Ventricular Arrhythmia Models Research Articles

Risk stratification of severe ventricular arrhythmias in Brugada syndrome

Abstract Funding Acknowledgements Type of funding sources: None. Background Predicting likelihood of severe ventricular arrhythmias in Brugada syndrome (BrS) patients is challenging due to conflicting evidence. Objectives The goal of this study was to construct a prediction model of severe ventricular arrhythmias (VAs) for BrS patients. Methods Two hundred forty-two BrS patients were enrolled from 2008 to 2019 in a single-center cohort study. Those patients were followed up until December 2021. Clinical data and multiple ECG markers were collected and analyzed to determine the risk factors of severe VAs and sudden cardiac death (SCD). Multivariate logistic regression analysis was then used to develop a risk prediction model for adverse arrhythmic outcomes in BrS patients. Results During the follow-up (90.1 ± 45.8 months) of 242 BrS patients (mean age 42.3 ± 12 years; 94.6% male), 49 (20.2%) patients had syncope/pre-syncope due to VAs and 7 (2.9%) patients had aborted cardiac arrest. In multivariable analysis, epsilon wave, early repolarization sign, S wave duration in lead I, QRS duration in V2 and Tp-e duration were significant associated with adverse arrhythmic outcomes. A clinical model including these five significant predictors had a good performance to predict outcomes with balanced accuracy of 0.86 and area under curve of 0.93 (95% CI, 0.89-0.96, p < 0.001) indicating a good discriminative ability. Furthermore, the Hosmer–Lemeshow test and the calibration plot showed a good fit between the predicted and observed probabilities of the predictive model. Conclusions This study constructed a risk prediction model for severe VAs in BrS patients with a high predictive accuracy.

A prediction model for ventricular arrythmias in the acute phase of infarction

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) in the acute phase of infarction (first 24-48 hours) has declined over recent decades, probably due to the uptake of reperfusion strategies and the early use of beta-blockers. However, according to some series, 6–8% of patients still develop hemodynamically significant VT or VF during this phase. Purpose The objective of our study was to evaluate the baseline characteristics of patients who suffered VT or VF in the acute phase of the infarction and to create a predictive model of ventricular arrhythmias in this setting which allow us to anticipate arrhythmic events. Methods We performed an observational, retrospective, and single-centre study carried out through the review of clinical records of patients who suffered an acute myocardial infarction with ST-segment elevation (STEMI) and were admitted in our Coronary Care Unit between July 2011 and August 2022. Results In our cohort we observed 179 episodes of VT/VF (10,7%) in a population of 1668 patients underwent STEMI. The mean age in this subgroup was 61,69±12,61 years old, 78% were males and 56% smokers. Approximately a quarter of the patients were diabetic or obese. There was a very low percentage of previous myocardial infarction (12%) and heart failure (3%) (Table 1). We estimated the best prediction model (Mallows’ Cp=5.12) for VT/VF. The variables included in our model (LL=-435,43) were: male sex, absence of diabetes, smoking habit, use of fibrinolysis, worst Killip at admission and hypotension at admission (Table 2). Conclusion The presence of VT or VF in the acute phase of infarction is still considered a controversial factor in the prognosis of these patients. In our cohort we identified that males, smokers, non-diabetics, and the use of fibrinolysis and the worst haemodynamical situation at admission were independent predictors of developing VT/VF in this context.

Whole-heart ventricular arrhythmia modeling moving forward: Mechanistic insights and translational applications.

Ventricular arrhythmias are the primary cause of sudden cardiac death and one of the leading causes of mortality worldwide. Whole-heart computational modeling offers a unique approach for studying ventricular arrhythmias, offering vast potential for developing both a mechanistic understanding of ventricular arrhythmias and clinical applications for treatment. In this review, the fundamentals of whole-heart ventricular modeling and current methods of personalizing models using clinical data are presented. From this foundation, the authors summarize recent advances in whole-heart ventricular arrhythmia modeling. Efforts in gaining mechanistic insights into ventricular arrhythmias are discussed, in addition to other applications of models such as the assessment of novel therapeutics. The review emphasizes the unique benefits of computational modeling that allow for insights that are not obtainable by contemporary experimental or clinical means. Additionally, the clinical impact of modeling is explored, demonstrating how patient care is influenced by the information gained from ventricular arrhythmia models. The authors conclude with future perspectives about the direction of whole-heart ventricular arrhythmia modeling, outlining how advances in neural network methodologies hold the potential to reduce computational expense and permit for efficient whole-heart modeling.

