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Objectives: In normal conditions, sudden heart rate acceleration provokes a rapid reduction in ventricular action potential duration (APD). The protracted APD rate adaptation favors early afterdepolarizations and precipitates arrhythmia. Nevertheless, it is uncertain as to whether the rate-dependent changes of ventricular repolarization can be adversely modified by arrhythmogenic drugs (quinidine and procainamide) and hypokalemia, in comparison to the agents with safe therapeutic profile, such as lidocaine., Design: The rate adaptation of QT interval and monophasic APD obtained from the left ventricular (LV) and the right ventricular (RV) epicardium was examined during rapid cardiac pacing applied in isolated, perfused guinea-pig heart preparations., Results: At baseline, an abrupt increase in cardiac activation rate was associated with a substantial reduction of the QT interval and ventricular APD in the first two cardiac cycles, which was followed by a gradual shortening of repolarization over subsequent pacing intervals. The time constants of the fast (τ fast ) and slow (τ slow ) components of the APD dynamics determined from a double exponential fit were longer in RV compared to LV chamber. Quinidine, procainamide, and hypokalemia prolonged ventricular repolarization and delayed the rate adaptation of the QT interval and APD in LV and RV, as evidenced by increased τ fast and τ slow values. In contrast, lidocaine had no effect on the dynamic changes of ventricular repolarization upon heart rate acceleration., Conclusions: The rate adaptation of ventricular repolarization is delayed by arrhythmogenic interventions, such as quinidine, procainamide, and hypokalemia, but not changed by lidocaine, a clinically safe antiarrhythmic agent.

Background: Ventricular tachycardia (VT) and ventricular fibrillation are the causes of approximately 300,000 deaths per year in the United States. VT is classified based on hemodynamic status and appearance. Stable, monomorphic VT treatment is controversial., Objective: Our aim was to provide emergency physicians with an evidence-based review of the medical management of stable, monomorphic VT., Discussion: Stable, monomorphic VT is part of a larger class of ventricular dysrhythmias defined by a rate of at least 120 beats/min with QRS > 120 ms without regularly occurring P:QRS association. Little controversy exists for the treatment of hemodynamically unstable VT. The medical management of hemodynamically stable monomorphic VT is surrounded by controversy. Direct current cardioversion is most efficacious. Guidelines for the treatment of stable VT from the American Heart Association provide a IIa recommendation for procainamide, compared with a IIb recommendation for both amiodarone and sotalol. Studies evaluating procainamide, lidocaine, amiodarone, and sotalol suffer from poor design, difference in inclusion and exclusion criteria, small sample size, and outcome determination. Procainamide demonstrates the greatest efficacy. If procainamide is selected, a maximum dose of 10 mg/kg at 50-100 mg/min intravenous (IV) over 10-20 min should be provided with monitoring of blood pressure and electrocardiogram. Monomorphic VT with acute myocardial ischemia requires further study., Conclusions: Optimal management of stable, monomorphic VT includes direct current cardioversion. If medical management is chosen, procainamide is most efficacious, though current literature suffers from poor design., (Published by Elsevier Inc.)

Procainamide is class Ia Na(+) channel blocker that may prolong ventricular repolarization secondary to inhibition of IK r , the rapid component of the delayed rectifier K(+) current. In contrast to selective IN a blockers such as lidocaine, procainamide was shown to produce arrhythmogenic effects in the clinical setting. This study examined whether pro-arrhythmic responses to procainamide may be accounted for by drug-induced repolarization abnormalities including impaired electrical restitution kinetics, spatial gradients in action potential duration (APD), and activation-to-repolarization coupling. In perfused guinea-pig hearts, procainamide was found to prolong the QT interval on ECG and left ventricular (LV) epicardial monophasic APD, increased the maximum slope of electrical restitution, enhanced transepicardial APD variability, and eliminated the inverse correlation between the local APD and activation time values determined at distinct epicardial recording sites prior to drug infusion. In contrast, lidocaine had no effect on electrical restitution, the degree of transepicardial repolarization heterogeneities, and activation-to-repolarization coupling. Spontaneous episodes of monomorphic ventricular tachycardia were observed in 57% of procainamide-treated heart preparations. No arrhythmia was induced by lidocaine. In summary, this study suggests that abnormal changes in repolarization may contribute to pro-arrhythmic effects of procainamide., (© 2013 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2 channels and to what extent RyR2 channel inhibition contributes to antiarrhythmic efficacy in CPVT., Methods and Results: We first measured the effect of all class I antiarrhythmic drugs marketed in the United States (quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone) on single RyR2 channels incorporated into lipid bilayers. Only flecainide and propafenone inhibited RyR2 channels, with the S-enantiomer of propafenone having a significantly lower potency than R-propafenone or flecainide. In Casq2(-/-) myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca(2+) waves at clinically relevant concentrations, whereas Na(+) channel inhibitors without RyR2 blocking properties did not. In Casq2(-/-) mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice, P<0.05). QRS duration was not significantly different, indicating a similar degree of Na(+) channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy., Conclusions: RyR2 cardiac Ca(2+) release channel inhibition appears to determine efficacy of class I drugs for the prevention of CPVT in Casq2(-/-) mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic on β-blockers.

The inhibitory effects of cationic drugs (beta-adrenoreceptor antagonists, calcium (Ca)-channel blocker, I(f) channel inhibitor, antiarrhythmic drugs, and antibacterial drugs) that inhibit 1-methyl-4-phenylpyridinium (MPP) and/or metformin uptake into hOCT1-3/rOct1-3-expressing cells and human/rat hepatocytes were investigated in this study. The drug-drug interaction (DDI) potential of these drugs for the hOCT/rOct-mediated hepatic/renal uptake process was also assessed. The IC(50) values of cardiovascular drugs, including an I(f) channel inhibitor with a new mechanism of action, were greater for hOCT2/rOct2 than those for hOCT1/rOct1 or hOCT3/rOct3. No species differences in these values were observed between hOCTs and rOcts. As for hOCT2-mediated uptake, the IC(50) values of quinidine and the I(f) channel inhibitor for metformin uptake were lower than those for MPP uptake. However, previous clinical studies found that the IC(50) values of these drugs for hOCT1/rOct1 and hOCT2/rOct2 were much greater than their unbound plasma concentrations, which suggests that the DDIs of these cationic compounds may not be related to hOCT/rOct-mediated hepatic/renal uptake pathways. In addition, investigation of the luminal transporters of cationic compounds in the kidney, as well as the in vitro DDI potential of their inhibitors, is important for the clarification of cationic compound DDIs in humans.

