Arrhythmic Ratio Research Articles

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 4th communication: influence on experimentally induced ventricular arrhythmia in dogs.

Influence of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]- 1,2,5,6,-tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013) and vesnarinone (CAS 81840-15-5) on the arrhythmia experimentally induced by three different methods was investigated in dogs. In digitalis-induced arrhythmia, SCH00013 (3 mg/kg i.v.) showed a tendency to improve the arrhythmia with a decrease in the arrhythmic ratio and an increase in the conducted beats (CB), though these changes did not reach a significant level; it decreased significantly the blood pressure (BP) with no change in the total heart rate (THR) and atrial rate (AR). Vesnarinone (3 mg/kg i.v.) did not affect these parameters except for BP that was decreased significantly. In two-stage coronary ligation-induced arrhythmia, SCH00013 (1 and 3 mg/kg i.v.) did not change the arrhythmic ratio, CB, AR and BP, while the THR being slightly decreased; the arrhythmic ratio showed a tendency to decrease with SCH00013 when examined at 24 h after coronary ligation. Vesnarinone (3 mg/kg i.v.) did not affect these parameters at 24 and 48 h after ligation. In epinephrine (adrenaline)-induced arrhythmia, both SCH00013 and vesnarinone showed exacerbation of arrhythmia. SCH00013 at 1 mg/kg i.v. did not elicit ventricular fibrillation (VF) in five dogs examined, but at 3 mg/kg i.v. it elicited VF in two of three dogs. Vesnarinone at 1 mg/kg i.v. induced VF in all of three dogs examined. Incidence of VF induced by optical isomers of SCH00013 was not significantly different from each other: both isomers elicited VF in two of six dogs at 1 mg/kg i.v. and at 3 mg/kg i.v. each of them induced VF in two dogs examined. The present results indicate that SCH00013 is a cardiotonic agent that is equivalent to or less arrhythmogenic than vesnarinone in animal models of arrhythmia, such as adrenaline- and digitalis-induced arrhythmia and the two-stage coronary ligation-induced arrhythmia. Optical isomers of SCH00013 were essentially equieffective in eliciting exacerbation of adrenaline-induced arrhythmia in the dog.

Effects of SEA0400, a Na +/Ca 2+ exchange inhibitor, on ventricular arrhythmias in the in vivo dogs

SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline), a novel and selective inhibitor of Na +/Ca 2+ exchanger, was investigated for its possible antiarrhythmic effects on arrhythmias of Ca 2+ overload induced by coronary ligation/reperfusion and by digitalis in the dog. SEA0400 (1.0 mg/kg) did not change the hemodynamics but slightly prolonged the QRS duration ( P<0.05). Pre-ischemic administration (10 min before coronary occlusion) of SEA0400 (1.0 mg/kg) and post-ischemic administration (1 min before reperfusion) of SEA0400 (0.3, 1.0 and 3.0 mg/kg) had no effects on the incidence of ventricular fibrillation induced by coronary ligation/reperfusion. On the other hand, SEA0400 (3.0 mg/kg) decreased the arrhythmic ratio in the digitalis arrhythmias ( P<0.01). However, atrioventricular block and cardiac standstill were induced in two digitalized dogs. In conclusion, SEA0400 has no significant antiarrhythmic effect on arrhythmias induced by coronary ligation/reperfusion, but has an obvious suppressing effect on tachyarrhythmias induced by digitalis in in vivo canine models.

Development of a Halothane-Adrenaline Arrhythmia Model Using In Vivo Guinea Pigs

In vivo antiarrhythmic effects of diltiazem hydrochloride and nifekalant hydrochloride, a pure class III antiarrhythmic drug (Vaughan Williams’ classification), on adrenaline induced ventricular arrhythmias were examined in halothane anesthetized guinea pigs. Continuous adrenaline infusion (12.5 μg/kg per min) induced ventricular arrhythmias. Arrhythmogenicity was significantly increased with vagotomy and higher concentration of halothane. After injection of diltiazem at 0.5 mg/kg, the arrhythmic ratio (the number of ventricular ectopic beats divided by the total heart beats) was significantly reduced compared with the predrug control value (0.69 vs 0.04, P<0.05). No significant change of arrhythmic ratio was observed after injection of nifekalant (0.57 vs 0.61, ns). After administration of nifekalant, the mean minimum adrenaline infusion rate that induced ventricular arrhythmia decreased from 9.29 to 6.43 μg/kg per min. On the other hand, before administration of diltiazem, the mean arrhythmogenic rate of adrenaline was 8.50 μg/kg per min, but ventricular arrhythmias were no longer induced during continuous infusion of diltiazem at 0.5 mg/kg per min. These results were qualitatively consistent with previous experiments using the canine halothane-adrenaline model. In conclusion, the halothane-adrenaline arrhythmia model using the in vivo guinea pig is useful for screening drugs with potential anti- or pro-arrhythmic properties.