Pinocembrin ameliorates arrhythmias in rats with chronic ischaemic heart failure

Objective Ventricular arrhythmias (VAs) are a common complication of chronic ischaemic heart failure (CIHF). The purpose of this study is to investigate the efficacy of pinocembrin in a rat model of VAs induced by CIHF and further examine the possible mechanism. Methods Rats were subjected to ligation of left anterior descending coronary artery to mimic CIHF and then received pinocembrin treatment daily for 2 months. The vivo electrophysiology were performed to determine the effect of pinocembrin on ventricular electrical activity. The expression of Cav1.2, Kv4.2, and NGF was determined by Western blot. The structural change of ventricle was tested by the Echocardiography, Masson staining, and HE staining. The effect of pinocembrin on sympathetic nerve-related markers was detected by the immunostaining and the ELISA was used to test for biomarkers associated with heart failure. Results Pinocembrin increased the expression of ion channel protein Cav1.2 and Kv4.3, ameliorated the shortening of action potential duration (APD) and reduced the incidence and duration of ventricular fibrillation (VF). Pinocembrin also reduced the expression of nerve growth factor (NGF) and improved the autonomic nerve remodelling. In addition, pinocembrin reduced the area of infarct area and myocardial fibrosis, accompanied by increasing the expression of connexin protein 43 (CX43). Conclusion We demonstrate that pinocembrin reduces cardiac nerve remodelling and protects against Vas induced by CIHF. The findings suggest that pinocembrin can be a promising candidate for the treatment of VAs.

Characterization of Magnesium Sulfate as an Antiarrhythmic Agent.

BACKGROUND: Recently, intravenous magnesium therapy has been used for the treatment of ventricular arrhythmias, but data to establish a causal link between the electrophysiological properties and the antiarrhythmic actions are lacking. METHODS AND RESULTS: The acute antiarrhythmic effect of magnesium sulfate was assessed using epinephrine-, digitalis-, and coronary ligation-induced canine ventricular arrhythmia models. The intravenous administration of magnesium sulfate (100 mg/kg) reduced the incidence of the ventricular arrhythmias of all models. The antiarrhythmic effect on the epinephrine-induced arrhythmia was potent and long-lasting, while those on the other arrhythmia models were weak and transient. The direct cardiovascular effects were assessed using the canine isolated, blood-perfused sinus node, papillary muscle, and atrioventricular node preparations. The intracoronary administration of magnesium sulfate (0.1-30 mg) suppressed sinoatrial automaticity and ventricular contraction, while it increased atrio-His and His-ventricular conduction time, coronary blood flow, and the duration of monophasic action potential in a dose-dependent manner. The effects on His-ventricular conduction and monophasic action potential duration were less potent compared with the other cardiovascular effects. CONCLUSIONS: These results suggest that magnesium sulfate possesses multiple electrophysiological properties and that the effects related to the calcium channel inhibition may be the most relevant for the antiarrhythmic actions.

Antiarrhythmic activity of new 2-methoxyphenylpiperazine xanthone derivatives after ischemia/reperfusion in rats.

We have previously shown significant prophylactic and therapeutic antiarrhythmic activity in adrenaline-induced arrhythmia, as well as α1-adrenolytic properties of new derivatives of xanthone. Herein, we investigated their antiarrhythmic activity in the model of ischemia/reperfusion in isolated hearts. Furthermore, we assessed antioxidant activity in biochemical studies. Antiarrhythmic activity in the model of ischemia/reperfusion in isolated perfused hearts was performed according to the Langendorff technique. Antioxidant activity was measured by lipid peroxidation level in tissue homogenate and in the FRAP assay. All studied compounds (MH-94, MH-99 and MH-105) showed significant antiarrhythmic activity in the model of ventricular arrhythmias associated with coronary artery occlusion and reperfusion. However, they did not demonstrate antioxidant effect, probably, because of the lack of free hydroxyl group(s) at a key position in the xanthone scaffold. The present study provides evidences for antiarrhythmic activity of some 2-methoxyphenylpiperazine derivatives of xanthone.