Atrial electrical remodeling (ER) after spontaneous or pacing-induced atrial fibrillation has been previously described in humans. We investigated atrial ER induced by a 5-minute period of rapid atrial pacing and the pharmacologic effects of verapamil and procainamide on this atrial ER phenomenon. The atrial effective refractory periods (ERPs) at drive cycle lengths of 400 (ERP 400 ) and 600 (ERP 600 ) ms, at five representative atrial sites (high right atrium [HRA]; proximal, middle and distal coronary sinus; interatrial septum), were determined in 20 patients at baseline and immediately after cessation of a 5-minute period of rapid pacing from the HRA at a rate of 150 bpm. The degrees of atrial ERP 400 and ERP 600 shortening after pacing were calculated as acute atrial ER. The same protocol was repeated in another 15 patients after intravenous administration of verapamil (0.15 mg/kg) and in another 15 patients after intravenous administration of procainamide (15 mg/kg). The results demonstrated that, in the control state acute atrial ER can be significantly demonstrated at each atrial representative site ( p < 0.001). The mean ERP 400 and ERP 600 shortenings were 9 +/- 4% and 8 +/- 4%, respectively. After procainamide infusion, but not after verapamil, baseline ERP 400 and ERP 600 values were significantly prolonged at the five representative atrial sites ( p < 0.01). Acute atrial ER could still be demonstrated at each atrial site after procainamide or verapamil infusion ( p < 0.001). In conclusion, acute atrial ER can be demonstrated after only a 5-minute period of rapid atrial pacing in humans. Intravenous verapamil or procainamide does not abolish this ER process.

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.

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The cardiac arrhythmic suppression trial (CAST) reported that antiarrhythmic treatments in post-myocardial infarction (MI) patients resulted in poor outcome and decreased in heart rate variability indices (HRV). The goal of the present study was to determine whether aprindine and procainamide, antiarrhythmic agents that increase HRV, result in beneficial effects in post-MI rabbits. Four weeks before experiment, MI was induced in four rabbits by ligating the major branch of left coronary artery. A total of eight rabbits (four post-MI and four normal rabbits) were randomly assigned to treatment with either intravenous aprindine (1 mg/kg) or intravenous procainamide (15 mg/kg). Frequency domain HRV (low frequency spectra, LF, 0.04-0.15 Hz; high frequency spectra, HF, 0.15-0.40 Hz) were assessed by MemCalc software. Aprindine significantly increased HF and LF in both MI and normal rabbits, whereas procainamide tended to decrease HF and LF in MI and normal rabbits (in total rabbits; aprindine, LF, from 6.3 +/- 7.9 to 16.5 +/- 15.0 ms(2)/Hz, P < 0.05; HF, from 8.0 +/- 11.7 to 17.5 +/- 15.0 ms(2)/Hz, P < 0.05; procainamide, LF, from 4.9 +/- 7.4 to 4.8 +/- 8.5 ms(2)/Hz, NS; HF, from 11.1 +/- 23.0 to 5.1 +/- 10.6 ms(2)/Hz, NS). Under pharmacological denervation with propranolol (0.1 mg/kg) and atropine (0.04 mg/kg), aprindine increased LF and HF (LF, from 0.2 +/- 0.2 to 0.8 +/- 0.7 ms(2)/Hz, P < 0.05; HF, from 0.1 +/- 0.0 to 0.2 +/- 0.0 ms(2)/Hz, P < 0.05). These data suggest that aprindine can increase HRV in post-MI rabbits. Further experiments in human subjects would be of benefit.

It has been observed that decrease of DNA methyltransferase 1 (DNMT1) activity is associated with low content of the CD3-zeta (zeta) chain in T cell receptor (TCR)/CD3 complex of T cells in systemic lupus erythematosus (SLE) patients. The CD3-zeta chain plays a pivotal role in intracellular signal transmission between TCR/CD3 complex and nuclei. The compounds 5'-azacytidine (AZC) and procainamide (PCA) belong to inhibitors of DNMT1, whose low activity correlates with increase in transcription of various genes. Using the reverse-transcription and real-time quantitative PCR (RQ-PCR) analysis, we indicated that AZC and PCA did not profoundly affect on CD3-zeta chain transcription in Jurkat T leukemia cells clone E6-1. However, the flowcytometric analysis revealed that AZC and PCA decreased intracellular contents of CD3-zeta chain in these cells in dose dependent manner. Our results suggest that decrease of DNMT1 activity may alter intracellular signal transmission without effect on transcription level of CD3-zeta chain.

The aim of the study was to investigate the effect of class IA antiarrhythmic drug procainamide and its new derivatives PA20, PA23, PA28 and PA53 on carbachol-induced action potential duration and contraction force in guinea pig atrial muscles. Experiments were carried out using standard method of registration of myocardium electromechanical activity. Under control conditions (perfusion of atrial strips with Tyrode solution), mean action potential duration measured at 90% (AP90) and 50% (AP50) of repolarization were 92.5+/-4.5 ms and 44.4+/-2.9 ms (n=18), respectively, and contraction force was of 2.7+/-0.5 mN (n=12). Carbachol (10(-6) M), an agonist of muscarinic acetylcholine receptor and activator of K(Ach) channels, markedly decreased AP90 to 32.4+/-2.4%, AP50 - to 25.4+/-2.2% (n=18) (p<0.001) and contraction force - to 24.2+/-5.8% (n=16) (p<0.05), vs. control. Procainamide and its new sulfonylcarbamide derivatives PA20, PA23, PA28 (10(-5)-3x10(-3) M), and PA53 (10(-5)-10(-3) M) reversed the carbachol-induced action potential duration shortening at different extent: procainamide derivative PA20 (N-cyclohexylsulfonylcarbamide fragment is linked up to benzene ring) had the most potent anticholinergic effect on action potential duration and contraction force of guinea pig atrial muscles. N-ethylsulfonylcarbamide fragment in PA23 or permanent positive charge of aliphatic nitrogen in PA28 had a weaker anticholinergic effect (similar to procainamide action) on action potential duration and contraction force than PA20. The weakest anticholinergic effect was induced by procainamide derivative PA53 with isosteric form of sulfonylcarbamide.

Antiarrhythmic drugs have been considered to be transported by the organic cation transport system. The purpose of this study was to elucidate the molecular mechanism underlying the transport of antiarrhythmic drugs using cells from the second segment of the proximal tubule (S2) cells of mice expressing human-organic cation transporter 3 (S2 human-OCT3). The antiarrhythmic drugs tested were cibenzoline, disopyramide, lidocaine, mexiletine, phenytoin, pilsicanide, procainamide and quinidine. Human-OCT3 mediated a time- and dose-dependent uptake of quinidine and lidocaine, with Km values of 216 and 139 microM, respectively. Human-OCT3 also mediated the uptake of disopyramide and procainamide but not that of phenytoin. All antiarrhythmic drugs tested inhibited histamine uptake mediated by human-OCT3 in a dose-dependent manner. The IC50 values of antiarrhythmic drugs for human-OCT3 ranged between 0.75 and 656 microM. Kinetic analysis revealed that disopyramide, lidocaine, procainamide and quinidine inhibited histamine uptake mediated by human-OCT3 in a competitive manner. In conclusion, these results suggest that human-OCT3 mediates the transport of antiarrhythmic drugs, which may be the mechanism underlying the distribution and the elimination of these drugs.

