The chief electrophysiologic characteristic of azimilide (NE-10064, (E)-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-l-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride) is prolongation of action-potential duration in cardiac fibers of calf, dog, ferret, guinea pig, sheep, and human (1-6). This increased refractoriness has been ascribed to blockade of the fast (IKr) and slow (IKs) components of the delayed rectifier potassium current (3,4,7). Azimilide is a more potent inhibitor of IKr (20% inhibition in guinea pig ventricular myocytes at 0.2-0.4 μM) than of IKs (20% inhibition at 1-2 μM) (3,4,8). Azimilide had no effects on the transient outward current (Ito) of rat (4) or dog ventricular myocytes (8), but at 3-10 μM inhibited the inward rectifier IK1 of guinea pig and dog cells (3,4,8) and, at a higher concentration, the L-type calcium current (ICaL) of rat, (4) [50% effective concentration (EC50 = 43.6 μM] and guinea pig (7) myocytes. Although azimilide blocks IKr, it is chemically different from other blockers of the rapid component of the delayed rectifier, lacking, in particular, the methylsulfonamide group found in dofetilide and sotalol. These in vitro electrophysiologic properties could account for the antiarrhythmic efficacy of azimilide in several rodent models of ischemia-induced ventricular arrhythmia (9,10). Although a full report has appeared of the antifibrillatory properties of azimilide in one dog model of sudden cardiac death (11), no such account of other antiarrhythmic actions in dogs has been reported.
To determine the antiarrhythmic efficacy of azimilide in a clinically relevant model, we tested the compound in infarcted dogs for ability to suppress ventricular arrhythmias induced by programmed electrical stimulation (PES). In these dogs, a mottled infarct created by ligation and reperfusion of a coronary artery provided the substrate for reentrant arrhythmias comparable to those induced in humans with coronary artery disease (12). This canine PES model is similar to that used in other laboratories (13-16); as a critical efficacy test for class III antiarrhythmic agents (17) and performed in patients with ischemic heart disease for optimizing antiarrhythmic therapy (18-21). Because arrhythmias such as sustained ventricular tachyarrhythmia (SVT) can be repeatedly induced in the same dog, experimental drugs may be characterized as antiarrhythmic by rendering the tachyarrhythmia noninducible or nonsustained or proarrhythmic by facilitating the arrhythmia induction or causing a more severe arrhythmia. To validate the model, we examined efficacy of racemic sotalol, which has shown efficacy in dogs subject to PES (22,23) and in humans undergoing this type of testing (24,25). A preliminary report of some of these results has appeared (26).
MATERIALS AND METHODS
Azimilide dihydrochloride (Procter & Gamble Pharmaceuticals) and dl-sotalol hydrochloride (Bristol-Myers Squibb) were dissolved in 5% (wt/vol) dextrose in water at 1 mg/ml on the day of use. All other chemicals were obtained commercially and were of the highest purity, usually reagent grade.
Purpose-bred male mongrel dogs (18-29 kg) were purchased from Laboratory Research Enterprises (Kalamazoo, MI, U.S.A.). Dogs with unique tattooed identification numbers were caged individually and provided with Purina Canine Diet 5006 (Purina Mills, Inc., St. Louis, MO, U.S.A.) and water ad libitum. Animals had been given necessary immunizations and were certified free of heart worms. Care of animals was under supervision of an attending veterinarian in a facility registered with the United States Department of Agriculture and accredited by the American Association for Accrediation of Laboratory Animal Care. Experiments were conducted under a protocol approved by the facility Institutional Animal Care and Use Committee. At the end of experimentation, the dogs were killed under anesthesia by direct-current fibrillation.
Dogs were anesthetized with sodium thiamylal (7-17.5 mg/kg i.v.) and intubated for gaseous anesthesia. Halothane was administered at 5% to induce anesthesia and at 0.25-1.0% to maintain anesthesia. Either oxygen or nitrous oxide/oxygen mixture (9:1 for preperfusion hypoxia and 1:1 after reperfusion) was used as carrier gas in a closed system. Ventilation was controlled by an anesthesia ventilator system (SAV-75, JD Medical Distributing Co., Phoenix, AZ, U.S.A.) at respiratory rates of 4-12 times per min and an inspiratory pressure of 15 cm H2O.