Antiarrhythmic activity of some xanthone derivatives with β1-adrenoceptor affinities in rats

A series of aminoalkanolic derivatives of xanthone with high affinity for β1-adrenoceptors was evaluated for antiarrhythmic activity in the model of ischemia-reperfusion in isolated hearts, as well as in barium chloride- and adrenaline-induced model of arrhythmia. In order to better understand biological activity of studied compounds, the influence on β2-adrenoceptors in guinea-pig trachea and vasorelaxant properties in rat aorta were evaluated. Furthermore, due to assessed antioxidant activity, some biochemical studies were also performed. All tested compounds showed prominent antiarrhythmic activity in the model of ventricular arrhythmias associated with coronary artery occlusion and reperfusion. In this experiment the most active was compound MH-97. Whereas, compound MH-82 was the most active in barium- and adrenaline-induced arrhythmia after i.v. or p.o. administration, respectively. These two compounds have higher affinity to β1-adrenoceptors than compound MH-87, thus it suggests that blocking properties of β1-adrenoceptors are involved in the observed antiarrhythmic effects. All studied compounds have revealed antagonistic potency for β2-adrenoceptors in tracheal smooth muscle, however weaker than that of propranolol. None of tested compounds demonstrated antioxidant effect. They also had weak calcium entry blocking activity. The results of this study suggest that new compounds with antiarrhythmic activity might be found in the group of xanthone derivatives.

Ischemic ventricular arrhythmias during heart failure: A canine model to replicate clinical events

Development of experimental animal models has played an invaluable role in understanding the mechanisms of ventricular arrhythmias. The purpose of this study was to evaluate a new canine model of myocardial infarction (MI), heart failure, and ischemic ventricular arrhythmias in an attempt to replicate clinical conditions. Thirty-six mongrel dogs underwent placement of a permanent ventricular pacemaker and induction of an anterior MI by percutaneous transcatheter embolization of polyvinyl foam particles into the left anterior descending coronary artery (just distal to the first septal branch). After a 2-week recovery period, heart failure was induced by continuous rapid ventricular pacing at 200 to 240 ppm for 3 weeks. Transient (4-minute) myocardial ischemia was induced via balloon occlusion of the proximal left circumflex coronary artery. Echocardiographic and electrophysiologic testing was performed before MI creation and repeated prior to acute ischemia induction. Seven dogs (19%) died within several hours of MI creation. All surviving dogs developed severe left ventricular systolic dysfunction. Significant increases in the intraatrial and intraventricular conduction intervals were observed following MI creation and heart failure induction compared with baseline values, as evidenced by increases in the duration of the P wave and QRS complex. Significant increases in corrected QT interval and ventricular refractoriness were observed. Acute transient ischemia induced sustained ventricular tachycardia or ventricular fibrillation in 21 of 29 dogs (72%). This canine model can serve as a useful tool for studying ventricular arrhythmias during the interactions of healed infarction, heart failure, increased sympathetic tone, and myocardial ischemia.

Effects of Spironolactone and Fosinopril on the Spontaneous and Chronic Ventricular Arrhythmias in a Rat Model of Myocardial Infarction

We documented chronic ventricular arrhythmias in a first group of 58 rats after myocardial infarction (MI), then assessed the effects of spironolactone and fosinopril on morphological indexes and arrhythmias in a second group (n = 33). Rats underwent Holter monitoring at 2 months after MI. Treatment was randomly given from 1 until 4 months after MI: placebo in 12 rats (P), fosinopril in 9 (F) and spironolactone + fosinopril in 12 (SF). The score of ventricular premature beats (VPBs) was related to the MI size and the delay from MI (p < 0.01). VPB’s reduction/increase required to demonstrate anti/pro-arrhythmic effects were 55 and 59%. Mass indexes were lower in F and SF (p = 0.01). VPB’s difference (4 months vs. 1) was positive in P, significantly lower in F and negative in SF (p = 0.04). In this relevant model of spontaneous and chronic ventricular arrhythmias, SF association did not increase mortality but lowered the arrhythmic score.