QT-prolonging class I drug, disopyramide, does not aggravate but suppresses adrenaline-induced arrhythmias. Comparison with cibenzoline and pilsicainide

We investigated the effects of class I antiarrhythmic drugs on corrected QT (QTc) interval and adrenaline-induced arrhythmias in halothane-anaesthetized, closed-chest dogs. For this purpose, we plotted a dose–response curve for adrenaline by calculating the arrhythmic ratio, which is the number of ventricular ectopic beats induced by adrenaline divided by the total heart rate, and observed the changes in the arrhythmic ratio–adrenaline dose relation before and after administration of class I drugs. Disopyramide and cibenzoline decreased the arrhythmic ratio induced by adrenaline. Disopyramide prolonged the QTc interval by 20% ( P<0.01), but cibenzoline did not. Pilsicainide prolonged the QTc interval (12%), but this drug did not change the arrhythmic ratio. These results indicate that in contrast to the class III drugs which we have reported earlier, i.e. 1,3-dimethyl-6-{2-[ N-(2-hydroxyethyl)-3-(4-nitrophenyl)-propylamino]ethylamino}-2,4 (1 H,3 H)-pyrimidinedione hydrochloride (MS-551), 1-(2-amino-4-methanesulfonamidophenoxy)2-[ N-(3,4-dimethoxyphenethyl)- N-methylamino]ethane hydrochloride (KCB-328) and E-1-{[(5-(4-chlorophenyl)-2-furanyl)methylene]amino}-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride (azimilide), class I drugs do not aggravate adrenaline-induced arrhythmias even though some drugs prolong the QTc interval.

MS-551 and KCB-328, two class III drugs aggravated adrenaline-induced arrhythmias.

We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 microg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. MS-551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interval by 20% (P<0.01). During the 30 min of MS-551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS-551 decreased the latent interval of the adrenaline arrhythmias produced by the inducing dose (30+/-2 s compared with 43+/-3 s of the control interval, P < 0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmias by non-inducing adrenaline doses (P<0.05). Effect of a new class III drug KCB-328 infusion, 0.3 mg/kg/30 min, was compared witih MS-551 using the same model. KCB-328 decreased the HR by 21% (P<0.01) and prolonged the QTc interval by 25% (P<0.01). During the 30 min of infusion, arrhythmias occurred in five out of seven dogs (TdP in two dogs). KCB-328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31+/-3 s compared with 49+/-7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. Adrenaline induced TdP only after MS-551 or KCB-328 was administered, i.e. after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. To examine the direct arrhythmogenic effect of MS-551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre-treated dogs, MS-551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). In conclusion, these observations indicate that MS-551 and KCB-328 induced arrhythmias and intensified proarrhythmic effects of adrenaline, MS-551 being stronger than KCB-328 at the same QTc prolonging doses. The direct arrhythmogenic effect of MS-551 was not influenced by beta-blocker treatment.

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.

Antiarrhythmic effects of DHA-As on ventricular arrhythmias in rat and dog hearts

DHA-Ascorbic acid (DHA-As), a new derivative of docosahexaenoic acid (DHA) was tested for its possible antiarrhythmic effects on coronary artery ligation/reperfusion arrhythmias in rat hearts, and adrenaline-induced arrhythmias in canine hearts. DHA-As (3 mg/kg i.v.) did not change the total duration of VT, and tended to suppress the incidence of VT, VF and mortality of reperfusion in rat hearts. The heart rate, QT90 and systolic blood pressure did not change, and the diastolic blood pressure was decreased by DHA-As in the rat hearts. DHA-As significantly decreased the arrhythmic ratio only at two time points (14 and 15 min after injection), and also decreased the heart rate and mean blood pressure in canine hearts. In conclusion, DHA-As tended to suppress the reperfusion-induced arrhythmias in rat hearts. However, the change was not statistically significant. In addition, DHA-As has a weak suppressing effect on adrenaline-induced arrhythmia.

