact stellates (0.35 +/- 0.06 mV) and with the denervated dogs (0.19 +/- 0.05 mV). The data indicate that the sympathetic nervous system is capable of a direct arrhythmogenic influence on the ischemic myocardium independent of heart rate. The rate-independent arrhythmogenic effects of the sympathetic nervous system may be mediated by an increase in severity of the ischemic insult.

Animals↗
PubMed1985

Frequency-dependent effects of amitriptyline on ventricular conduction and cardiac rhythm in dogs.

Although overdoses of tricyclic antidepressant are known to produce both sinus tachycardia and ventricular tachyarrhythmias in man, these have been assumed to occur by independent mechanisms. This study was designed to evaluate the relationship of ventricular activation frequency to the cardiotoxic effects of amitriptyline. When amitriptyline was infused into dogs with formalin-induced atrioventricular (AV) block to evaluate a broad range of pacing frequencies, the drug produced dose-related QRS prolongation that was markedly frequency dependent. Similar frequency-dependent depression of the maximum rate of depolarization (Vmax) was noted for canine Purkinje fibers superfused with amitriptyline in vitro. The time constant of recovery from amitriptyline-induced block was dose independent and averaged 228 msec in vivo and 216 msec in vitro. When amitriptyline was infused into dogs with intact AV conduction, sinus tachycardia occurred within 15 min, followed by progressive QRS prolongation and ventricular tachyarrhythmias after an average 29 min. Slowing of sinus rate by vagal stimulation (seven dogs) or intravenous metoprolol (five dogs) reproducibly reversed the QRS prolongation and ventricular tachyarrhythmias caused by amitriptyline. These studies show that amitriptyline produces frequency-related depression of ventricular conduction in vivo, with a time dependence similar to effects on the maximum rate of depolarization in vitro. Interventions that slow heart rate reverse the adverse effects of amitriptyline on ventricular conduction and cardiac rhythm.

Action Potentials↗
PubMed1984

Lidocaine therapy with an exponentially declining infusion. Clinical evaluation of an optimized dosing technique.

A novel technique to achieve rapidly and continually maintain therapeutic lidocaine concentrations was designed according to known pharmacokinetic properties of the drug and was tested in 12 patients who required immediate lidocaine prophylaxis because of suspected acute myocardial infarction. The serum lidocaine concentrations achieved by this method remained within the therapeutic range (1.2 to 5.0 mg/L) in 83 of 84 determinations and showed little fluctuation over time for individual patients. Unlike previously recommended dose regimens for lidocaine, this technique uses an exponentially declining infusion and has the advantages of greater simplicity, less chance of medication error, and avoidance of rapid changes of lidocaine concentrations. Furthermore, similar methods can be applied when rapid attainment of stable plasma drug concentrations is needed for clinical or experimental pharmacologic studies.

Drug Administration Schedule↗
PubMed1984

Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in dogs.

This study was designed to analyze the effects of lidocaine and sodium bicarbonate on ventricular arrhythmias resulting from amitriptyline infusion in dogs. Amitriptyline was infused i.v. at 0.5 mg/kg/min for 30 min, followed by 1 mg/kg/min to dogs anesthetized with morphine and alpha-chloralose. When arrhythmia occurred, the infusion rate was reduced by one-third and the effect of various interventions studied. In the initial 18 dogs, lidocaine, sodium bicarbonate or isotonic saline was administered i.v. to six dogs each in a randomized, blinded fashion. The prevalence of ventricular ectopic complexes was not changed after isotonic saline, but was reduced by lidocaine at concentrations greater than or equal to 5 mg/l and by sodium bicarbonate. The effects of lidocaine were transient and associated with significant blood pressure reduction. Sodium bicarbonate produced more dramatic and sustained arrhythmia reversal along with a reduction in amitriptyline-induced conduction slowing. Administration of hypertonic sodium chloride in equimolar quantities to sodium bicarbonate failed to affect amitriptyline-induced ventricular arrhythmias significantly, but hyperventilation to a pH similar to that produced by sodium bicarbonate (7.48) significantly reduced the frequency of amitriptyline-induced ventricular ectopy. When amitriptyline was infused into dogs ventilated with various respiratory rates, ventricular arrhythmia resulted in 18 of 18 (100%) dogs with pH less than 7.42, 2 of 4 (50%) dogs with pH between 7.48 and 7.51 and 0 of 8 (0%) dogs with a pH between 7.59 and 7.65 (P less than or equal to .001). These results suggest that sodium bicarbonate is effective treatment for amitriptyline-induced cardiac arrhythmias with beneficial effects largely due to alkalinization.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitriptyline↗
PubMed1984