In Vivo Antiarrhythmic Profile of AP-792 Assessed in Different Canine Arrhythmia Models

The antiarrhythmic effects of a novel antiarrhythmic drug AP-792, 4-(5H-dibenzo[a,d]cyclo-hepten-5-ylidene)-1-[4-cyclohexylbutyl]piperidine hydrochloride, were analyzed using the epinephrine-, digitalis- and two-stage coronary ligation-induced canine ventricular arrhythmia models. Intravenous administration of AP-792 (0.3 or 1.0 mg /kg) effectively suppressed each of the ventricular arrhythmias, an action that resembles that of a typical cardioselective Ca2+ channel blocker, AH-1058. The antiarrhythmic action of AP-792 was slow in onset and longer-lasting than those in our previous studies using more than 50 antiarrhythmic drugs, including Na+ and Ca2+ channel blockers. These results suggest that AP-792 can become a unique long-acting antiarrhythmic drug.

Antiarrhythmic and cardiohemodynamic effects of a novel Ca 2+ channel blocker, AH-1058, assessed in canine arrhythmia models

The antiarrhythmic profile and cardiohemodynamic effect of a novel Ca 2+ channel blocker, 4-(5 H-Dibenzo[ a, d]cyclohepten-5-ylidene)-1-[( E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride (AH-1058), were analyzed using the epinephrine-, digitalis- and two-stage coronary ligation-induced canine ventricular arrhythmia models. Intravenous administration of AH-1058 (100 μg/kg) effectively suppressed each of the ventricular arrhythmias accompanied by weak hypotensive effects. The results contrast well with those of a typical Ca 2+ channel blocker, verapamil, which suppresses only the epinephrine-induced ventricular arrhythmia with severe hypotension. These results indicate that AH-1058 may possess a more selective inhibitory action on Ca 2+ channels in the heart than on those in the vessels. Furthermore, the antiarrhythmic actions of AH-1058 were slower in onset and longer-lasting, than those in our previous studies using other antiarrhythmic drugs, including Na + and Ca 2+ channel blockers. The antiarrhythmic effects of AH-1058 did not correlate with its plasma concentrations when administered either intravenously or orally. These results suggest that AH-1058 can become a long-acting Ca 2+ channel blocker with unique antiarrhythmic properties, and that AH-1058 may be used in certain pathological processes, for which selective inhibition of the cardiac Ca 2+ channels is essential.

Effects of azimilide, a K V(r) and K V(s) blocker, on canine ventricular arrhythmia models

Using canine coronary artery ligation/reperfusion and adrenaline arrhythmia models, we determined the effects of azimilide, a class III antiarrhythmic agent, E-1-{[(5-(4-chlorophenyl)-2-furanyl) methylene]-amino}-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride. The coronary ligation/reperfusion arrhythmia experiments were divided into two groups, one using low heart rate halothane-anesthetized and the other using high heart rate pentobarbital-anesthetized dogs. Azimilide (6 mg kg −1+0.1 mg kg −1 min −1 i.v.) prolonged the corrected QT interval (QTc), decreased the heart rate and suppressed the premature ventricular complexes during ligation (35±17 beats/30 min as compared with 909±246 in the control group), and also suppressed ventricular fibrillation induced by coronary ligation/reperfusion in the two groups (1/8 halothane-anesthetized dogs as compared with 7/8 dogs in the control group and 2/8 pentobarbital-anesthetized dogs as compared with 8/8 dogs in the control group). In adrenaline arrhythmia, azimilide hastened the onset of adrenaline arrhythmias and also aggravated the arrhythmias, showing proarrhythmic effects.

Antiarrhythmic effects of a novel class III drug, KCB-328, on canine ventricular arrhythmia models.