Focal discharges (FDs) are present in thoracic veins during atrial fibrillation (AF). We hypothesize that procainamide exerts its anti-AF action by suppressing FDs in the thoracic veins. We studied six mongrel dogs (22-27 kg) with sustained (>6 h) AF induced by 47 +/- 20 days of chronic rapid LA appendage (LAA) or pulmonary vein (PV) pacing. Procainamide was infused intravenously until AF was terminated or a cumulative dose of 20 mg/kg was reached. High-resolution mapping during AF showed FDs in the vein of Marshall, PVs, and the LAA. Procainamide significantly (P < 0.05) reduced the frequency of these FDs and suppressed the interactions of wave fronts between PVs and LA. The cumulative dose of PA needed to terminate AF correlated negatively (r =-0.9, P < 0.05) with the baseline effective refractory period (ERP) of PV and positively (r = 0.8, P < 0.05) with the baseline maximum dominant frequency (DF) of AF. In four of five dogs, AF converted to atrial tachycardia originating from the PVs before termination. Attempts to reinduce sustained AF were unsuccessful in these five dogs. AF was resistant to procainamide in the sixth dog. In conclusion, procainamide reduced the rate of FDs in the thoracic veins and the LA and suppressed the interaction between PVs and LA. Second, FDs in the PV are more resistant to procainamide's action than FDs in the atria. Third, inherent PV ERP is important in determining the antifibrillatory efficacy of procainamide.

The drug-drug interactions between antiarrhythmic drugs were studied in chick embryos. Fertilized eggs of White Leghorns were incubated and investigated. Procainamide or flecainide with and without propranolol was injected into the air sac of a fertilized egg. Electrocardiograms (ECGs) were recorded 0 to 60 min after the injection. After each drug injection alone, the heart rate was not different compared with the control. However, the heart rate was significantly decreased by combinations of procainamide and propranolol or flecainide and propranolol. In addition, arrhythmia was produced in combination with propranolol. These findings indicate that the drug-drug interactions between antiarrhythmic drugs have a marked influence on the heart rate in chick embryos.

We have synthesized a series of hybrid compounds combining the pharmacophoric redox moieties of vitamin E and key features responsible for the antiarrhythmic properties of the class I antiarrhythmics procainamide and lidocaine. Procainamide analogue (2a) and lidocaine analogues (14a) and (14b) are very strong inhibitors of lipid peroxidation. All analogues tested at 100 or 30 microM enhanced the post ischemic recovery without inducing ventricular fibrillations while there was no evidence in our experiments for drug-induced pro-arrhythmia. In addition, they induced a widening of the QRS intervals. Our data suggest that the efficacy of the new compounds in preventing reperfusion arrhythmias could be attributed to their combined effects involving inhibition of free radical mediated damage coupled with antiarrhythmic properties.

In this study the membrane fluidity of fibroblasts under different pharmacological treatment was investigated. Two drugs, hydralazine and procainamide, were used to treat the immortalized mouse NIH 3T3 and hamster B14 fibroblasts. Membrane lipid dynamics was measured by fluorescence spectroscopy and electron spin resonance techniques. Two kinds of fluorescent probes (TMA-DPH and 12-(9-anthroyloxy)-stearic acid (12-AS)) and two spin labels (5-doxylstearic acid (5-DS) and 12-doxylstearic acid (12-DS)) were used to monitor fluidity in the upper polar and in the hydrophobic core regions of the lipid bilayer. The drugs influenced the membrane hydrophobic core, of which hydralazine induced fluidization and procainamide increased the rigidity. The membrane fluidity at the surface of the lipid bilayer was not modified by the drugs which indicates that both drugs intercalated mainly into the inner core of the cell membrane.

Background: The blockade of cardiac transmembrane potassium channels, which is commonly seen with various antiarrhythmic drugs, plays an important role in their mechanism of action. We studied and compared the less-explored effects of three Class IA antiarrhythmics on the transient outward current (I(to)) and on the inward rectifier (I(kl)), ATP sensitive (I(KATP)), and delayed rectifier (I(K)) potassium currents in rabbit ventricular myocytes., Methods and Results: Transmembrane currents were measured by applying the whole-cell configuration of the patch-clamp technique at 37 degrees C in myocytes enzymatically isolated from rabbit ventricular preparations. Quinidine (10 microM), disopyramide (10 microM), and procainamide (50 microM) were studied at concentrations close to or exceeding the therapeutic plasma level. All studied drugs significantly decreased the amplitude of I(KATP) (activated by 50 microM pinacidil) and I(K) currents. None of them influenced significantly I(kl). The amplitude of I(to) was decreased by quinidine and disopyramide but was not considerably altered by procainamide. The fast inactivation of I(to) was not changed by procainamide and was significantly accelerated by quinidine and disopyramide., Conclusion: Although quinidine, disopyramide, and procainamide are all classified as Class IA antiarrhythmics, these drugs had different effects on various potassium currents, which may partially explain their distinct effect on repolarization in various cardiac tissues and on cardiac arrhythmias in clinical settings.

To investigate the pharmacological effect of procainamide on transmural ventricular repolarisation in normal heart, the transmural activation-recovery intervals (ARI) and their responses to procainamide (20 mg/min i.v. for 20 min) were studied in 6 open-chest, pentobarbitone-anaesthetised sheep. ARI was measured from the unipolar ECGs acquired with 4 plunge needles inserted into the basal and apical parts of the left ventricular wall. During sinus rhythm (cycle length 500-700 ms), there was no significant difference in the pooled ARI between the epicardium (266.0 +/- 30.5 ms), midmyocardium (265.0 +/- 28.9 ms) and endocardium (265.7 +/- 28.1 ms) (p > 0.05). Procainamide prolonged ARI in all myocardial layers. The pooled ARI prolongation from the epicardium, midmyocardium and endocardium of the 6 animals was 66.8 +/- 18.3, 70.3 +/- 14.7 and 65.3 +/- 15.7 ms (p > 0.05), respectively. In conclusion, sodium channel blocker procainamide results in a similar repolarisation prolongation in the left ventricular epicardium, midmyocardium and endocardium of a healthy heart.

In preceding papers, we proposed that procainamide hydrochloride, a class I antiarrhythmic agent, was able to protect mice and rats from cisplatin-induced nephrotoxicity and that it could exert its action through accumulation in kidneys followed by coordination with cisplatin (or its hydrolysis metabolites) and formation of a less toxic platinum compound similar to the new platinum(II) triamine complex cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate, obtained by the reaction of cisplatin with procaine hydrochloride. Hepatotoxicity is not considered as a dose-limiting toxicity for cisplatin, but liver toxicity can occur when the antineoplastic drug is administered at high doses. Here, we report that procainamide hydrochloride, at an i.p. dose of 100 mg/kg, reduces cisplatin-induced hepatotoxicity, as evidenced by the normalization of plasma activity of glutamic oxalacetic transaminase and gamma-glutamyl transpeptidase, as well as by histological examination of the liver tissue. Twenty-four hours after i.p. treatment with the combination of 7.5 mg/kg cisplatin and 100 mg/kg procainamide, a significant increase of procainamide (+56%, P<0.05), total platinum (+31%, P<0.05), platinum-DNA adducts (+31%, P<0.05) and percent DNA-DNA interstrand cross-links (+69%, P<0.02) was found in liver tissue, as compared to animals treated with cisplatin alone. Moreover, in accordance with these findings, we also observed a slightly lower concentration and cumulative excretion of platinum in the feces. Since mitochondrial injury is considered a central event in the early stages of the nephrotoxic effect of cisplatin, the distribution of platinum in these subcellular organelles obtained from hepatocytes was determined after treatment with cisplatin with or without procainamide hydrochloride, together with platinum concentration in their cytosolic fraction. Our data show that the coadministration of procainamide hydrochloride produced a rearrangement of subcellular platinum distribution in hepatocytes with a slight decrease in mitochondria (-15%, P<0.10) and a slight increase in the cytosolic fraction (+40%, P<0.10) of platinum content, compared to the treatment with cisplatin alone. In analogy with our previous results in the kidney, confirmed here by our data in vitro, we suggest that the hepatoprotective activity of procainamide hydrochloride is linked to the formation of a less toxic platinum complex, which leads to inactivation of cisplatin itself and/or its highly toxic hydrolysis metabolites and to a different subcellular distribution of platinum.