A left thoracotomy was made through the fifth intercostal space and the heart suspended in a pericardial cradle. The left anterior descending coronary artery (LAD) and collateral arteries feeding the anterior left ventricle (LV) were occluded for 90 min. Before reperfusion, hypoxia was induced by changing pure oxygen to a 9:1 mixture of nitrous oxide/oxygen. On reperfusion, the LAD was stenosed to the diameter of a 19-G needle to reduce hyperemic response. The oxygen supply was increased to approximate 50% of the inspired gases. Lidocaine was given as needed during surgery. The chest was closed in layers. The dog was allowed to recover and given a daily dose of antibiotic (penicillin G with dihydrostreptomycin) for the next 2 postoperative recovery days.
Programmed electrical stimulation
Four to 6 days after the surgery, the dogs were anesthetized with Dial urethane (0.6 mg/kg i.v.), intubated, and ventilated by a Harvard respiratory pump at ≈ 17 breaths per min and tidal volume of ≈ 15 ml/kg. A femoral artery and vein were cannulated for monitoring arterial blood pressure and drug administration, respectively. A Millar catheter transducer was placed in the LV through the left carotid artery for the recording of left ventricular pressure (LVP) and the peak value of the first derivative of LVP (LV dP/dtmax). The chest was reopened through the left fifth intercostal space and the heart suspended in a pericardial cradle.
A bipolar electrode (Inapres, Norwich, NY, U.S.A.) was sutured to the left atrial appendage for atrial pacing. One tripolar and one bipolar electrode were sutured at the right ventricle (RV) base near the pulmonary artery. The second tripolar electrode was sutured distal to the site of occlusion of the LAD in the infarcted zone (IZ) of the LV, and a third tripolar electrode was sutured distal to the left circumflex artery in the normal zone (NZ) near the base of the LV. Electrical stimulation of atrium and ventricle were done by a WPI A300 pulse generator with constant-current isolation units (World Precision Instruments, New Haven, CT, U.S.A.). Epicardial ventricular electrograms were recorded by using Gould preamplifiers (Gould Electronics, Cleveland, OH, U.S.A.). The signals for blood pressure, LVP, ECG, and epicardial electrograms were sent to an on-line data-acquisition system (Po-Ne-Mah, Storrs, CT, U.S.A.), through which heart rate (HR), mean arterial blood pressure (MABP), and LV dP/dtmax were derived. Core body temperature was maintained at 39 ± 1°C.
Electrophysiologic tests were performed by pacing the atrium or ventricle or both. Conduction time (CT) and effective refractory period (ERP) were measured at twice the excitation threshold (ET). ET is the minimal amount of current required to pace the heart in the diastolic period. CT is expressed as the interval between a stimulus and the sharpest spike of the electrogram measured in the right ventricle during basic pacing from the NZ electrode. For ERP determination, six to 10 ventricular stimuli at a pacing (S1) cycle length of 300 ms were immediately followed by one premature ventricular stimulus (S2). The ERP was defined as the longest S1-S2 interval (ms) at which no propagated response was produced by the premature stimulus.
For the induction of ventricular arrhythmias, two PES protocols were used. The initially used train protocol induced a ventricular arrhythmia by a train of three premature stimuli (4-ms pulse width at 2 × ET) delivered to the RV electrode during atrial pacing. The atrial pacing cycle length was set at 400 ms, or adjusted slightly less than the sinus cycle length (5-15 ms) if heart rate exceeded 150 beats/min. The frequencies of the train stimulation were fixed at 5.5, 6.0, 6.5, 7.0, 7.5, and 8.0 Hz. The train started at an S1-S2 interval of ≈0.7 times the paced cycle length and decreased in 10-ms steps until no response could be elicited by the first extrastimulus. For the sequential protocol, which was tried to more closely mimic the clinical stimulation method, the heart was paced by the RV electrode at a pacing (S1) cycle length of 300 ms for 8-15 stimulated beats. This was immediately followed by two to three premature ventricular stimuli (S2-S4) introduced as follows. Once the ERP of the basic (S1) paced beat was determined, the S2 delay was set to ERP + 5 ms. The ERP of the S2 response was similarly determined by using another premature stimulus (S3). The S3 delay was set to ERP + 5 ms. One more premature stimulus (S4) was similarly added, if necessary, until reentrant tachyarrhythmias were induced. For azimilide, induction was by the train protocol in four, sequential in five, and both protocols in one dog. Because no differences in inducibility could be attributed to the stimulation protocol, data were combined for dogs tested by either protocol. For sotalol, all dogs were induced by the sequential protocol.
The induced arrhythmias were categorized as NSVT (nonsustained ventricular tachyarrhythmia) consisting of at least six spontaneous depolarizations lasting <10 s; SVT lasting ≥10 s with regular electrograms; VF (ventricular fibrillation) characterized by chaotic electrograms, or NI (non-inducible) if fewer than six reentrant impulses were induced. Illustrations of the electrocardiographic definitions of SVT and NSVT, as used in this laboratory, are provided in D'Alonzo et al. (27).