KCB-328 is a newly synthesized class III drug. To determine whether this drug has antiarrhythmic or proarrhythmic effects, we used canine ventricular arrhythmia models induced by coronary ligation and reperfusion, programmed electrical stimulation (PES), two-stage coronary ligation, digitalis, or epinephrine. KCB-328, in an intravenous infusion of 0.5 mg/kg/30 min, prolonged the QTc interval only 11%, but had antiarrhythmic effects on the reentry arrhythmias induced by PES (12 of 12 dogs with old myocardial infarction; p < 0.05). KCB-328, in an infusion of 1 mg/kg/h, suppressed the occurrence of fatal ventricular fibrillation (VF) induced by coronary ligation and reperfusion under either halothane anesthesia (p < 0.05) or pentobarbital anesthesia (p < 0.05). Under the halothane anesthesia, KCB-328 alone showed proarrhythmic effects [i.e., induction of ventricular premature contractions (VPCs)], but it did not induce a more severe effect such as torsades de pointes-type ventricular tachycardia (VT). In addition, KCB-328 had weak antiarrhythmic effects on the automaticity arrhythmias induced by 24-h coronary ligation but was effective neither on 48-h coronary ligation arrhythmias nor on the digitalis- and epinephrine-induced arrhythmias. Our results indicate that KCB-328 has powerful antiarrhythmic effects with fewer proarrhythmic potencies.

Effects of a cardioselective M2 receptor antagonist, AF-DX 116, on ventricular arrhythmias in dogs.

AF-DX 116 is a cardioselective M2 receptor antagonist and, thus, it should induce sinus tachycardia. Since normal ventricular automaticity is suppressed by atrial overdriving, AF-DX 116 might become an antiarrhythmic drug and act by increasing the sinus node automaticity. Ventricular arrhythmia models used in this study were induced either by two-stage coronary ligation, digitalis, or adrenaline in beagle dogs. AF-DX 116 (0.3 mg/kg i.v.) tended to increase the sinus rate of the conscious beagles compared to the pre-drug level (although the effect was not significant) but had no antiarrhythmic effect (i.e., there was no decrease in the arrhythmic ratio defined as the number of PVC divided by the total heart rate) on the ventricular tachycardia (VT) induced 24 h after aseptic ligation of the left anterior descending coronary artery. AF-DX 116 did not alter the blood pressure. The drug also did not suppress digitalis-induced VT and did not increase the atrial rate, which was already increased to about 210 beats/min by ouabain. AF-DX 116 decreased the arrhythmic ratio, 9 min after bolus injection, and increased the atrial rate in the adrenaline VT model. The maximum plasma concentration of AF-DX 116 reached nearly 1microg/ml 1 min after the bolus injections in the digitalis and adrenaline arrhythmia experiments, which is close to the maximum concentration expected to be attained in the clinical application of this drug. Although AF-DX 116 increased the heart rate, under the present experimental conditions of increased atrial rate, the extent of tachycardia was not strong enough to suppress the 24-h coronary ligation and digitalis-induced arrhythmias. The late onset of the antiarrhythmic effect of AF-DX 116 on adrenaline-induced arrhythmia cannot be explained by the overdrive suppression mechanism.

Azimilide (NE-10064) can prolong or shorten the action potential duration in canine ventricular myocytes: dependence on blockade of K, Ca, and Na channels.

Azimilide (NE-10064) has antiarrhythmic and antifibrillatory effects in canine models of ventricular arrhythmia. The goal of the present study was to examine the effects of azimilide on action potential and membrane currents of canine ventricular myocytes. Membrane voltage and current were recorded using the whole cell, patch clamp method. Azimilide at 1 microM induced a consistent prolongation of action potential duration (APD): on average APD90 was prolonged by 25% and 17% at stimulation rates of 0.33 and 1 Hz, respectively. Elevating the drug concentration to 5 microM induced APD prolongation in some cells but APD shortening in the others at 0.33 Hz, and a consistent APD shortening at 1 Hz. Azimilide suppressed the following currents (Kd in parenthesis): IKr (< 1 microM at -20 mV), IKs (1.8 microM at +30 mV), L-type Ca current (17.8 microM at +10 mV), and Na current (19 microM at -40 mV). Azimilide was a weak blocker of the transient outward and inward rectifier currents (Kd > or = 50 microM at +50 and -140 mV, respectively). Azimilide blocked IKr, IKs, and INa in a use-dependent manner. Furthermore, azimilide reduced a slowly inactivating component of Na current that might be important for maintaining the action potential plateau in canine ventricular myocytes. Azimilide has variable effects on APD in canine ventricular myocytes due to its blocking effects on multiple currents with different potencies. Its Class III antiarrhythmic action is most likely seen at low concentrations (< 5 microM).