The post-repolarization refractoriness (PRR) is an important factor to determine the conduction block in cardiac muscle. Recently, we proposed the block coupling interval (BCI) as an useful electrophysiological index for evaluating the PRR. In the present study, the effect of procainamide on PRR was evaluated using the BCI and the effective refractory period (ERP). In five beagle dogs, radiofrequency linear ablation was performed on the right atrial surface parallel to the AV groove, forming an artificial isthmus (8-10 mm width and 15-20 mm length). Bipolar recordings were performed in the isthmus at a resolution of 1.2 mm and single extrastimuli with eight basic drive trains were delivered to cause conduction blocks in the isthmus. When a conduction block occurred, the recorded coupling interval at the recording site just proximal to the site of block was defined as BCI. At the site of the block, the ERP and duration of the monophasic action potential (MAP) at each drive cycle length was measured. The PRR was calculated using two different formulas: (1) [ERP-MAP] and (2) [BCI-MAP]. Procainamide was administrated intravenously at a dose of 15 mg/kg after the control study and the whole study protocol was repeated. The site of the block in an individual dog was always the same. BCI, ERP, and MAP were all shortened in accordance with the shortening of the basic drive cycle length, and the BCI was always the longest, ERP the middle, and the MAP was the shortest. The administration of procainamide prolonged each parameter, but the order of BCI > ERP > MAP remained unchanged. The PRR calculated as [BCI-MAP] was prolonged from 15 +/- 10 ms to 29 +/- 8 ms by the administration of procainamide (P = 0.048), but [ERP-MAP] was unchanged (8 +/- 10 ms vs 8 +/- 4 ms). In the conduction block model in the canine right atrium, procainamide prolonged the [BCI-MAP], but did not change the [ERP-MAP]. The procainamide effect of prolonging the PRR might be expressed better by the change in the BCI than the ERP.

The Vaughn Williams classification divides antiarrhythmic agents into four groups according to their effects on various ion channels. Class I agents block sodium channels and are subdivided into three groups. The use of class Ia agents is gradually on the decline, secondary to lack of a favorable risk/benefit ratio. Class Ib agents include lidocaine, which is extensively used for the acute treatment of ventricular tachyarrhythmias. Class Ic drugs are not advisable for patients with structural cardiac abnormalities secondary to a high risk of proarrhythmia. They are mainly used for supraventricular tachyarrhythmias. beta blockers form class II. Class III agents, such as amiodarone and sotalol, prolong action potential duration and repolarization and are among the most widely used antiarrhythmics. They are the subject of active research, and newer agents are being developed. Calcium-channel blockers are grouped under class IV. Digoxin and adenosine have unique antiarrhythmic properties, which can be useful in the management of selected patients. All antiarrhythmic drugs have the potential to provoke arrhythmias and, therefore, should be used with caution. The risk of proarrhythmia is increased in patients with abnormal cardiac substrate, with electrolyte abnormalities, and during drug initiation. Correction of electrolyte imbalance and prevention of bradycardia while the drug is metabolized and/or excreted are the cornerstones of proarrhythmia management.

The relaxant effect of procainamide, a class Ia antiarrhythmic agent, was examined in bovine tracheal smooth muscle. Procainamide produced concentration-dependent decreases in tension and full relaxation in the preparations contracted with methacholine (0.3 microM). By comparison, in preparations contracted with 40 mM K(+), procainamide had only slight relaxant effects. The relaxant effects of cromakalim and salbutamol on 40 mM K(+)-contracted preparations were significantly (P<0.01) smaller than those on 0.3 microM methacholine-contracted ones. On the other hand, the concentration-response relationships for quinidine, lidocaine, mexiletine and propafenone were not so dramatically different between 0.3 microM methacholine- and 40 mM K(+)-contracted preparations. Tetraethylammonium (300 microM), iberiotoxin (30 nM) and Ba(2+) (1 mM) significantly (P<0.05) attenuated the relaxant effects of procainamide on methacholine-induced contractions, whereas apamin (100 nM), 4-aminopyridine (300 microM), and glibenclamide (10 microM) did not affect them. The inhibitory effect of a combination of iberiotoxin and Ba(2+) was greater than that of iberiotoxin or Ba(2+) alone (P<0.01). These results suggest that the activation of at least two types of K(+) (maxi-K(+) and inward rectifier K(+)) channels contributes to the procainamide-induced relaxation of bovine tracheal smooth muscle.

Background: Patients with inducible sustained ventricular tachycardia (VT) sometimes receive intravenous procainamide during electrophysiologic testing. Unfortunately, the responses to intravenous and subsequent oral drug therapy are variable and may be discordant., Hypothesis: It was the aim of this study to determine whether this variability might be explained by heterogeneity in the electropharmacologic response, even in a homogeneous population., Methods: We studied 42 patients who had spontaneous malignant ventricular arrhythmia and were inducible to sustained monomorphous VT during electrophysiologic testing. Each received 15 mg/kg of intravenous procainamide followed by a 2 mg/min infusion. Serum levels were drawn immediately following programmed stimulation. The mean procainamide level was 6.7 +/- 1.4 mcg/ml with an N-acetyl procainamide level of 1.0 +/- 0.5 mcg/ml. The 14 procainamide responders (5 of whom were noninducible and 9 whose VT cycle length increased > 100 ms) and the 28 nonresponders had similar procainamide and NAPA levels (6.5 +/- 1.4 vs. 6.7 +/- 1.4 mcg/ml)., Results: There was no significant difference in baseline clinical parameters, His to ventricular electrogram (HV) interval, effective refractory period, or VT cycle length. Prolongation of the effective refractory period and infra His conduction time occurred to a similar extent in responders and nonresponders., Conclusion: We conclude that procainamide has a consistent dose-response relationship with respect to refractoriness and conduction in patients with malignant arrhythmias. However, acute antiarrhythmic efficacy of procainamide cannot be predicted by clinical factors, drug levels, or drug-induced changes in common electrophysiologic parameters.

The ventricular proarrhythmic actions of five class III antiarrhythmic agents were compared in the Carlsson rabbit model. In adrenergically stimulated anesthetized rabbits, azimilide, clofilium, dofetilide, sematilide, and d,l-sotalol caused premature ventricular contractions and nonsustained and sustained ventricular tachyarrhythmias (NSVT and SVT) at pharmacologically equivalent intravenous doses that increased QTc intervals 20% (ED20). There were no significant differences between agents in the percentage of rabbits with serious arrhyhthmias at the ED20 doses of 5.2, 0.033, 0.015, 0.66, and 2.8 mg/kg i.v., respectively. Proarrhythmia was dose-dependent. Linear regression analysis of arrhythmia score versus log dose estimated the NSVT doses as 6.2, 0.055, 0.0089, 1.5, and 5.7, respectively. Analysis of arrhythmia states during a 10-min window after infusion when QTc prolongation was 20% showed that the compounds differed significantly in the proportion of time treated rabbits spent in SVT and combined NSVT and SVT. Rabbits treated with azimilide spent significantly less time in SVT and combined NSVT and SVT, followed in order of increasing time by d,l-sotalol, sematilide, clofilium, and dofetilide.