Antiarrhythmic effects of HOE642, a novel Na +-H + exchange inhibitor, on ventricular arrhythmias in animal hearts

HOE642 (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate), a novel Na +-H + exchange subtype 1 inhibitor, was investigated for its possible antiarrhythmic effects on coronary artery ligation/reperfusion and ouabain-induced arrhythmias in the canine heart which may occur after intracellular Ca 2+ overload. Also, the effects of HOE642 on coronary artery ligation/reperfusion of the left coronary artery were tested in rat hearts. HOE642 (1 mg/kg) significantly suppressed the occurrence of fatal ventricular fibrillation during coronary artery ligation and after reperfusion in dogs (2 out of 8 dogs in the treated group compared to 7 out of 8 dogs in the control group, P<0.05), but did not suppress ventricular premature contractions and ventricular tachycardia during ischemia in the canine hearts. HOE642 at the same dose markedly reduced the total duration and the incidence of reperfusion-induced ventricular tachycardia, and the incidence and mortality of reperfusion-induced ventricular fibrillation in rats (ventricular tachycardia duration, 159±12 s to 21±8 s, P<0.01; ventricular tachycardia, 100% to 69%; ventricular fibrillation, 89% to 0%, P<0.01; mortality, 89% to 11%, P<0.01). The heart rate, blood pressure, QT interval and ST segment did not change in the canine and rat hearts. HOE642 slightly decreased the arrhythmic ratio of the ouabain-induced arrhythmia only at two time points (28 and 35 min after injection) in the canine hearts. In conclusion, HOE642 has obvious antifibrillatory effects on ischemia/reperfusion arrhythmias and, in addition, has a weak suppressing effect on the ouabain-induced arrhythmia.

Effects of zatebradine on ouabain-, two-stage coronary ligation- and epinephrine-induced ventricular tachyarrhythmias

To determine whether a hyperpolarization-activated current ( I f) participates in ventricular tachyarrhythmias, we investigated the effects of zatebradine, an I f inhibitor, on the ventricular tachyarrhythmias induced by ouabain, two-stage coronary ligation and epinephrine infusion in the dog heart. We determined atrial rate, ectopic ventricular rate, total heart rate and arrhythmic ratio (the number of ectopic ventricular beats divided by total heart beats). Zatebradine (0.15, 0.5 and 1.5 mg/kg, i.v.) dose dependently decreased the arrhythmic ratio, ectopic ventricular rate and atrial rate of the ouabain-induced ventricular tachyarrhythmias in pentobarbital-anesthetized dogs. The inhibition by zatebradine of the ventricular arrhythmias needed larger doses than the inhibition of the atrial rate. Zatebradine weakly depressed the ectopic ventricular rate but not the arrhythmic ratio of the ventricular arrhythmias induced by two-stage coronary ligation 24 h after the ligation in conscious dogs. Although neither the ectopic ventricular rate nor the arrhythmic ratio of the epinephrine-induced ventricular arrhythmias was affected by zatebradine, after treatment with zatebradine, the arrhythmias elicited by epinephrine developed more slowly. Together with the previously reported spectra of the effects of the antiarrhythmic agents in three ventricular tachyarrhythmia models, our results suggest that zatebradine may improve automaticity-related ventricular tachyarrhythmias due to I f inhibition or to other undetermined mechanisms in the heart.

Effects of gallopamil, a Ca 2+ channel blocker in models of ventricular arrhythmia in dogs

The antiarrhythmic effects of gallopamil on adrenaline-, digitalis- and two-stage coronary ligation-induced arrhythmias and on adrenaline-induced triggered arrhymia were investigated. Gallopamil suppressed adrenaline-induced and adrenaline-induced triggered arrhythmias, and these antiarrhythmic effects of gallopamil were similar to those of verapamil. Gallopamil also showed some antiarrhythmic effect on the 48-h coronary ligation-induced arrhythmia. The plasma concentration of gallopamil which decreased the arrhythmic ratio for adrenaline-induced arrhythmia by 50% (IC 50)_was 32 ng/ml. These results indicate that gallopamil may be a clinically useful antiarrhythmic drug.

