Interaction of metoprolol and lidocaine on the ventricular fibrillation threshold in the anesthetized dog

In the present study, we evaluated the antiarrhythmic interaction (s) of metoprolol and lidocaine in 16 dogs using the ventricular fibrillation threshold (VFT) method. The right ventricle was stimulated with a 100 Hz train of 12.4 ms pulses delivered after every eighth atrial paced beat at a basic cycle length of 300 ms. Lidocaine dosage was 2 mg/kg followed by a 70 micrograms/kg/min infusion and metoprolol dosage was a 75 micrograms/kg bolus. In Group 1, lidocaine was followed by metoprolol; in Group 2, first lidocaine then metoprolol and again lidocaine were given; and in Group 3, dogs received first metoprolol, then lidocaine, and subsequently metoprolol. Drug dose intervals were 45 min. In Group 1, lidocaine elevated the VFT to 149% +/- 20% and metoprolol to 204% +/- 30% of control, (p less than 0.01). In group 2, the VFT remained elevated after the second lidocaine administration (p less than 0.05 vs. Group 1). In Group 3, the VFT was increased by metoprolol to 227% +/- 30% of control (p less than 0.01). Interestingly, defibrillation induced by the combination of metoprolol and lidocaine occurred after 3.2 +/- 0.5 s in four out of 16 animals (p less than 0.05). This "chemical" defibrillation never occurred when only metoprolol or lidocaine alone was administered. Fibrillation was often more organized in the presence of the combination of metoprolol plus lidocaine, which might relate to the observed defibrillation associated with metoprolol plus lidocaine. In conclusion, the combination of metoprolol and lidocaine has no proarrhythmic effects and may enhance the electrical stability of the ventricles as measured by the VFT method.     

The impact of acute myocardial ischemia on the ventricular defibrillation threshold during chronic oral azimilide therapy

The effects of chronic oral azimilide therapy on the ventricular defibrillation threshold (DFT) during ischemia are unknown. The effects of azimilide on defibrillation efficacy under ischemic condition were investigated in a closed-chest animal model. Azimilide (20 mg/kg/d) was administered orally for 7 days to 10 pigs (20 to 25 kg). The control group (no treatment) comprised 15 pigs. A 2-lead defibrillation system was used. Each shock was delivered after 8 seconds of ventricular fibrillation. A step-up and step-down protocol was used to calculate mean DFT before and 10 minutes after coronary artery occlusion using an angioplasty balloon in the left descending artery. The basal DFT of the azimilide group did not differ from controls (20.8 +/- 4.8 versus 18.8 +/- 2.8; P = 0.33). After ischemia, the mean DFT of the azimilide-treated animals was similar to controls (21.8 +/- 5.2 versus 23.2 +/- 3.8 J; P = 0.54), despite significant lengthening of ventricular repolarisation (428.2 +/- 51.8 versus 494.1 +/- 46.6 msec; P = 0.005) and significant prolongation of the ventricular fibrillation cycle length (85.1 +/- 13 versus 104.7 +/- 24 msec; P < 0.04). Chronic oral azimilide treatment does not affect the DFT at baseline or during acute myocardial ischemia.     

Failure of lidocaine to suppress lethal ischemic ventricular arrhythmias in a canine model of previous myocardial infarction.