Background: Ventricular fibrillation (VF) is maintained by 2 mechanisms: first by reentry formation and second by spontaneous wave break or wave splitting. We hypothesized that spontaneous wave break results from a critical shortening of the action potential duration (APD) during VF and that its prevention by procainamide eliminates spontaneous wave break., Methods and Results: The endocardial surfaces of 7 isolated, perfused swine right ventricles were mapped with a 3.2x3.8 cm plaque with 477 bipolar electrodes. Activation pattern during VF was visualized dynamically while simultaneously recording epicardial action potentials with a glass microelectrode. APD restitution curves were constructed during VF (dynamic) and during S(1)S(2) protocols. At baseline, VF was maintained by 5.3+/-1 wavelets. Procainamide (PA) at 10 microgram/mL decreased the number of wavelets to 3.5+/-1 (P<0.05). At baseline VF was maintained by spontaneous wave break and by new reentrant wave front formation. PA eliminated spontaneous wave break during VF while having no effect on reentry formation. PA increased the cycle length of the VF (148.5+/-41.2 ms vs 81+/-10 ms, P<0.01) and the core area of the reentry from 5.8 to 14.5 mm(2) (P<0.05). Dynamic APD restitution curve during VF showed that PA eliminated the initiation of activation with APDs shorter than 30 ms. The effects of PA on cellular properties and wave front dynamics were reversed during 60 minutes of drug-free perfusion., Conclusions: Critically short APDs during VF promote spontaneous wave break. Their elimination with PA, however, maintains VF by generating new reentrant wave front.

Lidocaine, procainamide and quinidine binding to human placenta was investigated in vitro. Pooled whole human placental homogenate supplemented with either non-radiolabelled lidocaine, procainamide or quinidine over the concentration range 50-5,000 x 10(-7) mol/L was submitted to equilibrium dialysis against phosphate buffer, pH 7.4, 0.1 mol/L. Post-dialysis drug concentrations were measured by enzyme immunoassay. Data were analyzed by the method of Scatchard. No binding to placenta was noted for either lidocaine or procainamide. In contrast, up to 22 percent of quinidine was bound. Two binders were defined as follows: #1 (Ka, 7.37 x 10(5) L/mol; Bo, 1.55 x 10(-7) mol/L) and #2 (Ka, 7.11 x 10(4) L/mol; Bo, 4.05 x 10(-6) mol/L). The concentrations of quinidine binding sites in moles per gram of placenta were 1.55 x 10(-9) and 4.05 x 10(-8), respectively. These data suggest that quinidine may be accumulated in human placenta.

The slow delayed rectifier potassium current (I(Ks)) is unique in its slow activation and deactivation kinetics. It is important during cardiac repolarization, especially when the heart rate is fast. We compared the effects of quinidine, procainamide, sotalol, and amiodarone on I(Ks) and correlated the findings with the clinical reverse use-dependent effects of potassium channel blockers. Human minK RNA was obtained by reverse transcription-polymerase chain reaction using explanted human heart. The RNA was injected into Xenopus oocytes for heterologous expression of I(Ks). A two-electrode voltage clamp technique was performed to investigate the I(Ks). We demonstrated that quinidine, sotalol and procainamide had no effects on I(Ks) up to a concentration of 300 microM while amiodarone inhibited I(Ks) in a concentration-dependent manner starting from 10 microM. The inhibition by amiodarone was state-dependent with gradual unblocking after depolarization. The degree of inhibition was 53% immediately after depolarization and 19% at the end of a 5-second depolarization. I(Ks) is 30 times more sensitive to amiodarone than to quinidine, sotalol, and procainamide. Quinidine, sotalol and procainamide have reverse use-dependent effects while amiodarone does not. This is compatible with the hypothesis that no inhibition of I(Ks) at clinical concentrations contributes to the clinical reverse use-dependent effects.

Introduction: The measurement of microvolt level T wave alternans (TWA) is a technique for detecting arrhythmia vulnerability. Previous studies demonstrated that the magnitude of TWA is dependent on heart rate. However, the effects of antiarrhythmic drugs on TWA are unknown., Methods and Results: This was a prospective evaluation of intravenous procainamide on TWA in 24 subjects with inducible sustained ventricular tachycardia (VT). Measurements of TWA were performed at baseline in the drug-free state and after procainamide loading (1,204+/-278 mg). Recordings were made in normal sinus rhythm, and during atrial pacing at 100 beats/min and 120 beats/min. The magnitude of TWA in the vector magnitude lead was decreased by procainamide at all heart rates: 0.6+/-0.8 to 0.3+/-0.4 microV in sinus rhythm, 2.0+/-1.6 to 0.7+/-0.7 microV at 100 beats/min, and 3.0+/-2.0 to 1.7+/-1.8 microV at 120 beats/min (P<0.001 by analysis of variance). The sensitivity of TWA for the induction of VT at baseline was 5% in sinus, 60% at 100 beats/min, and 87% at 120 beats/min, while it decreased with procainamide to 5%, 19%, and 60%, respectively. Decreases in TWA in response to procainamide were independent of the antiarrhythmic effects on VT inducibility., Conclusions: These results indicate that the magnitude of TWA decreases with acute procainamide loading and this effect decreases the sensitivity of TWA for the induction of sustained VT.

Procainamide (PA), a cardioactive drug, inhibited the degradation of both cocaine (COC) and cocaethylene (CE) when either was incubated in human liver homogenates for 3 h at 37 degrees C. PA appeared to enhance the formation of CE when COC and ethanol (ETOH) were incubated together in liver homogenate. These observations are clinically significant because cardiotoxicity is common after COC abuse and because PA may be administered to individuals who use COC alone and with ETOH.

Normally, ventricular APD exceeds the VERP. However, under specific circumstances this relation may change and can become inverse. This phenomenon of postrepolarization refractoriness may be caused by a decrease in excitability. The threshold current (TC) for pacing has never been quantified as a possible explanation for these observations. Using a MAP pacing catheter in the right ventricular apex, the rate dependent behavior of TC, VERP, and APD before and after procainamide (dose 20 mg/kg in 10 min + 5 mg/min infusion) was determined in 17 dogs with chronic complete AV block. Initially, TC was determined with 0.1 mA accuracy. Using a pacing current of at least twice TC, VERP and APD showed a similar, rate dependent shortening for PCLs 800, 575, and 350 ms. Procainamide treatment led to an equal, rate independent VERP and APD increase: no post repolarization refractoriness. Subsequently, accuracy for TC determination was increased to 0.01 mA. Comparing PCLs 800 and 250 ms, TC doubled from 0.05 +/- 0.01 to 0.10 +/- 0.09 mA during control and almost tripled from 0.06 +/- 0.02 to 0.17 +/- 0.10 mA (P < 0.05) after procainamide. Using a fixed pacing current of exactly twice TC found at 800 ms PCL during control, VERP exceeded APD after procainamide treatment at 300 and 250 ms PCL: postrepolarization refractoriness. Increasing the pacing current to twice the rate dependent TC, the relation between VERP and APD normalized: no postrepolarization refractoriness. We conclude that after procainamide, rate dependent TC increase is of major importance for the phenomenon of postrepolarization refractoriness.