Effects of β-adrenoceptor antagonism upon delayed reperfusion arrhythmias in conscious dogs

Whereas isolated heart preparations or anesthetized animals have been used to assess the actions of β-adrenoceptor antagonists upon reperfusion-induced arrhythmias, this study evaluated the possible antiarrhythmic effects of β-adrenoceptor antagonism in conscious animals. Conscious, chronically instrumented dogs were subjected to a temporary occlusion of the left anterior descending coronary artery for 4 h. After the first hour of reperfusion, flestolol (N-(1,1-dimethyl-2-ureidoethyl)-2-hydroxy-3-(O-fluorobenzoyloxy)-propylamine sulfate), an ultra short-acting β-adrenoceptor antagonist, was administered i.v. at infusion rates of 1 and 2.6 (μg/kg per min. A control group received the equivalent volume of saline during this period. Delayed reperfusion-induced arrhythmias were evaluated by using a computerized analysis system. Treatment with flestolol did not affect the total number of beats, the number of normal and ectopic beats, and the arrhythmic ratio, i.e. the ratio of ectopic beats to the total number of beats. Hence, β-adrenoceptor antagonism does not appear to suppress delayed ectopic activity during coronary reperfusion in conscious dogs.

Holter monitoring in conscious dogs: Assessment of arrhythmias occurring during ischemia and in the early reperfusion phase

Myocardial ischemic episodes of 5 min, 15 min, and 4 hr duration, with interposed reperfusion periods, were induced in the same conscious, chronically instrumented dogs. A drop in systolic blood pressure and an increase in heart rate and in the arrhythmic ratio ( AR% = number of ectopic beats × 100 total number of beats, as assessed by Holter monitoring) was registered in response to the induction of myocardial ischemia. Reperfusion-induced salvage after coronary occlusion of 5 and 15 min duration was documented by an immediate return of systolic blood pressure, heart rate, and AR to the preocclusion control level. However, after coronary occlusion lasting for 4 hr, reperfusion induced a further drop in blood pressure and an increase in heart rate and in AR. We conclude that in conscious dogs, reperfusion-induced arrhythmias do not occur after short-lasting myocardial ischemic episodes. Reperfusion after long-lasting ischemia induces marked ventricular ectopic activity, yielding an arrhythmic ratio of more than 80%. Although these reperfusion-induced arrhythmias impair the hemodynamic state, they are well tolerated in the conscious dog and can be assessed by the Holter monitoring technique. This new experimental approach promises to be of clinical relevance for investigations on the therapeutic efficacy of new antiarrhythmic drugs.

Holter monitoring in conscious dogs: Assessment of arrhythmias occurring in the late reperfusion phase after coronary occlusion

Arrhythmias occurring in the late reperfusion phase, i.e., up to 3 days after episodes of 5 min, 15 min, and 4 hr of coronary occlusion (CAO), were investigated in six conscious, chronically instrumented dogs using the Holter monitoring technique. The arrhythmic ratio ( AR% = number of premature ventricular complexes × 100 total number of beats ) of a 24-hr preocclusion control record was 0.004% and did not differ from the values assessed for day 1 (0.004%) and 2 (0.001%) of the late reperfusion phase after 5 min CAO. After 15 min, CAO increased, but insignificantly elevated AR values were registered on days 1 (2.5%), 2 (0.26%), and 3 (0.1%) of the late reperfusion phase. On day 1 of the late reperfusion phase after 4 hr CAO, the AR increased markedly to 75%. On day 2 of this phase, the AR was lower (20%) but still significantly elevated. On day 3, the AR was 3.5%, a value still markedly, although not significantly, above the preocclusion control level. We conclude that in conscious dogs, arrhythmias in the late reperfusion phase do not occur after 5 min CAO. However, after 15 min CAO and, especially, after 4 hr CAO, an increase in arrhythmic activity occurs in the late reperfusion phase and gradually declines towards the preocclusion control level over a period of 3 days. Thus, it could be demonstrated that the long-term assessment of reperfusion arrhythmias by ECC monitoring using the Holter technique is feasible in conscious dogs. This method represents a promising approach to clinically relevant experimental investigations on the therapeutic efficacy of new antiarrhythmic drugs.