The antiarrhythmic actions of high-dose intravenous (i.v.) lidocaine infusions were assessed in conscious dogs with spontaneous ventricular ectopy subacutely (48 h) after anterior myocardial infarction and in anesthetized dogs with ventricular tachyarrhythmias inducible by programmed ventricular stimulation at 4-11 days after anterior myocardial infarction. In conscious dogs administered cumulative doses of lidocaine at 48 h after myocardial infarction, a significant reduction in the frequency of spontaneous ventricular ectopic complexes (from 61 +/- 12 to 11 +/- 9% of total complexes) occurred only after administration of 10 mg/kg i.v. lidocaine. In anesthetized postinfarction dogs responding to baseline programmed stimulation with ventricular tachyarrhythmias, lidocaine administration (6 mg/kg i.v. loading dose + 100 micrograms/kg/min i.v. maintenance infusion) resulted in a selective increase in infarct zone conduction time (53.0 +/- 5.6 to 60.5 +/- 6.2 msec; p less than 0.05), increases in infarct zone relative refractory periods (RRPs 182 +/- 5 to 193 +/- 5 ms; p less than 0.05), and effective refractory periods (ERPs 156 +/- 4 to 165 +/- 3 ms; p less than 0.05), and an increase in noninfarct zone ERP (154 +/- 5 to 166 +/- 8 ms; p less than 0.05). The induction of ventricular arrhythmias by programmed stimulation was suppressed by lidocaine (6 mg/kg + 100 micrograms/kg/min i.v.) in 5 of 10 postinfarction animals tested, with an additional 3 animals displaying favorable stabilizations of induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correlations of parotid saliva and plasma lidocaine concentrations in rats.

The concentration ratios of parotid saliva to plasma lidocaine were determined in rats after a single dose (10 mg of lidocaine/kg) and constant infusion (60 micrograms of lidocaine/kg/min). Parotid saliva and plasma samples were obtained at 10, 20, and 30 min after single-dose lidocaine administration and at 70, 80, and 90 min after the initiation of a lidocaine infusion. The saliva/plasma concentration ratios for lidocaine after single-dose administration decreased from 1.13 +/- 0.03 at 10 min to 0.51 +/- 0.06 at 30 min, whereas the ratios determined during the lidocaine infusion remained constant (0.43 +/- 0.03, 0.45 +/- 0.03, and 0.43 +/- 0.04) over the time period tested. The variable saliva/plasma concentration ratios obtained after single-dose administration may be associated with rapid drug distribution between the plasma and peripheral compartments and variation in lidocaine binding to plasma proteins. However, during constant lidocaine infusion, a steady-state concentration was achieved within 70 min, as demonstrated by the constant saliva/plasma concentration ratios.     

Effect of drugs on defibrillation capacity

Over 300,000 people die of sudden cardiac death (SCD) in the US annually. Implantable cardioverter-defibrillators (ICDs) have been shown to be more effective than antiarrhythmic drugs for the prevention of SCD in specific susceptible populations. Many patients in whom ICDs have been implanted receive concomitant therapy with antiarrhythmic drugs, for the purpose of reducing the frequency of appropriate and inappropriate defibrillation shocks. Drugs may influence defibrillation capacity and therefore influence the function of ICDs. The objective of this article is to review and update the literature regarding the effects of drugs on defibrillation capacity.A literature search was performed using PubMed (1966 to December 2007) to identify clinical studies, case reports and animal studies describing the effects of drugs on defibrillation capacity. Search terms included: antiarrhythmic drugs; cardiovascular drugs; amiodarone; sotalol; flecainide; propafenone; dofetilide; ibutilide; beta-blockers; lidocaine; procainamide; N-acetylprocainamide; mexiletine; disopyramide; moricizine; calcium channel blockers; defibrillation threshold; defibrillation energy requirements; defibrillation energy changes; defibrillation efficacy; implantable cardioverter defibrillators; and external defibrillators.Evidence from clinical studies indicates that amiodarone may increase defibrillation threshold (DFT). In addition, some data indicate that drugs including lidocaine, mexiletine, moracizine (moricizine), verapamil, venlafaxine and anaesthetic agents may increase DFT. In contrast, agents including sotalol, dofetilide and beta-adrenergic receptor antagonists (beta-blockers) may reduce DFT. Propafenone and procainamide appear to have minimal effect on DFT. For those antiarrhythmic drugs with both sodium and potassium channel blockade (e.g. amiodarone), the effect of sodium channel blockade predominates, resulting in an increase in DFT.Numerous drugs may affect defibrillation capacity. These effects must be considered when managing patients who have an ICD and require concomitant pharmacotherapy.     