Atrial fibrillation is the most common cardiac rhythm disorder associated with hospitalization. Two therapeutic options have been available: antiarrhythmic drug therapy, and external or internal electrical cardioversion. Electrical cardioversion of atrial fibrillation remains one of the most widely used and effective treatments for the restoration of normal sinus rhythm. However, many patients continue to receive an antiarrhythmic drug before and after cardioversion in an attempt either to cardiovert the arrhythmia chemically or to maintain sinus rhythm after successful cardioversion. Because some pharmacological agents can affect the cardioversion procedure for atrial fibrillation or flutter, and because many patients with such arrhythmias may require electrical cardioversion when they are taking antiarrhythmic drugs, the question of a possible effect of drug therapy on the efficacy and safety of electrical cardioversion of atrial fibrillation arises. Early reports of direct current cardioversion provoking potentially lethal ventricular arrhythmias raised suspicions of an arrhythmogenic role for digoxin antiarrhythmic therapy, and it is customary to withhold these drugs for 24 to 48 h before cardioversion is attempted. However, this complication is likely to arise only in patients who are close to, or actually manifesting, signs of drug toxicity. On the other hand, treatment with therapeutic concentrations of antiarrhythmic drugs before cardioversion may in some cases be associated with a significant reduction in the number of shocks and decreased energy required to restore sinus rhythm, a lower incidence of postshock arrhythmias and a reduced risk of early recurrence of atrial fibrillation.

Background: Conduction block may be both antiarrhythmic and proarrhythmic. Drug-induced postrepolarization refractoriness (PRR) may prevent premature excitation and tachyarrhythmia induction. The effects of propafenone and procainamide on these parameters, and their antiarrhythmic or proarrhythmic consequences, were investigated., Methods and Results: In 11 isolated Langendorff-perfused rabbit hearts, monophasic action potentials (MAPs) were recorded simultaneously from six to seven different right and left ventricular sites, along with a volume-conducted ECG. All recordings were used to discern ventricular tachycardia (VT) or ventricular fibrillation (VF) induced by repetitive extrastimulation (S2-S5) or 10-second burst stimulation at 25 to 200 Hz at baseline and after addition of procainamide (20 micromol/L) or propafenone (1 micromol/L) to the perfusate. MAPs were analyzed for action potential duration at 90% repolarization (APD90), conduction times (CT) between the pacing site and the other MAPs, and PRR (effective refractory period-APD90=PRR) and related to the induction of VT or VF. During steady-state pacing, procainamide and propafenone prolonged APD90 by 12% and 14%, respectively. Procainamide slowed mean CT by 40% during S2-S5 pacing, whereas propafenone slowed mean CT by up to 400% (P<0.001 versus baseline and procainamide). Wavelength was not changed significantly by procainamide but was shortened fourfold by propafenone at S5. Both drugs produced PRR, which was associated with a 70% decrease in VF inducibility with procainamide and elimination of VF with propafenone. Despite this protection from VF, monomorphic VT was induced with propafenone in 57% of burst stimulations., Conclusions: Drug-induced PRR protects against VF induction. Propafenone promotes slow monomorphic VT, probably by use-dependent conduction slowing and wavelength shortening.

Background: There is increasing evidence that both functional reentrant wave fronts and multiple wavelets are present during ventricular fibrillation (VF). However, the effects of procainamide on the characteristics of activation waves during VF are poorly understood., Methods and Results: Seven dogs were studied; six underwent subendocardial chemical ablation procedures. A plaque with 317 to 480 bipolar electrodes was sutured to the right ventricular free wall, and the patterns of activation were registered with a computerized mapping system. VF was electrically induced, and the patterns of activation were registered at baseline and during procainamide infusion (serum concentration, 9.3+/-1.9 microg/mL). Among the six dogs that had their subendocardium ablated, reentrant wave fronts were present in 6 of the 108 runs of VF at baseline and in 6 of the 100 runs of VF during procainamide infusion. By analyzing the wave fronts, we found that the cycle length, refractory period, conduction velocity, and wavelength at baseline were 101+/-9 ms, 54+/-5 ms, 0.93+/-0.21 mm/ms, and 51+/-16 mm, respectively, and during procainamide infusion, values became 125+/-11 ms (P<.001), 119+/-7 ms (P<.001), 0.42+/-0.02 mm/ms (P<.001), and 50+/-4 mm (P=.8), respectively. The vast majority of the activation waves do not form organized reentry. These activation waves broke up more frequently at baseline than during procainamide administration. The number of activation waves was 7.25+/-1.39 s(-1) x cm(-2) at baseline and 4.45+/-1.80 s(-1) x cm(-2) during procainamide administration (P<.001). The dog without subendocardial ablation had similar results., Conclusions: Procainamide decreases the number of wavelets during VF by preventing spontaneous wave breaks. This represents a novel mechanism of antiarrhythmic drug action.

1. The cardiac anticholinergic effects of procainamide (1 mg kg(-1) min(-1)) and its N-acetylated metabolite (NAPA) at equimolar dose (1.16 mg kg(-1) min(-1)) were studied using in vivo experimental pharmacological and in vitro radioligand binding studies. 2. Procainamide and NAPA progressively reduced vagal stimulation-induced bradycardia in chloralose-anaesthetized dogs. As indicated by the ED50, the vagolytic activity of NAPA is 1.5-2.0 times weaker than that of procainamide. Both drugs increased heart rate, with lowering of mean blood pressure during the second part of procainamide infusion, but not during NAPA infusion. 3. Binding studies on rat heart membranes yielded Ki values that were 1.5 times higher for NAPA than for procainamide. 4. These results show that NAPA exerts a weaker cardiac vagolytic action than procainamide, which is probably linked to a lower ability to bind to cardiac muscarinic receptors.

Monomorphic sustained ventricular tachycardia (MSVT) was revisited in relation to the electrophysiologic findings and their relation to the drug efficacy. Old myocardial infarction is less common cause of MSVT in Japan, and the majority (about 2/3) of MSVT is unrelated to coronary artery disease but, the mechanism shared a common mechanism: reentry with an excitable gap as others. The reentrant mechanism was supported from the inducibility, the terminability of VT by electrical stimulation, and by the ability to entrain with rapid pacing. In MSVT associated with underlying heart diseases, diseased myocardium showed low amplitude and fragmented electrograms and the area was considered to participate as the central common pathway of reentrant circuit. The area of slow pathway showed a decremental conduction or all-or-nothing conductive property. The width of the excitable gap seemed to be determined by the maximal conductive frequency but not by the duration of action potential: effective refractory period. As to the drug efficacy, there was no baseline characteristics in predicting the efficacy. However, the significant narrowing of the width of the excitable gap was associated with the drug efficacy and VT became non-inducible after addition of the same drug. The response pattern of the excitable gap to specific drug including class III, was not predictable. Further electropharmacological studies will be warranted.

