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PubMed1983

The effects of cardiovascular drugs on the defibrillation threshold and the pathological effects on the heart using an automatic implantable defibrillator.

Internal defibrillating leads were implanted in 6 dogs through a left thoracotomy and in 6 pigs through a subxiphoid approach. The effects of digoxin (0.04 mg per kilogram of body weight), procainamide (15 mg per kilogram), and propranolol (0.2 mg per kilogram) on the defibrillation threshold was determined 30 to 60 minutes following intravenous administration. Resultant blood levels were equal to or greater than therapeutic levels. Individually these drugs resulted in no appreciable change in the defibrillation threshold from baseline. Pathological study of the myocardium obtained from 6 dogs that underwent more than two hundred shocks each did not demonstrate any abnormality. The 6 pigs were reliably defibrillated, this indicating that thoracotomy is not required for successful implantation. The automatic implantable defibrillator is not the definitive treatment for recurrent ventricular arrhythmias, but is a practical regimen of therapy for a select group of high-risk, out-of-hospital patients. These observations advance our knowledge of the use of this device and give more assurance for future implantation in this select group of patients.

Animals↗
PubMed1996

Longitudinal distribution of arylamine N-acetyltransferases in the intestine of the hamster, mouse, and rat. Evidence for multiplicity of N-acetyltransferases in the intestine.

Experimental and clinical evidence indicates that AcCoA:arylamine N-acetyltransferases (NATs; EC 2.3.1.5) are involved in the bioactivation and inactivation of a wide variety of arylamine, hydrazine, and carcinogenic arylamine xenobiotics. Longitudinal distribution of NATs in the intestine of the hamster, mouse, and two strains of rat was examined utilizing the model arylamine substrates procainamide(PA) and p-aminobenzoic acid (PABA) for the monomorphic (NAT1) and polymorphic (NAT2) enzymes in the rodent. NAT1 and NAT2 were distributed quite differently in each species examined. In particular, rat intestinal NATs were distributed equally throughout the intestinal tract. In contrast, hamster intestinal NATs decreased in activity from the proximal small intestine to the distal large intestine. Mouse NAT2 activity was highest in the cecum, whereas NAT1 was highest in the proximal small intestine. Although these model substrates have been shown to be selective for NATs, they are not specific. Therefore, a series of biochemical studies were undertaken to evaluate NAT multiplicity in the intestine of the F-344 rat. To assess multiplicity of NAT expression, selective inhibition, differential sensitivity to heat inactivation, and kinetic analysis were performed on intestinal cytosol. Eadie-Hofstee transformation of PA N-acetylation yielded a curvilinear plot indicative that a low affinity-high capacity enzyme aside from NAT1 (presumably NAT2) was contributing to PA N-acetylation activity. PA activity was found to exhibit approximately 4- to 5-fold greater thermostability than PABA activity. Furthermore, PA acetylation could be inhibited selectively with vinyl fluorenyl ketone (2.5 to 5 microM) but not with methotrexate (up to 2 mM). Taken together, these studies suggest the expression of both NAT1 and NAT2 in the intestine of the F-344 rat.

4-Aminobenzoic Acid↗
PubMed1978

Simultaneous determination of antiarrhythmia drugs by high-performance thin-layer chromatography.

A method is described for the determination of antiarrhythmia drugs in serum by high-performance thin-layer chromatography. Baseline separations are achieved for all the drugs and clozapine, an internal standard, in two developments with solvents of different polarity. Lidocaine and diphenylhydantoin are scanned at 220 nm after the first development. Procainamide, propranolol and quinidine are scanned at 290 nm after the second development. The relative standard deviation of the determination varies between 3 and 14% depending on the nature of the drug and its concentration.

Anti-Arrhythmia Agents↗
PubMed1985

[Affinity electrophoresis in polyacrylamide gel. Influence of the concentration in the gel on the apparent affinity of cholinesterase for an anionic ligand site].