The effect of intracoronary lidocaine on ventricular arrhythmia in the infarcted canine heart

The efficacy of intracoronary administration of lidocaine was studied in three groups of dogs with experimental myocardial infarction induced by occlusion of the left anterior descending coronary artery (LAD). Group 1 included 14 anesthetized and group 2, 7 conscious animals to which lidocaine 1.4 micrograms/kg/minute was administered as an intracoronary infusion. Group 3 consisted of 17 anesthetized dogs that received an intracoronary bolus of lidocaine 40 micrograms/kg over 30 seconds. In group 1, lidocaine reduced ventricular arrhythmia by 59 +/- 30% (p less than 0.001), whereas systemic lidocaine achieved a reduction by 61 +/- 37% (p 0.06). In seven dogs, lidocaine blood levels were measured in the great cardiac and femoral veins. At the end of the infusion the drug concentration was 3.4 +/- 2.2 micrograms/ml in the great cardiac and 1.3 +/- 1.1 micrograms/ml in the femoral vein (p less than 0.05). The reduction in ventricular arrhythmia correlated with the great cardiac vein lidocaine concentration (r = 0.70; p less than 0.05), but not with the drug level in the femoral vein (r = 0.06; NS). In group 2, lidocaine was ineffective by both routes of administration. This may have been related to higher sympathetic activity, as suggested by an elevated heart rate in conscious compared to anesthetized animals (186 +/- 6 vs 164 +/- 21 bpm; p 0.0054). In group 3, bolus injections of lidocaine into the LAD reduced ventricular arrhythmia by 66% (p 0.001). We conclude that by perfusing the infarcted zone with lidocaine, a significant antiarrhythmic effect can be achieved with 2% of the systemic dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of epicardial controlled-release lidocaine for ventricular tachycardia induced by rapid ventricular pacing in dogs.

The effects of epicardial lidocaine on ventricular tachycardia (VT) induced by rapid ventricular pacing (50 Hz) were studied in dogs. Lidocaine-polyurethane (28% wt/wt) matrixes (40-50 mg, 5 x 5 mm) were placed proximal to bipolar left ventricular epicardial electrodes in open-chest anesthetized dogs (n = 9) after VT was established by rapid ventricular pacing. In the first set of experiments, matrices were removed immediately after VT had converted to sinus rhythm. Control animals underwent VT induction protocol with a nondrug-containing matrix positioned next to the epicardial electrode. In the lidocaine-treated animals, VT conversion was noted in all animals and occurred after 51.7 +/- 8.9 s (mean +/- SE), with a VT threshold current elevation of 73.5 +/- 11.2% above baseline at the time of conversion which progressed to 259 +/- 44% of the initial value by 5.4 +/- 0.5 min post-matrix placement. Lidocaine 1.4 +/- 0.1 mg was delivered to the myocardium at the time of VT conversion (0.11 +/- 0.01 mg/kg). In comparison, accelerated VT persisted for 5 min in three of five control animals, and progressed to ventricular fibrillation (VF) in the other two animals. In a separate series of eight dogs, the lidocaine-polyurethane matrixes were left in palce for 4 h so that we could study the sustained antiarrhythmic action of controlled-release lidocaine on VT induction. The results of these experiments demonstrated a maintenance of the VT threshold elevation at a level of 53.9 +/- 10.8% after 4 h, with a net lidocaine dose of 0.52 +/- 0.06 mg/kg after 4 h of controlled release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prophylactic and curative effects of recombinant human superoxide dismutase in lethal rat endotoxemia