The effects of sematilide, a novel class III antiarrhythmic agent, on membrane currents were examined in single myocytes isolated from the rabbit left atrium, using the whole-cell voltage clamp technique. Application of 10, 30, 100 and 300 microM sematilide caused a concentration-dependent inhibition of the delayed rectifier K+ current (IC50 approx. 25 microM). The sematilide-sensitive current, which was recorded by means of a triangular voltage command, showed a strong inward rectification and had a peak at about -40 mV, suggesting that sematilide inhibits the rapidly activating delayed rectifier K+ current. The Ca2+-independent transient K+ and the inward rectifier K+ currents were not affected significantly by application of 100 microM sematilide. Moreover, voltage-dependent Na+ and Ca2+ currents were not affected significantly by 100 microM sematilide. These findings indicate that sematilide selectively blocks the rapidly activating delayed rectifier K+ current in atrial myocytes and provide evidence supporting the usefulness of the drug as a class III antiarrhythmic agent.

1. In whole-cell patch recording, the relative potency of the blocking action of sematilide on IK1 was found to be constant at each potential level of IK1 activation. Under more acidic condition, the degree of block was decreased. These results strongly suggested that the neutral form of sematilide may penetrate the cardiac cell membrane via hydrophobic pathway. 2. In cell-attached patches, sematilide prolonged the interburst interval and reduced the opening probabilities of the IK1 channel without affecting either the mean open time or the mean closed time within a burst.

Although no antiarrhythmic agent has ideal pharmacokinetic and pharmacodynamic characteristics, it is useful to evaluate antiarrhythmic agents in terms this ideal profile. The most desirable characteristics of an intravenous antiarrhythmic agent for treating ventricular arrhythmias are outlined. The basic pharmacokinetic and pharmacodynamic properties of the most commonly used agents for this indication-including amiodarone, bretylium, lidocaine, procainamide, and quinidine-are also reviewed, in light of this profile.

Introduction: How cell-to-cell electrical coupling influences an antiarrhythmic agent's effect on conduction is largely unknown. To investigate this, we evaluated the effects of procainamide on myocardial conduction at decreasing degrees of cell-to-cell electrical coupling induced by graded doses of heptanol., Methods and Results: Electrograms were recorded from 50 ventricular epicardial sites in a 1 cm x 0.5 cm area during pacing to produce conduction longitudinal or transverse to myocardial fiber orientation in Langendorff-perfused rabbit hearts. The effects of procainamide (15 mg/L) on conduction velocity were determined in the presence of increasing doses of heptanol (0.2, 0.5, and 1.0 mM). In addition, using standard microelectrode techniques in isolated superfused rabbit myocardium, intracellular potentials were recorded in the presence of 15 mg/L procainamide and heptanol (1.0 mM). In the absence of heptanol, procainamide slowed conduction velocity. In the presence of increasing doses of heptanol, procainamide's contribution to the depressant effect on conduction velocity was attenuated and reversed at the highest dose. The latter effect was preferentially seen for conduction longitudinal to myocardial fiber orientation. Heptanol had no effect on action potential amplitude or maximum rate of depolarization in the presence of procainamide., Conclusions: Procainamide's effect on conduction velocity is influenced by the underlying degree of cell-to-cell electrical coupling. The present model should be useful in evaluating the relative ability of other pharmacologic agents to modulate conduction under conditions of changing cell coupling.

The effects of increasing concentrations of procainamide on the composition of the excitable gap were determined in a canine model of atrial flutter. Using the model of a Y-shaped lesion in the right atrium, reentry around the tricuspid valve was induced by burst pacing in 10 open-chest chloralose-anesthetized dogs. Diastole was scanned with a single premature stimulus and the relationship between the coupling interval of the premature beat and the return cycle length (CL) determined a reset-response curve that described the excitable gap. This was repeated up to the maximum flutter CL while infusing procainamide (30 mg/kg) over 1 h. Procainamide progressively prolonged the flutter CL from 131 +/- 21 (+/-SD) to 188 +/- 46 ms (p < 0.01) and the effective refractory period from 96 +/- 19 to 149 +/- 47 ms (p < 0.01). At peak plasma levels of 77 +/- 33 mumol/L the drug terminated flutter only in two dogs. Neither the duration (35 +/- 10 to 39 +/- 13 ms) nor the composition of the excitable gap changed on drug. A fully excitable portion (7 +/- 3 ms or 20 +/- 11% of the excitable gap) persisted on procainamide (7 +/- 3 ms or 19 +/- 9% of the excitable gap). It was concluded that procainamide prolongs the atrial flutter CL and the effective refractory period but does not change either the duration or composition of the excitable gap even at plasma concentrations that significantly exceed those recommended in man.

1. The antiarrhythmic and haemodynamic effects of three class III antiarrhythmic drugs, MS-551, sematilide and dofetilide, were examined in the coronary artery, ligation-reperfusion model of pentobarbitone-anaesthetized rats, a species deficient in functional cardiac IK. MS-551 is a non-selective potassium channel blocker, while both sematilide and dofetilide are selective delayed rectifier potassium (K) channel (IK) blockers. 2. Before coronary ligation, 3 and 10 mg kg-1 MS-551 decreased the heart rate by 6% (P < 0.01) and 12% (P < 0.01), and increased mean arterial pressure (MAP) by 14% (P < 0.05) and 33% (P < 0.01), respectively. Sematilide at 10 and 30 mg kg-1 also decreased the heart rate by 4% (P < 0.01) and 9% (P < 0.01), respectively, and the higher dose of 30 mg kg-1 decreased MAP by 29% (P < 0.01). Dofetilide, 1 mg kg-1, decreased the heart rate (P < 0.01), but had no significant effect on MAP. 3. The QT interval was increased by 10% (P < 0.01) and 31% (P < 0.01), when 3 and 10 mg kg-1 MS-551 were given. Sematilide and dofetilide had no effect on the QT interval. 4. Immediately after reperfusion, lethal ventricular fibrillation (VF) was induced in 80% of the saline group. MS-551 at 3 and 10 mg kg-1, reduced the incidence of lethal VF to 50% and 20% (P < 0.05). Neither dofetilide 1 mg kg-1 nor sematilide (10 and 30 mg kg-1) decreased the incidence of lethal VF (70%, 80% and 50%, respectively). None of the three drugs had any effect on the occurrence of reperfusion-induced VT or the total incidence of VF. However, 10 mg kg-1 MS-551 delayed the onset of reperfusion-induced VF (27 +/- 5 s compared with 12 +/- 2 s of the control group, P < 0.05). 5. In conclusion, in rats which are deficient in cardiac IK MS-551 prolonged the QT interval and reduced the incidence of sustained VF after reperfusion. Blockade of channels other than IK might participate in the defibrillatory effect of MS-551. Sematilide and dofetilide, which are selective IK blockers, did not increase the QT interval nor did they show antiarrhythmic effects Mechanisms other than K channel block may be involved in the different effects of the three drugs on blood pressure.