Effects of yohimbine and desipramine on cardiac noradrenaline release and ventricular arrhythmias during acute coronary artery occlusion and reperfusion in anesthetized dogs.

Effects of yohimbine (YHMB, an alpha 2-antagonist) and desipramine (DMI, a neuronal uptake inhibitor) were compared on cardiac noradrenaline (NA) release either upon left ansa subclavia nerve stimulation during acute occlusion of the left anterior descending coronary artery (LAD) or upon subsequent LAD reperfusion without stimulation in anesthetized dogs. In control dogs, before LAD occlusion, coronary sinus (CS) NA output increased from 5.4 +/- 1.0 to 26.8 +/- 4.0 ng/min (p less than 0.05) upon stimulation (2 Hz, 30 s). The response to stimulation remained unchanged 25 min after LAD occlusion. During reperfusion 60 min after occlusion, the output of CS-NA and lactate increased from 6.1 +/- 0.8 to 51.3 +/- 19.4 ng/min (p less than 0.05) and from 2.7 +/- 0.5 to 6.7 +/- 1.3 mg/min (p less than 0.05), respectively. In dogs treated with YHMB, the stimulation-induced increase in NA output was potentiated at least fourfold (p less than 0.05) either before or during LAD occlusion, but not during reperfusion. In dogs receiving DMI, stimulation-induced CS-NA output was enhanced to a similar extent (approximately twofold, p less than 0.05) either before or during occlusion, while reperfusion-induced NA output was markedly potentiated by approximately ninefold (p less than 0.05). Maximum dP/dt of left ventricular pressure remained unchanged upon reperfusion in all groups. The total arrhythmic ratio in the drug-treated groups did not significantly differ from the ratio in control dogs upon either stimulation or reperfusion. The data suggest that an abrupt increase in NA output upon reperfusion may result from a washout of NA locally accumulated in the ischemic and (or) peri-ischemic region during the preceding occlusion period, and that NA thus released does not have substantial hemodynamic effects. The results indicate that in the presence of YHMB or DMI, the potentiated increase in NA release in response to either nerve stimulation during LAD occlusion or to reperfusion without stimulation did not aggravate ventricular arrhythmia, most probably owing to the antiarrhythmic properties of these substances.

Effects of sotalol, (−)-propranolol and prazosin on reperfusion-induced arrhythmias and increased cardiac norepinephrine release

The pharmacological actions of sotalol, (−)-propranolol and prazosin on norepinephrine (NE) concentration and creatine kinase (CK) activity in the coronary sinus blood of the ischemic heart were studied in open-chest dogs. A 60 min occlusion of the left anterior descending coronary artery was followed by a reperfusion period of 30 min. In saline-treated dogs, a significant increase in coronary sinus NE concentration occuring 30 s after the onset of reperfusion was followed by a rapid decrease to the initial value within 15 min. CK activity increased gradually and continuously starting 5 min after the beginning of reperfusion. A good correlation (r = 0.9, n = 8, P < 0.05) was obtained in saline-treated dogs when the calculated slope of the time-activity curves for CK release was plotted against the corresponding peak concentration of NE. The increase in coronary sinus NE concentration upon reperfusion was accompanied by an increased arrhythmic ratio. Sotalol (5 mg/kg i.v.) diminished the increase in coronary sinus NE concentration along with a significant decrease in the arrhythmic ratio. The administration of either (−)-propranolol (0.1 mg/kg i.v.) or prazosin (1 mg/kg i.v.) did not significantly affect the increase in coronary sinus NE concentration. The arrhythmic ratio was significantly reduced by prazosin but not by (−)-propranolol. The rise in coronary sinus CK activity was significantly diminished in the presence of either sotalol, (−)-propranolol or prazosin. These results suggest that the occurence of severe ventricular arrhythmias upon reperfusion may be related to the action of the increased myocardial NE on the cardiac α-adrenoceptors. The increased coronary sinus CK activity suggests that increased cardiac sympathetic activation may accelerate or aggravate the myorcardial damage. We conclude that the antiarrythmic effect of sotalol may be due at least in part to its inhibitory action on the release of cardiac NE upon reperfusion.

Anti-arrhythmic effects of (-)-carnitine chloride and its acetyl analogue on canine late ventricular arrhythmia induced by ligation of the coronary artery as related to improvement of mitochondrial function.