The continuous infusion of E. coli lipopolysaccharide (100 mg/kg in 4 h) caused a 100%-mortality in pentobarbital-anesthetized rats within 6 h. Recombinant human superoxide dismutase (r-HSOD) infused concomitantly with the E. coli endotoxin dose-dependently (0.1-1.0 mg/kg per min) increased survival rate up to 90%. Significant improvement of survival rate was also obtained when r-HSOD-infusion (0.464 mg/kg per min) was only started up to 3 h after beginning of the endotoxin application. Also, two single bolus injections of r-HSOD (20 mg/kg each) during endotoxemia significantly increased survival rate. Decrease of heart rate was prevented and decline of arterial blood pressure was diminished by r-HSOD (0.464 mg/kg per min) as compared to vehicle-treated endotoxemic rats. Lactic acidosis occurred with no significant statistical difference between r-HSOD- and vehicle-treated groups. Increase of hematocrit in endotoxemic control rats was balanced by fluid uptake. In contrast, in the groups treated with endotoxin plus r-HSOD or saline alone hematocrit decreased identically. Decrease of whole blood leukocytes (to 30.2 +/- 9.5% of baseline in endotoxemic controls) was less pronounced in the r-HSOD group (fall to 49.2 +/- 6.5% of baseline), but this difference did not reach statistical significance. Marked thrombocytopenia (to 12.9 +/- 3.2% of baseline) and consumption of plasma fibrinogen (to 39.5 +/- 10.3% of baseline) were significantly attenuated in r-HSOD-treated rats, where thrombocytes only decreased to 28.1 +/- 3.6% and plasma fibrinogen to 76.6 +/- 5.0% of baseline values at the end of endotoxin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pirmenol hydrochloride (CI-845): antiarrhythmic profile in coronary artery ligated conscious dogs

The antiarrhythmic profile of CI-845 (pirmenol hydrochloride) was assessed in conscious, coronary artery ligated dogs. In single-dose studies in these arrhythmic dogs, CI-845 administered by the intravenous, intranuscular, and oral routes was highly effective in restoring normal sinus rhythm. A 2.5 mg/kg dose was effective against the arrhythmias occurring on the second day after ligation, while 5 mg/kg was effective against the higher-rate arhythmias of the first day after ligation. The reference agents ajmaline, aprindine, disopyramide, lidocaine, mexiletine, procainamide, and quinidine were also tested, and in this model, CI-845 had greater efficacy, a longer duration of activity, and/or a wider safety margin. In slow rate intravenous infusion studies, 1-2 mg/kg/hr of CI-845 maintained near total arrhythmia conversion in first-day postligation dogs. Rapid rate intravenous infusion studies (10 mg/kg/hr) demonstrated a good correlation between the CI-845 dose, plasma level, and arrhythmia conversion, as well as a wide margin of safety. Mean conversions to 80% normal rhythm were achieved at 2.5 mg/kg, with associated plasma levels of 0.8 +/- 0.1 micron/ml, while first sings or gross toxicity occurred at 21.7 +/- 2.4 mg/kg at plasma levels of 6.2 +/- 0.4 micron/ml. There were minimal effects on cardiac conduction and blood pressure even at large doses. In drug interaction studies, CI-845 was safe and effective in combination with disopyramide, lidocaine, procainamide, propranolol, and quinidine. The results clearly show CI-845 to be an orally effective, long-acting antiarrhythmic agent with a favorable margin of safety in the coronary artery ligated dog model.     

Pharmacokinetics of high-dose diluted lidocaine in local anesthesia for facelift procedures