Affinity electrophoresis of three purified molecular forms of human plasma cholinesterase (monomer C1, dimer C3, tetramer C4) was carried out in polyacrylamide gels at various total acrylamide concentrations ranging from 3.48 to 9% in a discontinuous buffer system. A water-soluble linear copolymer supporting procainamide, a ligand of the anionic site of cholinesterase, was physically entrapped at various concentrations within the gel network. The combined effects of gel concentration and ligand concentration on the affinity pattern of the three molecular forms were studied. It was found that gel concentration influences the apparent binding activity of their anionic site: The apparent strength of interaction varied with the gel concentration: the denser the gel was, the higher the apparent affinity. The ligand-induced isomerization process was also depending on the gel concentration: the ligand concentration from which each zone is splitting into two moving zones decreased as the total gel concentration increased. These results show that the electrophoretic matrix plays an important role in the affinity process in affinity electrophoresis presumably by controlling kinetic effects: kinetics of protein-ligand complex formation and dissociation reactions, and mass transfer kinetics.

Butyrylcholinesterase↗
PubMed1990

Purification of histone H1 polypeptides by high-performance cation-exchange chromatography.

Calf thymus histone 1 (H1) was cleaved by chemical and enzymatic methods and the resulting polypeptides were fractionated by high-performance cation-exchange. Up to 1 mg of H1 polypeptides were loaded onto a 50 x 5 mm I.D. cation-exchange column and fractionated to greater than 95% purity in less than 30 min. This is the first report on the separation of H1 polypeptides by a strong cation-exchange matrix. In addition, the high-performance cation-exchange chromatography protocol represents a significant decrease in fractionation time when compared to conventional ion-exchange and gel filtration chromatography. The utility of this procedure is shown when the H1 peptides purified by the protocol were used to define antigenic domains of H1 band by procainamide-induced lupus and idiopathic systemic lupus erythematosus. The majority of the sera tested by enzyme-linked immunoassay (ELISA) reacted to the C-terminal peptides of H1 indicating this to be the major antigenic domain of H1.

Animals↗
PubMed1981

Wolff-Parkinson-White syndrome: T wave abnormalities during normal pathway conduction.

Forty-five patients with Wolff-Parkinson-White syndrome (WPW) were reviewed. The preexcitation using Boineau's classification was: right anterior (six patients), left lateral (nine patients), right posterior (15 patients) and left posterior (15 patients). Normal pathway conduction was observed to occur either spontaneously or after administration of ajmaline, procainamide, or by eye-ball pressure. Disappearance of preexcitation was associated with T wave abnormalities in 39 patients (86.6%). The orientation of the T spatial vector (SAT), after suppression of the WPW aspect, varied according to the site of ventricular preexcitation. In eight patients with left lateral ventricular preexcitation (LLVP), the frontal T wave axis was between +70 degrees and +120 degrees (mean +92 degrees) and the horizontal T wave axis was located in the left anterior quadrant. In the five patients with right anterior ventricular preexcitation (RAVP), the frontal axis was between + 40 degrees and - 10 degrees (mean + 26 degrees) and the horizontal axis was in the left posterior quadrant. The 26 cases with right posterior ventricular preexcitation (RPVP) and left posterior ventricular preexcitation (LPVP) had a frontal axis between - 10 degrees and - 70 degrees (mean -39 degrees) and the horizontal T wave axis in the left anterior quadrant. This study suggests that the T wave anomalies observed after suppression of the WPW aspect are in direct relation to the localization of the preexcitation according to Boineau's classification. The analogy between the abnormalities of the T wave and those which are observed after right ventricular pacing (VP) or after disappearance of left bundle branch block (LBBB) is discussed.

Adolescent↗
PubMed2001

N-substituted benzamides inhibit nuclear factor-kappaB and nuclear factor of activated T cells activity while inducing activator protein 1 activity in T lymphocytes.

N-substituted benzamides are compounds that have recently been reported to inhibit nuclear factor-kappaB (NF-kappaB) activity and induce apoptosis in a pre-B cell line. In this study, we focused on the effects of N-substituted benzamides on transcriptional regulation in Jurkat T cells. We used a model system where the cells can be stimulated either through TCR/CD28 or by treatment of the cells with PMA and ionomycin to induce transcription factors typical for T lymphocyte activation. Treatment of the Jurkat cells with procainamide did not influence the transcription factor profile of stimulated cells, while treatment with a derivative having an acetyl group in position 4 of the aromatic ring inhibited NF-kappaB and nuclear factor of activated T cells (NFAT) activity. Declopramide, which contains a chloride in position 3 of the aromatic ring, was inactive in this system, whereas also the acetylated derivative of this compound inhibited NF-kappaB and NFAT activity. In contrast, the transcriptional activity and nuclear expression of activator protein 1 induced by TCR/CD28 stimulation or PMA and ionomycin treatment was enhanced by the acetylated variants of the N-substituted benzamides. Finally, we investigated the effect of N-substituted benzamides on intact promoters for two genes central in immune regulation; the CD40 ligand (CD40L) and IL-2 promoters. The transcriptional activity of the CD40L promoter as well as surface expression of the CD40L induced by signaling through TCR/CD28 was inhibited by addition of acetylated N-substituted benzamides, while the transcriptional activity of the IL-2 promoter was enhanced. Taken together, these data indicate that derivatives of N-substituted benzamides are potential drug candidates for quantitative as well as qualitative modulation of immune functions.

