Effects of serotonin antagonists on digitalis-induced ventricular arrhythmias.

The present study was performed to determine whether pharmacological blockade of serotonin receptors would counteract digitalis-induced ventricular arrhythmias. The effect of the serotonin receptor blocking drugs, methysergide, cinansersin, and cyproheptadine on ventricular arrhythmias produced by ouabain was studied in anesthetized dogs. Each of the three serotonin receptor blocking drugs given as a bolus i.v. injection of 1.5--3.0 mg/kg produced an antiarrhythmic effect. In addition, methysergide administered in the above doses to cats intoxicated with deslanoside, restored an abnormal ventricular arrhythmia to either sinus or junctional rhythm. Methysergide, administered to cats intoxicated with deslanoside but pretreated with p-chlorophenylalanine, exerted an antiarrhythmic effect in less than half of the animals tested. These data indicate that serotonin antagonists are effective in counteracting digitalis-induced ventricular arrhythmias and support the notion that a serotonergic mechanism may be mediating the arrhythmogenic effect of digitalis.     

Deleterious effects of taurine in cats with digitalis-induced arrhythmias.

An established model of digitalis toxicity was used to investigate the antiarrhythmic properties of taurine. I.v. doses of taurine ranging from 0.01 to 4.0 mmole/kg were ineffective in converting a deslanoside-induced arrhythmia to sinus rhythm. Indeed, taurine was found to aggravate the arrhythmia and in three experiments precipitated ventricular fibrillation. In addition, pretreatment with 5 mmole/kg taurine i.v. had no significant effect on the doses of deslanoside to produce ventricular arrhythmia and fibrillation.     

Role of the sympathetic nervous system in the genesis of digitalis-induced cardiac arrhythmias

There are many experimental conditions under which an interaction between aigitalis and the sympathetic nervous system can be demonstrated. In the absence of viable sympathetic function, digitalis toxicity is decreased and the mode of death in experimental animals is changed from ventricular fibrillation to cardiac arrest. The interaction between digitalis and the sympathetic nervous system does not appear to be active in nature. That is, no causal relationship between either changes in adrenergic neuron transport or changes in sympathetic nerve activity and the development of cardiac arrhytmias has been demonstrated. The interaction that occurs appears to be passive. Endogenous norepinephrine which is released tonically serves to maintain certain specialized tissues of the heart in a state such that lower doses of digitalis which are non-toxic in sympathectomized animals can effect electrical changes which result in cardiac arrhythmias.     

苯那普利对高血压病左室肥厚及室性心律失常的影响

目的探讨血管紧张素转换酶(AEC_I)苯那普利对高血压病左室肥厚(LVH)和室性心律失常(VA)的影响。方法采用超声检查和动态心电图监测56例高血压病患者服用苯那普利前和后6个月的心脏形态和心律失常变化。结果检测的27例LVH患者VA发生率明显高于无LVH者(77.7 %对34.5 %) ,尤以复杂型VA多见(48.2 %对10.4 %) ;治疗6个月后 ,IVS、LVPW、LA和LVMI显著消退 ,VA发生率亦明显降低。结论高血压伴LVH时VA和复杂型VA发生率显著增多 ;苯那普利对高血压病的LVH有明显消退作用 ,VA亦随之减少     

Inhibitory effects of gamma-aminobutyric acid and diazepam on ventricular arrhythmias induced by hypothalamic electric stimulation

The experiments were carried out on rabbits with ventricular arrhythmias (VA) induced by hypothalamic electric stimulation. The effects of GABA or diazepam (Dz) and picrotoxin on VA were observed. After GABA 0.25, 0.5, 1 mg/rabbit were injected into cerebral ventricle (icv) or cisterna magna (icm), the VA was dose-dependently reduced, the similar effect was seen after Dz 0.1 mg was injected into subarachnoid cavity (sac) or icm. The effect was not induced by GABA sac or Dz icv. Picrotoxin 20 micrograms icv or 30 micrograms icm obviously increased VA, and this effect was partly antagonized by pretreatment with GABA 0.5 mg icv or icm and Dz 0.1 mg icm. The results suggest that central GABAergic system plays an important role in development of arrhythmias, and that increasing activity in this system may inhibit VA.     