Frequency-dependent effects of antiarrhythmic drugs on action potential duration and refractoriness of canine cardiac Purkinje fibers.

Antiarrhythmic drugs are known to have frequency dependent effects on Vmax and conduction. The purpose of this study was to determine whether the effects of antiarrhythmic drugs on action potential duration (APD) and refractory period depend on frequency. Standard microelectrode techniques were used to measure APD and refractory period after abrupt or sustained alterations in stimulation frequency. Increases in APD95 resulting from bretylium and quinidine and decreases resulting from lidocaine were 50 to 60% attenuated (P less than .01 for each) by sustained increases in activation rate. Unlike sustained rate increases, abrupt increases in rate enhanced quinidine-induced APD prolongation (P less than .01). Quinidine increased the time constant (222 +/- 6 to 346 +/- 36 msec, P less than .01) and decreased the magnitude of the rapid phase of APD abbreviation upon premature stimulation. In contrast, bretylium increased the magnitude of APD abbreviation upon premature stimulation, reducing the tendency of bretylium to prolong premature APD compared to basic APD. Changes in refractory period parallelled changes in APD95 with the exception of the effect of quinidine after sustained rate change. Despite attenuation of its effects oN APD95, quinidine prolonged refractory period more after sustained rate increases (P less than .01), apparently because of greater depression of maximum sodium conductance. These experiments show that the effects of antiarrhythmic drugs on APD and refractoriness depend on activation frequency and that abrupt changes in rate may alter drug effects differently from sustained rate changes.

Action Potentials↗
PubMed1983

Time course of the electrophysiological effects of quinidine on canine cardiac Purkinje fibers: concentration dependence and comparison with lidocaine and disopyramide.

We used standard microelectrode techniques to observe the time course of the appearance and disappearance of the cellular electrophysiologic effects of antiarrhythmic drugs during drug infusion and after washout. The slopes of phases 0 (Vmax), 2(V2) and 3(V3) of the action potential of canine Purkinje fibers were followed during 30 min of infusion of quinidine (0.2 - 1 x 10(-5) M), disopyramide (1 x 10(-5) M) or lidocaine (1 x 10(-5) M) and then during 60 min of washout with drug-free Tyrode's solution. All three drugs significantly reduced V3 and increased V2; quinidine and disopyramide also significantly reduced Vmax. The onset of the effects of quinidine and disopyramide on Vmax, V2 and V3 occurred at similar rates. Both the onset and disappearance of the effects of lidocaine were more rapid than those of quinidine and disopyramide. This may have been related to the greater lipid solubility of lidocaine with a heptane: water partition coefficient of 0.85 for lidocaine compared with 0.16 for disopyramide and 0.06 for quinidine. The effects of quinidine (1 x 10(-5) M) on V3 reversed much more slowly upon washout (T1/257 +/- 12 min, mean +/- S.E.) than the effects of quinidine on Vmax (T1/218 +/- 3 min, P less than .01) and V2 (T1/215 +/- 3 min, P less than .01). Concentration-response data showed that the time course of washout of the effects of quinidine was independent of drug concentration. These data suggest that rapidity of antiarrhythmic drug action is related to lipophilicity and that the effect of quinidine on V3 is due to action at a different cellular site from its effects on Vmax and V2.

Action Potentials↗
PubMed1982

Prevention of propranolol withdrawal mechanism by prolonged small dose propranolol schedule.