The maximal recommended local anesthetic dose of lidocaine is 7 mg/kg; higher doses are used in tumescent liposuction. The objective of this study was to characterize the pharmacokinetics of high-dose diluted lidocaine administered together with epinephrine for local anesthesia in facelift procedures. This was a prospective study of six female patients undergoing elective facelift surgery. The local anesthetic solution consisted of 0.33% lidocaine, 0.07% sodium bicarbonate, and 1:600,000 epinephrine in normal saline. Plasma lidocaine levels were determined in the course of 24 hours and were subjected to pharmacokinetic analysis. Patients' age was 58.5 +/- 8 years and weight 68.5 +/- 18.7 kg. Mean lidocaine dose was 21.6 +/- 3.6 mg/kg (range, 17.5-26.3 mg/kg) infiltrated subcutaneously over 20 minutes or less. No lidocaine-related adverse effects were recorded. Major bleeding was not observed. Postoperative analgesia was required only at 11.8 +/- 4.6 hours after surgery. Pharmacokinetic analysis was peak concentration 1.41 +/- 0.4 microg/mL, time to reach peak concentration 9.3 +/- 1.6 hours, terminal half-life 6.2 +/- 1.5 hours, area under the curve from time zero to last data point 1379.8 +/- 470 microg/min/mL, and area under the curve from time zero to infinity 1530.6 +/- 471.6 microg/min/mL. Plasma lidocaine concentrations formed almost a plateau between 2 and 12 hours (ie, at approximately 1.2 microg/mL) after infiltration. It is concluded that local anesthesia with diluted lidocaine at a dose 3.1 times higher than the currently recommended dose (7 mg/kg) administered with epinephrine yielded a peak plasma lidocaine level that was 72% below the level considered safe (5 microg/mL).     

Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs

Summary The aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 g/kg/min (i.v.). During 80 g/kg/min lidocaine (mean plasma level 3.5 g/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 g/kg/min and 4 of 8 to 120 g/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p<0.05), 67.7 ms (p<0.05), 70.0 ms (p<0.01) respectively.In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting. Send offprint requests to K. Krejcy at the above address     

Interaction of clonidine and morphine with lidocaine in mice and rats

Morphine and clonidine both elevated plasma levels of lidocaine to the same extent in mice while slowing lidocaine metabolism to deethylated products. The effects of clonidine on lidocaine disposition were reversed by yohimbine. Mice given morphine, 20 mg/kg sc, or clonidine, 0.2 mg/kg sc, had similar, 30-50%, elevation of plasma lidocaine levels at 15 min after lidocaine, 15 mg/kg iv, when compared to saline-treated animals. Despite similarity of effect on plasma lidocaine, mice treated with morphine were much more susceptible to lethal effects of lidocaine than were mice given clonidine. At iv doses of 22 mg/kg or higher, lidocaine caused death in nearly all morphine-treated mice, while even 32 mg/kg lidocaine caused only 11% mortality after saline or clonidine. Clonidine, 0.5 mg/kg sc, and morphine, 20 mg/kg sc, both raised plasma lidocaine levels in rats, but only morphine depressed respiration, causing hypoxia, hypercapnia, and acidosis and increasing lidocaine lethality. These data suggest that potentiation of lidocaine toxicity by morphine is due primarily to changes in blood gases rather than to elevation in lidocaine levels.     

Effects of lidocaine on catecholamine release in the ischemic rat heart

The effects of lidocaine (5 or 10 mg/kg bolus + 2.5 mg/kg/h) on arrhythmias and changes in myocardial and plasma catecholamines (CAs) after left coronary artery occlusion were investigated in anesthetized rats. Myocardial intraneuronal CAs were assessed histofluorimetrically and CA concentrations were measured using high-pressure liquid chromatography (HPLC). Both doses of lidocaine caused reductions in heart rate and blood pressure. The higher dose significantly reduced the number of ischemia-induced ventricular extrasystoles from 425 +/- 123 to 25 +/- 12 in the first 60 min of ischemia and abolished ventricular tachycardia and fibrillation. In the myocardium of untreated animals, the area of fluorescing adrenergic neurons (as percentage of total field area) was 0.42 +/- 0.02% after 60 min of ischemia as compared with 1.38 +/- 0.17% in sham-operated animals. Lidocaine pretreatment resulted in a dose-dependent inhibition of this ischemia-induced CA release from adrenergic neurons (0.96 +/- 0.06 and 1.30 +/- 0.05% for the lower and higher dose, respectively). Tissue and plasma CA concentrations were not significantly affected by lidocaine pretreatment and by coronary occlusion. It is concluded that lidocaine inhibits CA release from sympathetic nerve endings in the ischemic myocardium by its endoanesthetic and membrane-stabilizing properties. The reduction in CA release may also contribute to its antiarrhythmic effects.     