Electrophysiologic testing was performed twice before treatment and ≥5 min after the administration of each dose of the drug. Azimilide or dl-sotalol was administered i.v. after each testing. Burst pacing and DC shocks were used to convert SVT or VF back to sinus rhythm. When VF occurred, ≥30 min was allowed to elapse before the next electrophysiology testing was initiated.
The LV tissue was sectioned into slices (≈5-mm thick) and treated with 2,3,5-triphenyltetrazolium chloride stain to identify the viable tissue (28). The infarct size relative to the total LV was determined.
Azimilide and sotalol solutions (1 mg/ml) were infused intravenously at 1 ml/kg/min. Cumulative doses of 0.3, 1, 3, 10, and 30 mg/kg were infused ≈45 min apart. Typical experiments lasted 4-5 h. At least 5 min was allowed from the end of the infusion before beginning of the electrophysiologic testing and recording of hemodynamic data. Both azimilide and sotalol are long-acting compounds, and reported electrophysiologic and hemodynamic parameter values are peak values after the added dose. Although determinations of blood levels were not done in this study, subsequent work has shown that azimilide has a terminal half-life of administration of ≈2 h after i.v. administration in the dog. Thus it was not expected that parameters should return to baseline values during the 45-min interval between additional cumulative doses.
The second of two predose determinations was considered to be the baseline determination for statistical analysis. All numeric data are expressed as the mean ± SEM. A paired t test with Bonferroni adjustment (29) was performed to analyze the effects of drug treatment on hemodynamic and electrophysiologic parameters. Probabilities <0.05 were considered significant.
Of the 11 dogs tested with azimilide, nine were susceptible to PES-induced arrhythmias (inducible) during predose baseline PES determinations, whereas two were not susceptible (noninducible). All five dogs in the sotalol-treatment group were initially inducible. The group sizes for azimilide (nine) and sotalol (five) were adequate to show that both compounds had significant antiarrhythmic activity in this model. No direct comparison of efficacy was intended, so additional sotalol dogs were not tested.
For azimilide, hemodynamic changes were mild. Heart rate was not significantly changed by azimilide at 1, 3, and 10 mg/kg cumulative i.v. doses but was reduced a significant 19% after the 30 mg/kg dose (Table 1 and Fig. 1) MABP was not significantly changed. LV dP/dtmax measured during atrial pacing increased 5-12% at 0.3-30 mg/kg doses (significant elevation at 3 and 30 mg/kg). LV end-diastolic pressure (LVEDP) was significantly reduced 21-23% by 3-30 mg/kg azimilide.
For sotalol, hemodynamic effects were different and larger (Table 2 and Fig. 1). Heart rate decreased at all doses, and the 24, 34, and 44% changes at 3, 10, and 30 mg/kg, respectively, were significant. MABP also decreased. Significant depressions of 19, 33, and 53% from baseline were observed at cumulative i.v. doses of 3, 10, and 30 mg/kg. In contrast to azimilide, sotalol decreased LV dP/dtmax. LV dP/dtmax decreased significantly as a function of cumulative dose to 40% below baseline at the 30 mg/kg dose. LVEDP was elevated (<20% at 3-10 mg/kg i.v.), but never significantly changed.
Azimilide prolonged ERP in both the NZ and IZ of the LV as a function of dose (Table 3 and Fig. 2). Significant elevations of 7, 11, 20, and 38% were seen in the NZ at 1, 3, 10, and 30 mg/kg. Changes of a similar magnitude were seen in the IZ. The other measures of refractoriness, QT and QTc, also increased as a function of dose. QTc increases of 8, 16, and 32% at 3, 10, and 30 mg/kg were significant. ET tended to increase with increasing azimilide dose, but the large variability in this parameter made only the effect at 30 mg/kg in the LV NZ statistically significant. CT did not change.
dl-Sotalol prolonged ERP in both the normal zone (NZ) and infarct zone (IZ) of the LV as a function of dose (Table 4 and Fig. 2). The dl-sotalol dose-response curves for prolongations of ventricular ERP and QT interval differed from those of azimilide. The sotalol-treated dogs showed the maximum prolongation of NZ ERP, IZ ERP, and QT-interval after 10 mg/kg (21, 21, and 26%, respectively), with a lesser prolongation after the 30-mg/kg dose (19, 10, and 23%, respectively). No significant effects on QTc, CT, or ET were observed from dl-sotalol treatment. The lack of effect on QTc was caused by the marked slowing of heart rate by dl-sotalol.