Acecainide↗
PubMed1994

Effect of ethanol on hepatobiliary transport of cationic drugs. A study in the isolated perfused rat liver, rat hepatocytes and rat mitochondria.

The effect of ethanol on the hepatic uptake of various cationic drugs was studied in isolated perfused rat livers, isolated rat hepatocytes and isolated rat liver mitochondria. In isolated rat hepatocytes and in isolated perfused rat livers, the uptake of the model organic cation tri-n-butylmethylammonium was found to be markedly stimulated by ethanol in a concentration-dependent fashion. The uptake of tri-n-butylmethylammonium at 1 microM was increased to 120% and 137% at 0.5% (v/v, (= 87 mM)) and 1% (v/v. (= 174 mM)) ethanol, respectively. At 25 microM, tri-n-butylmethylammonium uptake was increased to 124% and 152% at 0.5% (v/v) and 1% (v/v) of ethanol, respectively. The uptake of the organic cations azidoprocainamide methoiodide, vecuronium, ORG 9426 and ORG 6368, the anionic compound taurocholate and the uncharged compound ouabain was not markedly increased at these ethanol concentrations. The mechanism of action of ethanol on the uptake of tri-n-butylmethylammonium was further studied. Competitive inhibitors for the type I organic cation uptake system, procainamide ethobromide and verapamil, almost completely blocked uptake of tri-n-butylmethylammonium (1 microM) in the presence of 1% (v/v) ethanol, indicating that carrier-mediated uptake is still involved and that additional passive diffusion is unlikely. Neither the plasma membrane potential nor the accumulation of the cation in mitochondria was altered after ethanol treatment, suggesting that potential driving forces for uptake and sequestration were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed2000

Mechanism for increase in expression of cerebral diazepam binding inhibitor mRNA by nicotine: involvement of L-type voltage-dependent calcium channels.

We investigated the mechanisms underlying the increase in diazepam binding inhibitor (DBI) and its mRNA expression induced by nicotine (0.1 microM) exposure for 24 h using mouse cerebral cortical neurons in primary culture. Nicotine-induced (0.1 microM) increases in DBI mRNA expression were abolished by hexamethonium, a nicotinic acetylcholine (nACh) receptor antagonist. Agents that stabilize the neuronal membrane, including tetrodotoxin (TTX), procainamide (a Na(+) channel inhibitor), and local anesthetics (dibucaine and lidocaine), dose-dependently inhibited the increased expression of DBI mRNA by nicotine. The nicotine-induced increase in DBI mRNA expression was inhibited by L-type voltage-dependent Ca(2+) channel (VDCC) inhibitors such as verapamil, calmodulin antagonist (W-7), and Ca(2+)/calmodulin-dependent protein kinase II (CAM II kinase) inhibitor (KN-62), whereas P/Q- and N-type VDCC inhibitors showed no effects. In addition, nicotine exposure for 24 h induced [3H]nicotine binding to the particulate fractions of the neurons with an increased B(max) value and no changes in K(d). Under these conditions, the 30 mM KCl- and nicotine-induced 45Ca(2+) influx into the nicotine-treated neurons was significantly higher than those into non-treated neurons. These results suggest that the nicotine-stimulated increase in DBI mRNA expression is mediated by CAM II kinase activation resulting from the increase in intracellular Ca(2+) through L-type VDCCs subsequent to the neuronal membrane depolarization associated with nACh receptor activation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Combined high-efficiency hemodialysis and charcoal hemoperfusion in severe N-acetylprocainamide intoxication.