Extracorporeal pump assistance — Novel treatment for acute lidocaine poisoning

Summary Accidental bolus administration of lidocaine ranging in dosages from 1000mg to 2000mg has caused death in humans. Because lidocaine clearance depends upon hepatic blood flow, drug clearance in a hypotensive overdosed patient is poor so that a drug overdose is likely to be irreversible. Traditional approaches to drug removal include hemodialysis and charcoal hemoperfusion. Neither treatment would be effective for lidocaine overdose because the drug is a myocardial depressant and because the clearance rates of these techniques are 100–200ml/min. Hepatic clearance of lidocaine is 1000ml/min in a human with normal cardiac output. We have tested a new concept for removal of high clearance drugs that are associated with myocardial depression. Cardiac bypass support was used in a dog experiment to demonstrate that restoration of cardiac output could restore high clearance of lidocaine. Sixteen anesthetized dogs were given 30mg/kg boluses of lidocaine. In one group of eight dogs, toxicity was treated with antiarrhythmic drugs, pressor drugs and cardioversion. Six out of eight of these animals died within 30min after lidocaine infusion. In the second group of eight dogs, an extracorporeal bypass pump was used for 90min after the lidocaine injection. None of these assisted animals died. Drug clearance in dogs treated with the extracorporeal pump was compared to drug clearance in eight dogs that received non-toxic lidocaine doses of 3mg/kg. Drug clearance was 39.75±4.16ml/kg/min in the overdosed animals compared to 38.29±8.6 ml/kg/min in the non-toxic animals. Thus, drug clearance was normal in dogs treated with the extracorporeal pump. These experiments suggest that short-term support of the circulation with an extracorporeal pump could theoretically be effective in reducing patient mortality from acute massive lidocaine overdose.This work was supported by a grant from Abbott Laboratories and by U.S. Public Health Service grants GM07063, NS09100, HL20194, and an RCDA HL00782 (CRF) Editorial's Remarks: According to our editorial rules this journal does not accept experimental studies in animals. In the following paper an exception seems to be justified, in so far as the study suggests a new approach to the treatment of certain intoxications in man. F.G. and H.J.D.     

Isoproterenol increases defibrillation energy requirements in dogs.

The effect of intravenous isoproterenol on the energy requirements for successful defibrillation (DF) was examined in anesthetized dogs following cholinergic blockade with atropine (n = 5) and following treatment with d- and d,l-sotalol (n = 16). Defibrillation shocks were administered through left and right ventricular epicardial patch electrodes and the energy requirements for DF were studied using two different methods. Multiple shocks of varying energies were delivered and the energies required for 50% success (E50) and 80% success (E80) in DF were estimated using logistic regression. Atropine (0.04 mg/kg) increased E50 by 32 +/- 30% (p = 0.046) and E80 by 39 +/- 38% (p = ns). Subsequent administration of isoproterenol (10 micrograms/ml), increasing the heart rate by 52 +/- 35% (p = 0.025), resulted in a further 108 +/- 21% (p = 0.015) and 88 +/- 55% (p = 0.02) rise in E50 and E80 values, respectively. In a second set of experiments, d- (n = 9) and d,l-sotalol (n = 7) (4 mg/kg bolus followed by 0.025 mg/kg/min maintenance infusion) were administered and baseline curves relating delivered energy to % success in DF were calculated. Isoproterenol (10 +/- 4 micrograms/min) was given to increase the heart rate by 54 +/- 32% (p less than 0.025), and resulted in decreases in % success at each of two energy levels, falling in the midrange of the dose-response curve. Following d,l-sotalol, % successful shocks fell from 60 +/- 15 to 42 +/- 28% (p less than 0.05); following d-sotalol, the % success fell from 66 +/- 13 to 38 +/- 36% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of intracoronary lidocaine infusion on acetylstrophanthidin-induced ventricular arrhythmia in dogs