Previous work in this laboratory demonstrated that, although some change from one arrhythmia category to another does occur with repeated inductions, the type of arrhythmias induced after vehicle administration does not change significantly over the PES study period (27). For this study, a treatment was considered efficacious if the arrhythmias induced after treatment were no more serious than NSVT. If the baseline control induced arrhythmia was NSVT, efficacy was indicated by conversion to the NI state.
Based on these criteria, azimilide showed efficacy in five of nine dogs at doses ranging from 1 to 30 mg/kg (Table 5, Fig. 3). One VF dog responded at the low dose of 1 mg/kg i.v., the two SVT dogs responded at 30 mg/kg, and the one NSVT dog responded at 10 mg/kg. The rate of the tachyarrhythmia induced by PES, which averaged 505 beats/min, was slowed by azimilide as a function of cumulative dose, and the rates of 426 and 350 beats/min at 10 and 30 mg/kg, representing reductions of 16 and 29%, respectively, were significantly slower than the control rate (Table 3, Fig. 2).
Efficacy of sotalol was more difficult to assess. In three of five dogs, although movement to either NSVT or NI occurred, higher doses returned these dogs to the original inducible state. One of two NSVT dogs became NI at 0.3 mg/kg, but NSVT could be reinduced at 10 mg/kg. Two of three SVT dogs moved to NSVT at 0.3 and 10 mg/kg but returned to the baseline inducible state at the next highest sotalol dose. In the two other dogs, efficacy was clearer. One NSVT dog became NI at 3 mg/kg. One SVT dog moved to NSVT at 3 mg/kg and to NI at 10 mg/kg (Table 5, Fig. 4). The slowing of the rate of the PES-induced tachyarrhythmia by dl-sotalol was comparable to that seen with azimilide and was significant after 30 mg/kg.
Two NI dogs were used for testing the proarrhythmic tendency of azimilide as indicated by the dog's becoming inducible after receiving the compound. Azimilide, ≤30 mg/kg, did not facilitate the induction of arrhythmias in one dog. The second dog showed SVT at 3- and 10-mg/kg azimilide doses but was NI at the highest 30-mg/kg dose (Fig. 3).
Postmortem infarcts averaged 28.2 ± 3.3% and 27.5 ± 3.5% of the LV for azimilide- and sotalol-treated dogs, respectively (Table 5).
Azimilide was an effective antiarrhythmic in 56% of anesthetized PES dogs at cumulative i.v. doses ranging from 1 to 30 mg/kg. Efficacy of azimilide covered the range of induced arrhythmias from VF to SVT to NSVT. Of significance may be the suppression by azimilide of VF induction in two of three dogs, because the potent class III agent dofetilide was ineffective for VF. Dofetilide partially suppressed PES-induced arrhythmias in six of 12 dogs at 900 μg/kg i.v. (30) and in six of 10 dogs at 30 μg/kg (31). Its efficacy, however, was confined to VT; dofetilide was unable to prevent induction of VF. In contrast, azimilide benefited dogs with VF. That the lessened inducibility of two of three VF dogs is caused by azimilide is indicated by the reproducible VF induction (twice in one dog, four times in the other) before an effective dose of azimilide was achieved. Furthermore, the inducibility pattern with these two dogs differed from that seen in this laboratory (27) with saline vehicle. Variability of inducibility unrelated to effective treatment is marked by (a) movement of only one category and (b) oscillation between categories. Inducibility did not oscillate in azimilide-treated dogs, and one moved three categories from VF to NSVT, and the other moved four categories from VF to NI.
In this study, we used two different stimulation protocols, train and sequential, for the induction of arrhythmias. Although the sensitivity and specificity of the protocol may be influenced by the methods of stimulation (32), no evidence in our data shows any difference in the yield of arrhythmias. Three of five responding azimilde dogs (VF to NI, VF to NSVT, and NSVT to NI) involved the train protocol. Two responding azimilide dogs (SVT to NI) were induced by sequential stimulation. The sequential PES protocol allows placement of the premature stimuli in the vulnerable period for reentry. The sequential PES protocol has the advantages of being less tedious and less time consuming than the train protocol and is often used for clinical electrophysiology testing (32,33).
SVT induced by PES in this canine model has a very short cycle length (≅120 ms), much faster than the tachyarrhythmias seen in cardiac patients (200-400 ms) (32,33). The dog arrhythmia is more severe than the clinical arrhythmia, because there was no cardiac pump function during the induced fast arrhythmias in dogs. Azimilide may have greater efficacy for the slower, less incapacitating human SVT.