Using the two-stage coronary ligation method, first described by Harris, (1950), anti-arrhythmic effects (AAE) of (-)-carnitine chloride (LCC) and acetyl (-)-carnitine chloride (ALCC) were studied in conscious unrestrained dogs in comparison with those of disopyramide (D). Two-stage ligation of the coronary artery resulted in a significant decrease in the myocardial free carnitine content. Intravenous administration of LCC (300 mg kg-1) and D (5 mg kg-1) suppressed the ventricular arrhythmia induced by coronary ligation after 24 hours. ALCC (300 mg kg-1) was found to be less potent. An improvement of the mitochondrial function (respiratory control index (RCI) and oxidative phosphorylation rate (OPR) ) was noted with LCC and ALCC and there was a linear correlation between AAE expressed as reduction of arrhythmic ratio and improvement in the OPR, whereas there was no improvement in mitochondrial function after D. Plasma carnitine concentration was increased after administration of LCC, attaining the value of around 8 mM at 10 min after 300 mg kg-1. At 60 min, the plasma carnitine concentration was still about half as high as at 10 min. After ALCC, both acetyl carnitine and free carnitine were found in the plasma. The concentration of the former was decreased after attaining a peak value of around 0.2 mM at 10 min, while the plasma concentration of free carnitine was gradually increased. The anti-arrhythmic effects of LCC and ALCC were ascribed to the improvement of mitochondrial oxidative phosphorylation, while effects other than the improvement of the mitochondrial activity were suggested as mechanisms of anti-arrhythmic effects of D.

Antiarrhythmic plasma concentrations of drugs on canine digitalis arrhythmia.

Antiarrhythmic effects of drugs and its minimum antiarrhythmic plasma concentrations were examined using the canine digitalis arrhythmia model and compared with those data obtained using coronary ligation (J. Pharmacol. Exp. Ther. 223:801, 1982) and halothane adrenaline arrhythmia (J. Cardiovasc. Pharmacol. 5(3): 1983). Cumulative injections of ouabain every 20 min produced sustained ventricular arrhythmia when the total dose reached 70 to 90 mcg/kg. Antiarrhythmic drugs of class 1, 2 and 4 were injected intravenously. Those drugs which significantly suppressed the arrhythmic ratio (the number of ventricular beats/total heart rate) were judged as effective, and the minimum effective plasma concentrations were calculated using the experimentally derived concentration time curves. All the class 1 drugs were effective, and their concentrations (mcg/ml) were: disopyramide,1.7 ; procainamide,10.1 ; aprindine, 0.8-, lidocaine, 3-5; Phenytoin, 11.3; mexiletine, 1.8. Beta-blockers, except for propranolol with a high membrane stabilizing concentration of 1.7 mcg/ml, and Ca-blockers were not effective on this arrhythmia. Phenytoin was not selectively effective on this arrhythmia. Canine digitalis arrhythmia seems to be a good model to differentiate class 1 drugs from other classes of antiarrhythmic drugs.

Antiarrhythmic effects of 1-carnitine and its acetyl derivative in beagle dogs and improvement of the mitochondrial function.

Using two-stage coronary ligation method (Harris’ method), antiarrhythmic effects (AAE) of 1-carnitine and acetyl-1-carnitine (ALCC) were studied in conscious unrestrained dogs in comparison with those of disopyramide (D). 1-Carnitine (LC)(300 mg/kg i.v.) and 1-carnitine chloride (LCC)(300 mg/kg i.v.) and D (5 mg/kg i.v.) suppressed the ventricular arrhythmia induced by coronary ligation, while 1-carnitine phosphate (LCP) had no effects. ALCC was found to be antiarrhythmic, though less potent. An improvement of the mitochondrial function (respiratory control index, RCI and oxidative phosphorylation rate, OPR) was noted with all the drugs used except LCP, and there was a linear correlation between AAE expressed as reduction of arrhythmic ratio and improvement of mitochondrial function with LC, LCC and ALCC. All drugs except D elevated cardiac LC contents and lowered FFA and long chain acyl carnitine. AAE of LC and LCC was ascribed to the improvement of mitochondrial lipid metabolism, while effects other than the improvement of the mitochondrial lipid metabolism are invoked to explain the failure of LCP and the low potency of ALCC to produce AAE.