Effect of sildenafil on ventricular arrhythmias in post-infarcted rat hearts

We have demonstrated that activation of ATP-sensitive potassium (K(ATP)) channels can attenuate sympathetic hyperinnervation. Sildenafil, a phosphodiesterase-5 inhibitor, has been shown to provide a preconditioning-like cardioprotective effect via opening of K(ATP) channels. The aim of this study was to investigate whether chronic administration of sildenafil attenuates cardiac sympathetic hyperinnervation after myocardial infarction through activation of K(ATP) channels and to compare it with the nitric oxide donor isosorbide dinitrate. Male Wistar infarcted rats induced by ligation of the anterior descending artery were randomized to either vehicle, nicorandil, sildenafil, isosorbide dinitrate, glibenclamide, or a combination of nicorandil and glibenclamide, or sildenafil and glibenclamide. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham-operated rats, consistent with sympathetic hyperinnervation after infarction assessed by immunohistochemical analysis for tyrosine hydroxylase, growth associated factor 43 and neurofilament and by protein expression and mRNA of nerve growth factor. Sympathetic hyperinnervation was reduced after administering either nicorandil or sildenafil. Arrhythmic scores during programmed stimulation in the sildenafil-treated rats were significantly lower than those treated with the vehicle. Furthermore, the beneficial effects of sildenafil-induced were reversed by the addition of either glibenclamide or 5-hydroxydecanoate, implicating mitochondrial K(ATP) channels as the relevant target. Isosorbide dinitrate failed to confer similar antiarrhythmia. 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one, a soluble guanylyl cyclase inhibitor, did not influence the effect of sildenafil on the nerve growth factor. These data indicate that sildenafil after infarction attenuated sympathetic hyperinnervation and arrhythmias by activation of mitochondrial K(ATP) channels through a guanylyl cyclase-cGMP-independent pathway.     

Effect of glucagon on ventricular arrhythmias after coronary artery occlusion and on ventricular automaticity in the dog

1. In anaesthetized dogs, glucagon (100 mug/kg i.v.), caused a significant increase in heart rate and decrease in mean arterial blood pressure. Ventricular automaticity, as determined by the time to the onset of first vagal escape beat and the number of such indioventricular beats during the 30 s period of vagal stimulation, was not significantly altered.2. In unanaesthetized dogs with ventricular arrhythmias produced by two-stage ligation of the anterior descending branch of the left coronary artery, glucagon (30 and 100 mug/kg i.v.), restored normal sinus rhythm in a few animals. In the remaining dogs, there was a significant reduction in the ventricular ectopic activity.3. The significant positive chronotropic response to glucagon elicited in anaesthetized animals was not observed in conscious dogs whose coronary arteries had been ligated.4. These findings enhance the potential usefulness of glucagon in the treatment of acute myocardial infarction, which may often be associated with disturbances of ventricular rhythm.5. In the light of observations made by other workers, it is suggested that the antiarrhythmic effect of glucagon may be due to movement of potassium ions into the cardiac cell.     

Pharmacokinetics of diazepam and nordiazepam in the cat

The cat has been used extensively as an experimental model for studying the pharmacology of compounds that exhibit CNS activity including diazepam and nordiazepam. However, since little is known about the distribution and elimination of diazepam in this species, the pharmacokinetics of diazepam and nordiazepam were studied in the cat following intravenous doses of 5, 10, and 20 mg/kg of diazepam and 5 and 10 mg/kg of nordiazepam. The disappearance of diazepam and nordiazepam from blood was fitted with classical equations. Theoretical and trapezoidal areas under the curve (AUCth and AUCtr) were calculated. The volumes of distribution (Vd beta) were calculated as model-independent parameters for diazepam and nordiazepam. Intrinsic hepatic clearance, extraction ratio, and tissue binding parameters were also calculated for diazepam. From the observed data, it is apparent that the blood concentrations and the resulting areas under the curves are proportional to the dose of diazepam administered and that the pharmacokinetics of diazepam were linear over the dose range studied. In addition, nordiazepam formed after diazepam administration appeared to be proportional to the dose of diazepam administered. The terminal elimination rate constant of nordiazepam remained constant over the dose range studied. It appears that both diazepam and nordiazepam are highly bound to tissue. The total body clearance of diazepam (4.72 +/- 2.45 mL/min/kg) is approximately six times that of nordiazepam (0.85 +/- 0.25 mL/min/kg). Approximately 50% of an administered dose of diazepam was biotransformed to nordiazepam in the cat.     

Comparative effects of verapamil, diltiazem and felodipine during experimental digitalis-induced arrhythmias