Antiarrhythmic drugs frequently cause extracardiac side effects that limit their use. If intracoronary delivery of a lower dose of drug to an electrically unstable focus can control arrhythmias, systemic adverse effects of these agents might be avoided. We investigated whether intracoronary lidocaine can suppress ventricular arrhythmia induced by acetylstrophanthidin, a rapidly acting digitalislike agent. We isolated and then cannulated either the left anterior descending or the left circumflex coronary artery in 12 pentobarbital-anesthetized dogs. Sustained ventricular tachycardia that persisted for 11.4 +/- 8.6 minutes was reliably induced by the intracoronary infusion. In all of 24 trials, an intracoronary lidocaine bolus at 2% of the usual systemic dose (0.77 mg/30 sec) abolished digitalis-induced ventricular tachycardia for an average of 2.0 +/- 1.8 minutes. This effect was not observed after a saline bolus. We conclude that an intracoronary bolus of low-dose lidocaine can suppress acetylstrophanthidin-induced ventricular arrhythmia.     

Opioid receptor blockade promotes weight loss and improves the display of sexual behaviors in obese Zucker female rats.

Obese Zucker female rats are hyperphagic, overweight, infertile, and hyporesponsive to the inductive effects of ovarian steroid hormones on sexual behaviors. It has been postulated that endogenous opioid activity may contribute to their obesity and reproductive dysfunction. To test this hypothesis, ovariectomized, adult obese Zucker rats were treated with the opioid receptor antagonist, naltrexone, or saline prior to measurement of steroid-induced sexual behaviors, food intake, and body weight. In estradiol benzoate (EB)-treated rats, naltrexone injection increased the display of sexual receptivity (lordosis quotient, LQ: saline, 11+/-10%; 5 mg/kg naltrexone, 54+/-15%, p < 0.05) and also elicited proceptivity (PRO), which was never observed after saline injection. In EB plus progesterone-treated animals, naltrexone administration enhanced both sexual receptivity and proceptivity (LQ: saline, 17+/-10%; 5 mg/kg naltrexone, 96+/-3%; p < 0.05; PRO: saline, 3.0+/-2.4 bouts/min; 5 mg/kg naltrexone, 45.3+/-12 bouts/min; p < 0.01). Naltrexone injection also decreased 24-h food intake (saline, 24.2+/-0.7 g; 5 mg/kg naltrexone, 17.6+/-1.2 g; p < 0.05) and weight change (saline, +7.3+/-0.8 g; 5 mg/kg naltrexone, -4.5+/-1.4 g, p < 0.01). Morphine treatment blocked these effects of naltrexone on sexual behaviors, food intake, and body weight. These data suggest that endogenous opioids contribute to hyperphagia, obesity, and behavioral hyporesponsiveness to ovarian steroid hormones in obese Zucker rats.     

Investigation of the interaction between argatroban and acetaminophen, lidocaine, or digoxin.

The potential pharmacokinetic interactions between argatroban and acetaminophen, lidocaine, or digoxin were examined. Three randomized crossover studies were conducted. In the first study, 11 subjects completed three sessions (with a five-day washout period between sessions), receiving two 500-mg acetaminophen caplets at 0, 6, 12, 18, and 24 hours; i.v. argatroban 1.5 micrograms/kg/min from hours 12 to 30; or a combination of both. In the second study, 12 subjects completed three sessions (with a five-day washout period between sessions), receiving lidocaine hydrochloride injection 2 mg/kg/hr for 16 hours (after receiving a loading dose of 1.5 mg/kg over 10 minutes), i.v. argatroban 1.5 micrograms/kg/min for 16 hours, or a combination of both. In the third study, 12 subjects completed two sessions (with a seven-day washout period between sessions), receiving oral digoxin 0.375 mg/day for 15 days and either i.v. placebo or argatroban 2 micrograms/kg/min on days 11 through 15. Primary pharmacokinetic values in each study included area under the drug concentration versus time curve and steady-state concentrations of argatroban and the concomitantly administered drug. Lack of a pharmacokinetic interaction (individually defined for each study) was demonstrated in each study. Argatroban, regardless of acetaminophen or lidocaine administration, prolonged activated partial thromboplastin time values approximately 1.6-1.8 times the baseline values. No deaths, unexpected adverse events, or clinically significant changes in safety laboratory values occurred. No pharmacokinetic interaction was detected between argatroban and acetaminophen, lidocaine, or digoxin. Argatroban is well tolerated during coadministration with these drugs. In practice, argatroban coadministered with these frequently prescribed drugs should require no dosage adjustments.     