An animal model of spontaneous arrhythmic death.

Ventricular arrhythmias and the proclivity for sudden death have been identified in German shepherd dogs. This disorder is inherited, and affected animals can be consistently produced from an established colony. The arrhythmias are most prevalent in young dogs between 22 and 26 weeks of age, with death most frequent at this same age. Death occurs most frequently during presumed sleep or at rest after exercise or excitement. The QT interval is not prolonged; however, more frequent notching of the T wave exists in affected dogs compared to control dogs. Polymorphic rapid nonsustained ventricular tachycardia occurs most frequently following long RR intervals. Accordingly, perturbations that decrease the heart rate or enhance sinus arrhythmia increase the incidence of ventricular arrhythmias. Because the arrhythmias are age, behavior, and heart rate dependent, the autonomic nervous system may play a role in their generation. As determined by metaiodobenzyl-guanidine scintigraphy and immunocytochemical staining of tyrosine hydroxylase, cardiac sympathetic innervation is regionally deficient in affected dogs. Evidence suggests that initiation of the ventricular arrhythmias is caused by early afterdepolarization (EAD)-induced triggered activity originating from left ventricular Purkinje fibers. Alpha 1-adrenergic stimulation provokes EADs in the Purkinje fibers and ventricular arrhythmias in the dogs. The development of EADs may be related to heterogeneity of repolarizing currents (Ito in particular) in affected dogs. From this canine model of spontaneous ventricular arrhythmias, the opportunity exists to investigate the interplay between abnormal development of cardiac innervation and the genesis of lethal ventricular arrhythmias.

Inhibition of centrally induced ventricular arrhythmias by rilmenidine and idazoxan in rabbits.

In a model of ventricular arrhythmias of central origin, we investigated the effects of rilmenidine, an oxazoline with antihypertensive properties, and idazoxan, an imidazoline that is an antagonist of the hypotensive effects of rilmenidine. Bicuculline, a GABAA receptor antagonist, was administered intracisternally (i.c.) to produce arrhythmias in pentobarbitone anaesthetised rabbits; 10 micrograms/kg bicuculline i.c. induced polymorphic ventricular ectopic beats and ventricular tachycardia while blood pressure increased by about 50-60% and sinusal heart rate decreased by about 20%. Rilmenidine, either administered intravenously (0.01, 0.1, 1 mg/kg i.v.) or i.c. (3, 10, 30 micrograms/kg) dose-dependently prevented the occurrence of bicuculline-induced arrhythmias while, because of a lower base-line, the blood pressure values reached were less as compared to controls. Idazoxan administered i.v. (3, 10 mg/kg) had a similar action. Idazoxan i.c. (15 micrograms/kg) had no significant antiarrhythmic effect but antagonized in part the haemodynamic and antiarrhythmic effects of rilmenidine (1 mg/kg i.v.; 30 micrograms/kg i.c.). It is suggested that the antiarrhythmic effects observed with rilmenidine are mainly mediated by blunting the bicuculline-induced increase in the sympathetic nervous output to the heart and the vascular beds. These effects of rilmenidine are likely to originate both from the central and peripheral nervous system. The antiarrhythmic effects of idazoxan i.v. might be related to a blocking action on alpha 2-adrenoceptors at the level of the coronary arteries and other vascular beds.

Characterization of Magnesium Sulfate as an Antiarrhythmic Agent.