Abrupt withdrawal of propranolol may be followed by a "propranolol withdrawal syndrome "due, at least in part, to enhanced beta adrenergic sensitivity. Tapering propranolol dosage is frequently used in the hope of preventing adverse withdrawal events but the success of such a maneuver has not been shown. The rationale for the dose tapering schedule in this study was based on earlier observations after abrupt withdrawal of propranolol. Nine hypertensive patients were gradually withdrawn from long-term propranolol therapy, either by serial dose reduction for 6 to 9 days (n = 3) or by reduction to a prolonged small dose (30 mg daily) for 2 weeks before complete withdrawal (n = 6). During dose reduction of propranolol and for 2 additional weeks of placebo therapy, serial measurements were made of cardiac sensitivity to isoproterenol, heart rate at rest, blood pressure, plasma catecholamines, serum thyroxine (T4) and triiodothyronine (T3) and symptoms. Serial dose reduction decreased but did not prevent cardiac hypersensitivity in two of three patients. The prolonged small dose therapy largely prevented cardiac hypersensitivity and overshoot in heart rate, blood pressure and plasma catecholamines and symptoms. Serum T4 decreased significantly and T3 tended to increase during and after prolonged small dose treatment. These results indicate that prolonged administration of small dose propranolol before complete withdrawal in hypertensive patients prevents enhanced cardiac beta adrenergic sensitivity and other adverse events.

Adult↗
PubMed1981

Alterations in regional myocardial distribution and arrhythmogenic effects of aprindine produced by coronary artery occlusion in the dog.

Little information exists regarding the effects of coronary artery occlusion on the distribution and actions of antiarrhythmic agents. We administered aprindine to dogs before, 5 min after, and 24 h after one-stage left anterior descending coronary artery (LAD) occlusion. Coronary artery occlusion performed after aprindine administration slowed the rate of disappearance of aprindine from the ischaemic zone compared with the normal zone, so that ischaemic zone aprindine concentrations averaged more than twice normal zone aprindine concentrations 1 h after LAD occlusion. When LAD occlusion was performed before aprindine administration, ischaemic zone aprindine concentrations were initially less than 15% of normal zone aprindine concentrations and increased with time to approach half of normal zone aprindine concentrations 70 min after LAD occlusion. Seventeen of 35 dogs (49%) receiving aprindine before LAD occlusion experienced sustained ventricular tachycardia or ventricular fibrillation, compared with 5/34 (14%) receiving aprindine immediately after LAD occlusion (P less than 0.01), 1/10 (10%) undergoing LAD occlusion without receiving aprindine (P less than 0.05) and 0/16 receiving aprindine without LAD occlusion (P less than 0.01). Aprindine administered 24 h after CO reduced premature ventricular complexes from a mean of 35 to 12 per 100 beats (P less than 0.01) occlusion importantly modifies the regional myocardial distribution of aprindine and its effects on ventricular arrhythmias after coronary artery occlusion.

Animals↗
PubMed1981

Autonomic control of ventricular refractoriness.

The effects of vagal and sympathetic stimulation on canine ventricular refractoriness were studied in vivo. Sympathetic stimulation reduced the left ventricular refractory period to an extent linearly related to the logarithm of nerve stimulation frequency. Vagal stimulation had no effect in the absence of sympathetic stimulation but produced a frequency-dependent attenuation of sympathetic effects when the two systems were stimulated simultaneously. The effects of combined vagal and sympathetic stimulation were best described by a multilinear regression model using the logarithm of vagal and sympathetic frequency as covariates. The magnitude of vagal attenuation of sympathetic effects did not show any regional variation at the five widely spaced sites (2 right ventricular, 3 left ventricular) studied.

Animals↗
PubMed1981

pH-dependent electrophysiological effects of quinidine and lidocaine on canine cardiac purkinje fibers.