Experimental treatment of the acute cardiovascular toxicity of caffeine

STUDY DESIGN: The intravenous infusion of caffeine-sodium salicylate (15 mg/kg/min) into artificially ventilated and anesthetized rats caused a progressive fall in arterial blood pressure which was mainly due to a decrease in peripheral resistance. Cardiac output increased initially by 15% but then declined after 30 minutes. The electroencephalogram showed sinus tachycardia and ectopic beats mainly in the form of monomorphic ventricular bigeminy which began after 22.8 minutes. Fatal ventricular fibrillation occurred in all animals by 66.9 +/- 3.1 minutes. Treatment of cardiac arrhythmia by repeated intravenous injections of propranolol (1 mg/kg) or verapamil (1 mg/kg) was effective and prolonged survival time to 91.7 +/- 4.4 or 84.3 +/- 2.9 minutes, respectively (p < 0.05). Propranolol also prolonged survival time when administered in a single dose of 20 mg/kg i.v. 10 minutes before the initiation of caffeine infusions. Repeated administrations of quinidine sulfate (5 mg/kg), phenytoin (5 mg/kg), or lidocaine (1-5 mg/kg), on the other hand, exerted very short antiarrhythmic activity and did not prolong survival time at all. Fluid therapy with polygeline plasma expander (0.5 mL/kg/min) did not influence caffeine-induced cardiovascular failure in any way. CONCLUSIONS: Ventricular ectopia leading to fibrillation accounts for the lethal outcome of caffeine poisoning in anesthetized rats and can be antagonized by treatment with propranolol or verapamil.     

Arrhythmias induced by myocardial ischaemia-reperfusion are sensitive to ionotropic excitatory amino acid receptor antagonists

We have investigated the effects of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK801), a non-competitive N-methyl-D-aspartate (NMDA) ionotropic excitatory amino acid receptor antagonist, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA ionotropic excitatory amino acid receptor antagonist, ketamine and memantine, NMDA receptor channel blockers, on ventricular arrhythmias induced by myocardial ischaemia and myocardial ischaemia-reperfusion. Coronary artery occlusion caused 100 +/- 2% ventricular tachycardia, in saline treated group, and 60 +/- 3% ventricular fibrillation. 66 +/- 6% of the animals recovered from ventricular fibrillation, while in 34 +/- 4% of animals the ventricular fibrillation caused mortality. The incidence of ventricular tachycardia, ventricular fibrillation and mortality was not modified by treatment of rats with MK801 (0.3 mg/kg i.v.), CNQX (1 mg/kg i.v.), ketamine (10 mg/kg) and memantine (1.5 mg/kg), injected 5 min prior to occlusion. Reperfusion caused severe arrhythmias which started within 5 +/- 2 s. For instance, in the saline treated group, the incidence of ventricular tachycardia was 100 +/- 5%, while ventricular fibrillation occurred in 87 +/- 3% of the animals and lasted 90 +/- 12 s. The mortality was 62 +/- 6%. The incidence of ventricular tachycardia, ventricular fibrillation and mortality induced by reperfusion was greatly (P < 0.01) reduced in animals treated with MK801 (0.3 mg/kg i.v.), CNQX (1 mg/kg i.v.), ketamine (10 mg/kg) and memantine (1.5 mg/kg), injected 5 min prior to occlusion. Therefore, reperfusion-induced arrhythmias, but not ischaemia-induced arrhythmias, are sensitive to NMDA/non-NMDA ionotropic excitatory amino acid receptor antagonists.