We compared the abilities of three different calcium (Ca2+) entry blockers, verapamil, diltiazem and felodipine to abolish ouabain-induced ventricular ectopy (100 X ectopic/total beats, VE) in anesthetized, closed-chest dogs. Ventricular tachycardia (VT) was produced in anesthetized, bilaterally vagotomized, closed-chest dogs by an average dose of 65 +/- 19 micrograms/kg ouabain. 30 min after establishing VT, either verapamil (25-50 micrograms/kg + 5-10 micrograms/kg/min), diltiazem (50-100 micrograms/kg + 20-50 micrograms/kg/min), felodipine (3 micrograms/kg + 0.3 micrograms/kg/min) or saline was administered for another 30 min. Verapamil, at the higher dose utilized, practically abolished ouabain-induced VT (97 +/- 3 to 8 +/- 19% VE); diltiazem was moderately effective (96 +/- 4 to 50 +/- 8% ectopy) at 100 micrograms/kg, and felodipine exerted no antiarrhythmic effects in this model. All three Ca2+ entry blockers lowered mean aortic pressure, felodipine lowering this parameter most prominently. Thus, these structurally and electrophysiologically dissimilar Ca2+ entry blockers differed in their abilities to abolish the digitalis glycoside-induced arrhythmias in vivo. The superiority of verapamil may be related to its multiple, additional electrophysiologic effects.     

Theophylline antagonizes the effect of diazepam on ventricular automaticity

The effect of diazepam on ventricular automaticity induced by a local injury was investigated in the isolated right ventricle of the rat in the presence of the diazepam central antagonist, RO 15-1788, and of the adenosine antagonist, theophylline. Theophylline but not RO 15-1788 antagonized the inhibitory effect induced by diazepam on ventricular automaticity. The inhibitory effect of adenosine but not that of 2-chloroadenosine was potentiated in the presence of diazepam. The results suggest that the inhibitory effect of diazepam on ventricular automaticity results from the inhibition of adenosine uptake.     

Differential action of diazepam on flight and defense behavior in the cat

The effect of diazepam (1 mg/kg bodyweight) on flight and defense behavior has been studied in 14 feral cats. Defense behavior is reduced while there is no reduction in the flight behavior at this dosage level. The possible selectivity of this drug for particular limbic structures is discussed.Sponsored in part by the Norwegian Research Council for Science and the Humanities. The authors are indebted to Tordis Dalland, Sissel Röyem, Reidun Ursin and Knut Wester for assistance with various control procedures.     

Pharmacokinetics of diazepam and four 3-hydroxy-benzodiazepines in the cat

Biotransformation and elimination of diazepam and four 3-hydroxy-benzodiazepines after i.v. injection in anaesthetized cats were investigated. Decay of plasma concentration of 3-hydroxy-benzodiazepines was slow and plasma concentrations of their glucuronides were lower than of unchanged parent compounds. In the urine, very low excretion rates of all investigated benzodiazepines were found during the first eight hours. It is concluded that cats poorly glucuronidate 3-dydroxy-benzodiazepines.     

Effect of antiarrhythmic drugs on serum free fatty acid levels during experimental cardiac arrhythmias in the cat

The level of free fatty acid (FFA) in serum has been estimated before and after ventricular fibrillation (VF) induced by electrical stimulation, intravenous administration of ouabain, aconitine or ligation of the left anterior descending branch of coronary artery. FFA contents were found to be significantly increased after VF. Quinidine, disopyramide, lidocaine and phenoxybenzamine, when administered intravenously 30 min before electrical stimulation (E.S.), have no effect on serum FFA contents by themselves. All the antiarrhythmic drugs except phenoxybenzamine prevent the rise in FFA contents normally observed after VF. These drugs in appropriate doses also protect the animals against VF upto 100 volts. Propranolol did not provide protection against VF but prevented increase in FFA levels. Verapamil neither showed any protection against VF nor blocked the elevation of FFA after E.S. These results indicate that most of the antiarrhythmic drugs which are effective against the precipitation of VF by E.S. block the increase in serum FFA levels.     

Advances in the pharmacologic treatment of ventricular arrhythmias

Introduction: Despite many advances in nonpharmacologic management of ventricular arrhythmias, antiarrhythmic drugs remain important in both the acute conversion and chronic prevention of ventricular arrhythmias.

Areas covered: Key trials related to antiarrhythmic drug use are reviewed, emphasizing the impact of recent discoveries. Sodium channel blockers are discussed with an emphasis on recently identified specialized uses. Beta blockers, amiodarone, sotalol, and dofetilide are discussed together in the context of structural heart disease, because they do not increase mortality in this group of patients. Other medications found to reduce ventricular arrhythmia burden are discussed last.

Expert opinion: Since most patients with ventricular arrhythmias have structural heart disease, pharmacologic treatment is limited to amiodarone, d-,l-sotalol, and dofetilide (off-label indication), in conjunction with defibrillator implantation. While amiodarone has superior reduction in arrhythmias, its long-term extracardiac toxicities can cause significant morbidity. A trial of sotalol is reasonable if there are no contraindications, recognizing that over 20% of patients have to discontinue it because of adverse effects. Beta blockers are first line therapy for most patients. Genetic testing is particularly informative regarding treatment approach in long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic VT. Research should continue to focus on developing more effective antiarrhythmic medications with less long-term toxicity.     