We used standard microelectrode techniques to evaluate the effects of lidocaine and quinidine on canine Purkinje fibers at normal pH (7.3) and in the presence of acidosis (pH 6.9). Acidosis alone reduced resting potential, action potential amplitude, and Vmax, while increasing APD90 and conduction time. Lidocaine concentrations of 6 x 10(-6) to 1.5 x 10(-5) M had minimal effect on resting potential, action potential amplitude, and Vmax at pH 7.3. At pH 6.9, the same lidocaine concentrations significantly reduced resting potential (3-10%), action potential amplitude (3-8%) and Vmax (14-22%). Quinidine (6 x 10(-6) to 1.5 x 10(-5) M) reduced resting potential (3-5%), action potential amplitude (4-9%), and Vmax (19-34%) at pH 7.3. At pH 6.9, quinidine produced significantly greater reductions in resting potential (4-15%), action potential amplitude (5-18%), and Vmax (22-49%). These changes were associated with much more quinidine- and lidocaine-induced prolongation of interelectrode conduction time at acidic than at normal pH. Inexcitability occurred at pH 6.9 in four of 14 experiments with 1.5 x 10(-5) M quinidine and in two of 10 with 1.5 x 10(-5) M lidocaine, and was reversed at the same drug concentration by normalizing pH. Acidosis did not alter the Vmax-resting potential relationship in either the absence or presence of antiarrhythmic agents. Furthermore, changes in ionization did not account for the alterations in electrophysiological effects of quinidine and lidocaine produced by acidosis. Our data suggest that extracellular pH changes may modify importantly the effects of antiarrhythmic agents.

Acidosis↗
PubMed1980

Indications for admission to a coronary care unit in patients with unstable angina.

One hundred cases with an admission diagnosis of acute coronary insufficiency or unstable angina were reviewed to establish criteria for admission to a coronary care unit. Myocardial infarction was subsequently diagnosed in 20 of the patients. Ventricular tachycardia occurred in 16 patients and ventricular fibrillation in 1 patient. Clinical features found to predict an increased risk of myocardial infarction included chest pain for more than 30 minutes within 24 hours prior to admission, new nonspecific electrocardiographic abnormalities consistent with ischemia, and diaphoresis. All patients with ventricular tachydysrhythmias had presented with both prolonged chest pain prior to admission and new electrocardiographic changes. The sensitivity, specificity and predictive value of various clinical criteria for identifying patients likely to have a myocardial infarction were calculated, and criteria with very high (greater than 90%) sensitivity were identified. These could be used to establish which patients are at increased risk of myocardial infarction and therefore require admission to a coronary care unit.

Angina Pectoris↗
PubMed1980

Mexiletine therapy in 15 patients with drug-resistant ventricular tachycardia.

Mexiletine therapy was administered to 15 patients with chronic and recurrent episodes of ventricular tachycardia or ventricular fibrillation. All patients were intolerant of or had arrhythmias resistant to conventional antiarrhythmic agents. At maximal dosages of mexiletine 2 patients had more than 90 percent reduction in frequency of premature ventricular complexes, whereas 11 patients had less than 50 percent reduction, as measured on 24 hour electrocardiographic recordings. Mexiletine was unsuccessful in preventing or abolishing ventricular tachycardia in 11 patients. Adverse side effects occurred in nine patients (60 percent) and were severe enough to necessitate discontinuation of therapy in six patients (40 percent). Side effects appeared to be dosage-related. Pharmacokinetic analysis indicated a mean elimination half-life of 12.6 +/- 1.6 hours following oral administration of mexiletine. In the patients studied, mexiletine exhibited limited antiarrhythmic efficacy and was associated with frequent adverse side effects.

Adult↗
PubMed1980

Duration of antihypertensive effect of a single daily dose of hydrochlorothiazide.

To assess the duration of antihypertensive effect of a single daily dose of the short-acting diuretic hydrochlorothiazide, a double-blind crossover study was performed in 11 patients previously well controlled with diuretics. Each patient received hydrochlorothiazide 100 mg in the morning for 12 wk and blood pressure were recorded 4 times daily (8 A.M., 12 noon, 4 A.M., and 8 P.M) on 3 separate visits. The crossover design also included a 12-wk placebo period either preceding or following active therapy. Blood pressure control was excellent and sustained throughout the day in all patients studied, indicating that a single daily dose of hydrochlorothiazide is a suitable regimen for hypertension therapy. The use of a placebo period before initiating the trial and during the active part of the trial confirmed the observation that patients who have been adequately treated for long periods will maintain lowered blood pressure for a variable period after stopping therapy.

Adult↗