Our objective was to define the actions of sematilide in rabbits and to assess the contribution of the delayed rectifier (IK) to rate dependence of action potential duration (APD) in rabbit ventricular myocardium. In studies in vivo, New Zealand White rabbits were used to obtain dose/response curves of the effects of sematilide on APD from contact monophasic action potentials (MAP), ventricular effective refractory period (VERP), and ECG. Sematilide or placebo was administered as an i.v. bolus followed by a 45-min infusion in the following cumulative manner: infusion 1 (1 mg/kg bolus + 8 micrograms/kg/min); infusion 2 (2 mg/kg + 20 micrograms/kg/min); and infusion 3 (7 mg/kg + 68 micrograms/kg/min). At each infusion level, VERP and APD at 75% repolarization (APD75) were measured during cardiac pacing between 200- and 400-ms cycle length (CL). Serum sematilide levels were analyzed by high-performance liquid chromatography (HPLC). In studies in vitro, sematilide's effects on the delayed rectifier were assessed in isolated rabbit ventricular myocytes by using patch-clamp techniques. Sematilide infusion in vivo resulted in stable serum levels of 1.3 +/- 0.5, 3.7 +/- 1.4, and 13.4 +/- 1.8 micrograms/ml during infusions 1, 2, and 3, respectively. Maximal effects occurred at infusion 2, such that at 400 ms CL, sematilide widened predrug APD75 (145 +/- 5 ms) by 27 +/- 4% (p < 0.001 vs. placebo), and at 200-ms CL, sematilide prolonged predrug APD75 (115 +/- 10 ms) by only 18 +/- 4% (p < 0.001 vs. placebo; p < 0.05 vs. 400-ms CL). Similar effects were observed in VERP. Sematilide enhanced rate dependence of APD and produced the same degree of APD prolongation at a given CL, during accommodation to and recovery from rapid pacing. Rabbit ventricular myocytes appeared to have at least two types of delayed rectifier. Sematilide selectively blocked IKr, and block was not relieved by repetitive stimulation. In conclusion, the APD-widening effect of sematilide was independent of previous pacing history. Sematilide had little influence on background processes likely responsible for shortening APD because of rapid repetitive stimulation.

Adenosine, verapamil, propranolol, and procainamide are widely used antiarrhythmic drugs. The interactions among them are still not known in human beings. Adenosine-induced negative dromotropic effects were assessed by rapid bolus injection of adenosine during constant high right atrial pacing in each patient. The initial dose of adenosine was 0.5 mg and was followed by a stepwise increment of 0.5 mg until atrioventricular (AV) nodal block occurred. The negative dromotropic actions of adenosine were examined in the control state and in the following three protocols in three groups of patients: (1) In 12 patients (group 1), intravenous verapamil, 0.15 mg/kg, was given; (2) In 12 patients (group 2), intravenous propranolol, 0.1 mg/kg, was given; and (3) in 10 patients (group 3), intravenous procainamide, 15 mg/kg, was given. The dose-response curves of adenosine on AV nodal conduction were almost identical in the control state and after verapamil, propranolol, or procainamide injection. However, verapamil, in contrast to propranolol, significantly reduced the dose of adenosine required to produce AV nodal block, from 4.4 +/- 0.7 mg to 2.7 +/- 0.3 mg (p < 0.01). Of note, procainamide exerted no significant effects on adenosine-induced negative dromotropism on AV nodal conduction or AV nodal block. In conclusion, the negative dromotropic effects of adenosine are preserved and independent even in the presence of verapamil, propranolol, or procainamide. Both verapamil and propranolol can exhibit additive effects with adenosine in prolonging AV nodal conduction time; however, only verapamil can reduce the dose of adenosine required to produce AV nodal block. This finding indicates that the dose of adenosine may be reduced for patients who have already been treated with verapamil.

The class I antiarrhythmic drug procainamide (Pd) was tested on BDF1 mice for its chemoprotective activity against cis-diamminedichloroplatinum(II) (DDP) toxicity. Pd at the dose of 50 mg/kg protected mice against otherwise lethal doses of DDP (survivors at Day 14 after 25 mg/kg DDP or 25 mg/kg DDP-Pd treatment: 0% vs 100%) and greatly reduced the weight loss induced by DDP. Moreover, the increased plasma urea nitrogen levels caused by a single ip administration of DDP in water (8 or 16 mg/kg) as well as the tubular degenerative changes detected by light microscopy were prevented by Pd. Pd had no effect on the sensitivity of P388 leukemic cells to DDP in vitro, but the administration of DDP (16 mg/kg) and Pd (50 mg/kg) to BDF1 mice bearing P388 leukemic cells produced a significant increase in survivals compared to mice receiving ip DDP alone diluted in 0.9% NaCl solution. The increased efficacy of this combination therapy in P388 leukemic mice compared to a single DDP treatment at the same dose was observed both when the drugs were administered ip simultaneously (p = 0.042) and when DDP and Pd were given ip and iv, respectively (p = 0.018). Since procaine, which differs from Pd merely in the replacement of the amide by the ester linkage, has also been reported to significantly enhance DDP efficacy (M. Esposito et al., 1990, J. Natl. Cancer Inst. 82, 677-684.), a comparison of their effects in tumored mice exposed to DDP has been made. Although both drug combinations were superior to that of DDP alone, in terms of both survival time and numbers of cures, Pd treatment seems to offer better protection against DDP-induced lethality than did procaine.

Objectives: This study sought to characterize the functional properties of decremental accessory atrioventricular (AV) pathways and to investigate their pharmacologic responses., Background: Although decremental AV pathways associated with incessant reciprocating tachycardia have been studied extensively, information about the electrophysiologic characteristics and pharmacologic responses of anterograde and retrograde decremental AV pathways is limited., Methods: Of 759 consecutive patients with accessory pathway-mediated tachyarrhythmia, 74 with decremental AV pathways were investigated (mean age 43 +/- 18 years). After baseline electrophysiologic study, the serial drugs adenosine, verapamil and procainamide were tested during atrial and ventricular pacing. Finally, radiofrequency catheter ablation was performed., Results: Five patients had anterograde decremental conduction over the accessory pathway but had no retrograde conduction. Of the 64 patients with retrograde decremental conduction over the accessory pathway, anterograde conduction over the pathway was absent in 41 (64%), intermittent in 5 (8%) and nondecremental in 18 (28%). In the remaining five patients, anterograde and retrograde decremental conduction over the same pathway was found. The anterograde and retrograde conduction properties and extent of decrement did not differ between anterograde and retrograde decremental pathways. Posteroseptal pathways had the highest incidences of anterograde and retrograde decremental conduction. Intravenous adenosine, procainamide and verapamil caused conduction delay or block, or both, in 10 of 10, 10 of 10 and 4 of 10 of the anterograde and 20 of 20, 20 of 20 and 8 of 20 of the retrograde decremental pathways, respectively. All patients had successful ablation of the decremental pathways without complications. During the follow-up period of 31 +/- 19 months, only one patient experienced recurrence., Conclusions: Decremental accessory pathways usually had functionally distinct conduction characteristics in the anterograde and retrograde directions. Their pharmacologic responses suggested the heterogeneous mechanisms of decremental conduction.

Effects of sematilide, a novel class III antiarrhythmic agent, on the delayed rectifier K+ current (Ik) were examined in guinea pig atrial myocytes using a voltage clamp technique. Sematilide inhibited both time-dependent outward current upon depolarization and tail currents (Ik-tail) at -40 mV. The concentration of sematilide required for a 50% decrease in Ik-tail was approximately 50 microM. The sematilide-sensitive current obtained using a triangular voltage command exhibited marked inward rectification and had the maximum amplitude at -30 mV. These results suggest that sematilide inhibits rapidly activating Ik in guinea pig atrial myocytes, resulting in the prolongation of action potential duration and refractoriness.