Several extracorporeal techniques have been used to remove N-acetylprocainamide (NAPA), the major metabolite of procainamide, in patients intoxicated with this substance. We report a patient with life-threatening NAPA intoxication who was rapidly and successfully treated with combined high-efficiency hemodialysis and charcoal hemoperfusion. The hemodialyzer and hemoperfusion cartridge were placed in series such that the patient's blood was dialyzed before reaching the cartridge. Overall clearance of NAPA was 153 mL/min, with clearance due to hemodialysis averaging 102 mL/min and that due to hemoperfusion averaging 88 mL/min. Thus, addition of the hemoperfusion cartridge into the extracorporeal circuit resulted in a 50% increase in clearance over that obtainable by high-efficiency hemodialysis alone. In comparison to other modalities, this technique is more effective than either hemodialysis or charcoal hemoperfusion alone and can achieve a more rapid reduction of serum NAPA levels than that observed with slow continuous hemofiltration or hemodiafiltration.

Acecainide↗
PubMed1986

Cellular electrophysiologic changes and "arrhythmias" during experimental ischemia and reperfusion in isolated cat ventricular myocardium.

The cellular electrophysiologic consequences of both regional and global experimental ischemia and reperfusion were studied in the isolated cat myocardium, using conventional microelectrode techniques. Oxygenated Tyrode's solution was perfused through the left anterior descending and circumflex coronary arteries, while the preparation was superfused with Tyrode's solution gassed with 95% nitrogen and 5% carbon dioxide. Electrophysiologic characteristics of endocardial muscle cells were normal during coronary perfusion. When perfusion was discontinued for 30 minutes, resting membrane potential was decreased by 21.6 +/- 4.1%, action potential amplitude was decreased by 29.1 +/- 8.6% and action potential duration was decreased by 54.1 +/- 12.5% (p less than 0.001). Ectopic activity occurred after 5 to 10 minutes of ischemia and was more frequent in regional than in global ischemia (p less than 0.05). Rapid ventricular activity was observed in only 5 (17%) of 29 preparations during ischemia, whereas it occurred in 24 (83%) of 29 preparations during reperfusion. Rapid ventricular activity began 5 to 40 seconds (mean 19) after the start of reperfusion, stopped spontaneously after a mean of 113 +/- 211 seconds and occurred after both regional and global ischemia. The cellular electrophysiologic changes induced by ischemia returned to baseline values within the next 5 minutes. Repeated ischemia and reperfusion runs reproduced the same electrophysiologic changes and rapid ventricular activity. Coronary perfusion with procainamide (20 mg/liter) aggravated the ischemic depressions of action potential amplitude and action potential duration and increased conduction delay during ischemia, but it did not prevent rapid ventricular activity induced by reperfusion. In contrast, verapamil (1 mg/liter) perfusion did not affect the changes in action potential variables during ischemia but prevented reperfusion-induced rapid ventricular activity. Perfusion with calcium ion (Ca2+)-free Tyrode's solution just before ischemia and during reperfusion slowed or prevented reperfusion-induced rapid ventricular activity, without affecting the action potential changes during ischemia. It is concluded that, in these isolated perfused ventricular muscle preparations, different mechanisms may be operative in ischemic and reperfusion arrhythmias and Ca2+ may play an important role in the development of arrhythmias during the reperfusion phase of ischemia/reperfusion sequences.

Action Potentials↗
PubMed1997

Electrophysiologic mechanisms of antiarrhythmic efficacy of a sotalol and class Ia drug combination: elimination of reverse use dependence.