BACKGROUND: Recently, intravenous magnesium therapy has been used for the treatment of ventricular arrhythmias, but data to establish a causal link between the electrophysiological properties and the antiarrhythmic actions are lacking. METHODS AND RESULTS: The acute antiarrhythmic effect of magnesium sulfate was assessed using epinephrine-, digitalis-, and coronary ligation-induced canine ventricular arrhythmia models. The intravenous administration of magnesium sulfate (100 mg/kg) reduced the incidence of the ventricular arrhythmias of all models. The antiarrhythmic effect on the epinephrine-induced arrhythmia was potent and long-lasting, while those on the other arrhythmia models were weak and transient. The direct cardiovascular effects were assessed using the canine isolated, blood-perfused sinus node, papillary muscle, and atrioventricular node preparations. The intracoronary administration of magnesium sulfate (0.1-30 mg) suppressed sinoatrial automaticity and ventricular contraction, while it increased atrio-His and His-ventricular conduction time, coronary blood flow, and the duration of monophasic action potential in a dose-dependent manner. The effects on His-ventricular conduction and monophasic action potential duration were less potent compared with the other cardiovascular effects. CONCLUSIONS: These results suggest that magnesium sulfate possesses multiple electrophysiological properties and that the effects related to the calcium channel inhibition may be the most relevant for the antiarrhythmic actions.

Efficacy of the class III antiarrhythmic agent azimilide in rodent models of ventricular arrhythmia.

Azimilide exhibited antiarrhythmic activity in several rodent models of ventricular arrhythmias. In the mouse chloroform model, azimilide provided limited efficacy by the i.p. route (50% at 100 mg/kg versus 20% by vehicle), and no efficacy by the oral route (300 mg/kg). In a rat model in which arrhythmias are induced by ligation and reperfusion of the left descending coronary artery (CALR model), azimilide provided dose-dependent (1-18 mg/kg) efficacy by the intravenous route. The estimated dose that suppressed ventricular fibrillation (VF) was 5.0 mg/kg i.v. At 18 mg/kg i.v. azimilide also partially suppressed ventricular tachyarrhythmia (VT) and extrasystoles (VES). Rats dosed orally (100 mg/kg) were fully protected from VF. In isolated guinea pig hearts exposed to 1 microM ouabain, azimilide at 10 microM prevented the VT and VF seen in 69% and 23%, respectively, of control hearts. In anesthetized guinea pigs, azimilide at 10 and 30 mg/kg i.v. increased the dose of ouabain required to induce VES. While sematilide, dofetilide, and E-4031 significantly increased sensitivity to the arrhythmogenic actions of ouabain (by lowering the dose that caused VF), azimilide did not. Azimilide's antiarrhythmic profile in these rodent models differs from that of other class III agents, since azimilide had less efficacy in the mouse chloroform model, could suppress VT and VES as well as VF in the CALR rat model, and protected from or did not aggravate cardiac glycoside-induced arrhythmias in guinea pigs. These results demonstrating the antiarrhythmic efficacy of azimilide in the intact animal suggest that the compound has a different profile than other class III agents.

Antiarrhythmic effects of optical isomers of disopyramide on canine ventricular arrhythmias.

Disopyramide is an effective class I antiarrhythmic drug and widely used for the treatment of arrhythmias, but it has anticholinergic side effects. In vitro studies demonstrated that dextrorotatory (D-) disopyramide has a stronger anticholinergic action, whereas the levorotatory (L-) isomer has a stronger Na channel blocking action. Because the antiarrhythmic mechanism of disopyramide suppressing digitalis- and two-stage coronary ligation-induced canine ventricular arrhythmias is the drug-induced Na channel block, we examined the antiarrhythmic efficacy of D- and L-disopyramide on two arrhythmia models. On ouabain-induced ventricular tachycardia (VT), L-disopyramide 3 mg/kg decreased the arrhythmic ratio (number of ectopic beats/total heart rate), whereas the same dose of the D-isomer was ineffective and a higher dose (5 mg/kg) was needed to suppress the arrhythmia. The effective plasma concentrations (IC50) decreasing the arrhythmic ratio to 50% of the control were 5.3 and 11.3 mu g/ml for L- and D-disopyramide, respectively. We obtained similar results using 24-h two-stage coronary ligation VT. The IC50 were 8.9 and 22.2 mu g/ml for the L- and D-isomers, respectively. Our results indicate that L-disopyramide is about twice as strong an antiarrhythmic drug as the D-isomer.