Conduction time was not significantly changed by azimilide, consistent with a lack of class I action. Azimilide also produced significant prolongation of ERP in normal and infarcted regions of the LV in the cumulative dose range of 1-30 mg/kg. The correlation of efficacy and increased refractoriness suggests that the class III properties of azimilide underlie antiarrhythmic action. It is not known, however, what contribution the block of IKr versus IKs might make to efficacy in this model. Other IKr blockers, such as dl-sotalol (34), E4031 (35,36), and MS-551 (37) have shown good efficacy in suppressing electrical induction of ventricular arrhythmias in infarcted dogs. The efficacy of sotalol could be the result of a combination of prolonging refractoriness and its β-adrenergic blocking actions. Increases in refractoriness caused by sotalol in this study are similar to those reported by Gomoll and Bartek (38). Ventricular ERP increases of 18 and 29 ms seen after 3- and 10-mg/kg doses in this study compare with 22- to 58-ms increases seen by Gomoll and Bartek after 2 and 8 mg/kg i.v. We observed slight, <10 ms, insignificant increases in QTc, over a wide dose range. Gomoll and Bartek reported increases of 62 and 106 ms at 2- and 8-mg/kg doses, respectively. Others reported that a 4-mg/kg i.v. dose of sotalol increased QTc insignificantly, 23-44 ms (39).
The correlation between efficacy in a PES-induced dog ventricular arrhythmia model and efficacy in the clinic is uncertain. Nevertheless, class I drugs such as quinidine and flecainide are much less effective than class III agents in the canine model (40), and a similar rank order exists for clinical success (24). In dogs, the success rate of azimilide in preventing PES-induced arrhythmias is comparable to that of other class III standards, such as sotalol and amiodarone. Good efficacy of sotalol in dogs is well documented. In eight dogs infarcted without reperfusion and induced by up to three extrastimuli, Buchanan et al. (22) found ≤100% efficacy of sotalol at cumulative i.v. doses between 1 and 10 mg/kg. Chézalviel et al. (23) used dogs prepared with LAD occlusion and reperfusion and induced arrhythmias with up to three extrastimuli plus burst pacing. Sotalol was effective in 82% of 16 inducible dogs treated with a loading dose of 4 mg/kg followed by an infusion of 1.5 mg/kg/h. Sotalol is effective clinically for suppressing PES-induced arrhythmias. Wichter et al. (24) reported that sotalol was effective in 68% of patients with inducible ventricular arrhythmias, and Gonzalez et al. (25) concluded that PES success was a good predictor of sotalol efficacy, even in patients who had failed to respond to other antiarrhythmic drugs. Efficacy of amiodarone in this dog model was shown by Abdollah et al. (41). To accommodate the unusual pharmacokinetics of amiodarone, these authors dosed inducible dogs with the drug for a week with 40 (low dose) and 60 (high dose) mg/kg/day. Although the high dose was ineffective, the low dose was effective in eight of 10 dogs in suppressing induction of SVT or VF.
Effects of azimilide on cardiac hemodynamics were mild. Blood pressure did not change significantly, and heart rate decreased significantly only after the highest cumulative dose (30 mg/kg). There were significant reductions in LVEDP and increases in LV dP/dtmax, suggesting that azimilide has positive inotropic properties. Good hemodynamic tolerance of azimilide has been reported in normal anesthetized dogs (42). These benevolent hemodynamic findings contrast to the effects of sotalol. Sotalol markedly depressed both heart rate and MABP, decreased LV dP/dt, and increased LVEDP.
Although this study was not designed to elucidate the proarrhythmic potential of azimilide, two noninducible dogs were available to determine if the compound facilitated induction of arrhythmias. Azimilide did not appear the increase inducibility of these dogs beyond the normal variability observed with vehicle-treated dogs (27). Furthermore, the clinical relevance of proarrhythmic studies in animal models for antiarrhythmic drugs has not yet been established (43).
These results in an infarcted dog model of PES-induced ventricular arrhythmias demonstrate that the class III drug azimilide, at a cumulative i.v. dose of 1 to 30 mg/kg, is efficacious in preventing ventricular arrhythmias in 56% of inducible dogs. In the same dose range, azimilide caused significant and dose-dependent prolongation in ERP at both NZs and IZs in myocardium without slowing conduction or compromising hemodynamic functions. The class III action of increasing refractoriness, by interrupting a reentrant arrhythmia path, may underlie the antiarrhythmic efficacy of azimilide in this model.
Acknowledgment: For technical assistance and discussions, we thank Dr. K. M. Wu and Dr. J. L. Butterfield.
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