OBJECTIVES: We sought to determine the electrophysiologic mechanisms explaining the efficacy of combination therapy with DL-sotalol and a type Ia drug in the treatment of ventricular tachycardia (VT). BACKGROUND: Combination antiarrhythmic drug therapy with low dose DL-sotalol plus a type Ia antiarrhythmic agent has been shown to prevent spontaneous and induced VT. The mechanisms underlying the efficacy of this drug combination have not been fully elucidated. METHODS: We studied 32 patients with spontaneous sustained VT by using programmed electrical stimulation in the drug-free condition and after treatment with DL-sotalol (average dose [mean +/- SE] 151 +/- 8 mg/day) and a class Ia agent (quinidine, 1,337 +/- 59 mg/day, or procainamide, 2,083 +/- 327 mg/day). Sustained VT was induced in all patients at baseline study, and induction was reattempted during drug therapy. Monophasic action potential duration at 90% repolarization (APD90) and ventricular effective refractory period (ERP) were recorded with use of a contact electrode. RESULTS: Ventricular ERP increased from 258 +/- 4 ms at baseline to 310 +/- 6 ms at a 600-ms drive cycle length (DCL600) with treatment (p < 0.001). APD90 increased from 288 +/- 6 ms by +10.1% at DCL600 and from 267 +/- 7 ms by +13.3% at a 400-ms drive cycle length (DCL400) (p < 0.001). Paced QRS duration increased from 141 +/- 3 to 158 +/- 6 ms at DCL400 (p < 0.05). At baseline, the shortest achieved coupling interval between successive propagated extrastimuli decreased progressively with respect to the first extrastimulus, following double and triple extrastimuli, at both DCL600 (-14.0% and -20.0%, respectively) and at DCL400 (-16.4% and -22.4%, respectively). This "peeling back" of refractoriness was attenuated on therapy with sotalol plus a class Ia antiarrhythmic agent to -6.7% and -10.5% (DCL600, p < 0.05), and -8.1%, -9.5% (DCL400, p < 0.05), for double and triple extrastimuli, respectively. The absolute prolongation of functional refractory periods by the drug combination increased with successive extrastimuli, from 55 +/- 6 ms for the V1V2 interval to 75 +/- 6 ms for V2V3 and 67 +/- 6 ms for V3V4 at DCL600, and from 51 +/- 5 ms for V1V2 to 69 +/- 6 ms for V2V3 and 74 +/- 7 ms for V3V4 at DCL400 (p < 0.001). CONCLUSIONS: The combination of low dose sotalol and a class Ia agent greatly prolongs refractoriness. The magnitude of the effect increases at shorter coupling intervals.

Action Potentials↗
PubMed1985

Pharmacology and pharmacokinetics of drugs used to treat cardiac disease in horses.

The rational therapy of cardiovascular disease in horses requires a thorough knowledge of the pharmacology and pharmacokinetics of several specific drugs (digitalis, digoxin). Calcium solutions, dopamine, and dobutamine are frequently used to treat congestive heart failure in horses. Quinidine, procainamide, lidocaine, and propranolol are used to treat a variety of supraventricular and ventricular arrhythmias. Furosemide, a highly potent loop diuretic, is used to eliminate edema and promote diuresis. A thorough understanding of the applied pharmacology, dosage recommendations, toxicity, and practical considerations must be attained before these drugs can be used effectively.

Administration, Oral↗
PubMed1995

Cocaine and the porcine coronary microcirculation: effects of chronic cocaine exposure and hypercholesterolemia.

OBJECTIVE: To examine the acute effect of cocaine on the coronary microcirculation and whether chronic cocaine administration with or without a concomitant high-cholesterol diet affects beta-adrenoceptor and endothelial functions in the coronary microcirculation. DESIGN: Prospective experimental study. SETTING: Laboratory and animal research facility. PARTICIPANTS: Yorkshire pigs. INTERVENTIONS: Pigs were fed a high (2%)-cholesterol diet or a regular diet for 3 months. Animals in both groups received cocaine chronically (7 mg/kg/day, IM). Control animals were fed a regular diet. MEASUREMENTS AND MAIN RESULTS: Responses of the porcine coronary arterioles (90 to 190 microns in diameter) were examined in vitro in a pressurized (40 mmHg) no-flow state using a video-imaging apparatus. Acute application of cocaine caused a significant contraction with a mean maximal diameter decrease of 14% +/- 5%, which was markedly reduced by muscarinic blockade but not significantly affected by alpha 1-adrenergic blockade. Lidocaine or procainamide had no vasoconstrictor effect. Chronic exposure of animals to cocaine diminished contractile responses to cocaine and reduced relaxation responses to the nonselective beta-adrenergic receptor agonist isoproterenol. Phenylephrine caused a minimal (< 4%) contraction of vessels in all groups. Chronic cocaine administration with concomitant high-cholesterol feeding attenuated endothelium-dependent relaxations to serotonin, whereas endothelium-dependent relaxations to bradykinin were unaffected. Endothelium-independent relaxations to sodium nitroprusside were similar in all groups. CONCLUSIONS: These results suggest that cocaine can exert a direct vasoconstrictor effect on the porcine coronary microcirculation via a muscarinic mechanism. Chronic exposure to cocaine significantly decreases beta-adrenoceptor-mediated relaxation and blunts endothelium-dependent relaxation to a small degree.

Adrenergic alpha-Antagonists↗
PubMed2003

DNA methylation and autoimmune disease.

DNA methylation plays an essential role in maintaining T-cell function. A growing body of literature indicates that failure to maintain DNA methylation levels and patterns in mature T cells can result in T-cell autoreactivity in vitro and autoimmunity in vivo. Defective maintenance of DNA methylation may be caused by drugs such as procainamide or hydralazine, or failure to activate the genes encoding maintenance DNA methyltransferases during mitosis, resulting in the development of a lupus-like disease or perhaps other autoimmune disorders. This paper reviews the evidence supporting a role for abnormal T-cell DNA methylation in causing autoimmunity in an animal model of drug-induced lupus, and discusses some of the mechanisms involved. T cells from patients with active lupus have evidence for most if not all of the same methylation abnormalities, suggesting that abnormal DNA methylation plays a role in idiopathic human lupus as well.

Animals↗
PubMed2004

Potentiometric immunosensor using artificial antibody based on molecularly imprinted polymers.

A potentiometric artificial immunosensor based on a molecularly imprinted polymer was prepared as a detecting element in micro total analysis systems with the intent of providing easy clinical analysis. As the structure and transducing mechanism of this sensor are very simple, construction of a single microsensor should be quite easy. Multimicrosensor arrays applicable to several kinds of analytes will be attainable by both changing the template molecule to be imprinted and reducing the sensor size. The response characteristics of this sensor were evaluated by measuring the response potential to serotonin, which was used as a model material. The obtained sensor was highly responsive to serotonin in water but not to tryptamine, acetaminophen, or procainamide. This phenomenon confirms that the sensor recognizes serotonin and that it functions as a specific artificial immunosensor. Quick measurement is possible because the response time, defined as the time required to achieve 95% of the magnitude of the equilibrated signal, correspond to approximately 12 s. The sensor's determination and detection limits were found to be 1 mumol/L and 100 pmol/L, respectively. These results suggest that our strategy can be applied to construction of a potentiometric artificial immunosensor.

Acetaminophen↗
PubMed1987

Synthesis and antiarrhythmic activity of new 3-[2-(omega-aminoalkoxy)phenoxy]-4-phenyl-3-buten-2-ones and related compounds.

A number of the title compounds (1) and a few related hydroquinone derivatives (2) have been synthesized and tested for antiarrhythmic activity in vivo (protection against CaCl2-induced ventricular fibrillation in anesthetized rat) and in vitro (ability to reduce the maximum driven frequency of an electrical stimulus in isolated rabbit atria). The effects induced by modification of the enol ether moiety in the parent compound 1a were also examined. Many of the compounds exhibited antiarrhythmic properties stronger than quinidine and procainamide, associated with a more favorable LD50/ED50 ratio. Compounds 1a (LR-18,460, 3-[2-[2-(diethylamino)ethoxy]phenoxy]-4-phenyl-3-buten-2-one) and 1h (LR-18,795, 3-[2-[3-(dimethylamino)propoxy]phenoxy]-4-phenyl-3-buten-2-one) were submitted to further antiarrhythmic testing, which confirmed their effectiveness and superiority to quinidine in all the experiments. After safety evaluation studies, both were selected for clinical investigation.

Amines↗
PubMed2007

Novel quinolizidinyl derivatives as antiarrhythmic agents.

Eighteen analogues of lidocaine, mexiletine, and procainamide were synthesized, replacing their aminoalkyl chains with the rigid and cumbersome quinolizidine nucleus. The target compounds were tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. Most compounds exhibited from moderate to high antiarrhythmic activity, and compounds 7, 9, and 19 were more active and potent than quinidine and lidocaine, while producing only modest inotropic, chronotropic, and vasorelaxant effects. These compounds were studied on spontaneously beating Langendorff-perfused gp heart. While quinidine and amiodarone produced a dose-dependent prolongation of all the ECG intervals, compounds 7, 9, and 19, even at concentrations 10-20 times higher than EC50 for the antiarrhythmic activity, only moderately prolonged the PR and QT intervals, leaving unchanged the QRS complex. Ether 7 deserves further investigations due to its interesting cardiovascular profile.

Amiodarone↗