Effect of flosequinan on ischaemia-induced arrhythmias and on ventricular cyclic nucleotide content in the anaesthetized rat.

1. Flosequinan, milrinone, isoprenaline and forskolin given intravenously at similarly hypotensive doses have been evaluated in separate studies for their effect on ischaemia-induced arrhythmias and on ventricular cyclic nucleotide content following coronary artery ligation in the pentobarbitone anaesthetized rat. 2. Flosequinan did not affect mortality or arrhythmias following coronary artery ligation in either study and no change in ventricular cyclic nucleotide content was observed. 3. Isoprenaline caused a significant increase in mortality (P < 0.05) in both studies whereas milrinone and forskolin caused a significant increase in mortality in only one of the two studies conducted. All three agents caused significant increases in cyclic AMP which were associated with increased incidence of arrhythmias. 4. When compared at similarly hypotensive doses, flosequinan, in contrast to milrinone, isoprenaline and forskolin, did not influence ischaemia-induced arrhythmias or raise ventricular cyclic nucleotide levels in the anesthetized rat.     

Toluene and benzene inhalation influences on ventricular arrhythmias in the rat

We have previously found that toluene did not share the capacity of benzene for increasing the arrhythmogenic action of epinephrine in the rat, but appeared to elicit the opposite effect. The present experiments were carried out to verify this observation in rats subjected to more severe ventricular arrhythmias. In animals previously inhaling either air, toluene or benzene and anesthetized with pentobarbital, arrhythmias were produced by coronary ligation or aconitine. In both models, toluene decreased and benzene increased the number of ectopic ventricular beats in the 30 min following induction of arrhythmia. Gas chromatographic measurement of toluene levels in the heart during and after inhalation revealed essentially constant concentrations at the time of arrhythmia evaluation, equivalent to approximately one-third the peak levels observed at the end of inhalation. Although the mechanism of the effect of toluene on arrhythmia could not be ascertained, nonspecific membrane stabilization or central serotonergic stimulation were considered as possible explanations. Since both mechanisms could be operant also in the case of benzene, the opposite effects of the solvents on arrhythmia could not be readily accounted for.     

Effect of chronic diuretics on epinephrine-induced ventricular arrhythmias: a comparison of hydrochlorothiazide and amiloride in the rat

The purpose of this study was to determine if chronic administration of the diuretics hydrochlorothiazide and amiloride alters the response to catecholamine-induced ventricular arrhythmias. The protocol consisted of four groups of Wistar rats. Group I, or control group, received daily subcutaneous injections of saline; group II received hydrochlorothiazide, 100 mg/kg/day s.c.; group III received amiloride, 0.5 or 1.0 mg/kg/day s.c.; and group IV received amiloride, 0.5 mg/kg/day, plus hydrochlorothiazide, 100 mg/kg/day. The treatment period lasted 18 days. After completion of the treatment period, under pentobarbital anesthesia, epinephrine was infused and the electrocardiogram and blood pressure recorded. Hydrochlorothiazide produced a significant (p less than 0.05) leftward shift in the dose-response relationship, that is, a smaller epinephrine concentration produced earlier onset of ventricular arrhythmias and mortality from fatal ventricular arrhythmias. Amiloride, at the higher dose, significantly (p less than 0.05) shifted to the right the dose-response relationship between epinephrine and occurrence of arrhythmias--i.e., a larger epinephrine dose was necessary to produce the same amount of arrhythmias. There were no significant differences in heart rate or blood pressure responses to epinephrine among the four groups. Serum and myocardial electrolytes were measured in a separate group of rats that did not receive epinephrine. There were no significant differences among groups for myocardial electrolytes. After hydrochlorothiazide administration, serum calcium and magnesium were decreased and bicarbonate was increased compared with the control group. In the amiloride group, only serum sodium was significantly changed, being slightly increased. This suggests that serum electrolyte levels may account for the effects of hydrochlorothiazide but do not account for the effect of amiloride.     

Effects of experimental diabetes on endothelin-induced ventricular arrhythmias in dogs

Endothelin-1 (ET-1) is known to have a direct arrhythmogenic effect in the mammalian heart. Diabetes mellitus is accompanied by a series of endothelial and cardiac disfunctions; however, little is known about ET-1-induced direct arrhythmias in diabetes mellitus. Therefore, we infused ET-1 (33 pmol/min) into the left anterior descending coronary artery of 28 mongrel dogs, and measured basic hemodynamic parameters, coronary flow and an electrocardiogram. Diabetes mellitus was induced by alloxan (Group 4) and experiments were carried out 8 weeks later. Metabolically healthy dogs served as controls (Group 2). In a further control group, local hyperglycemia was induced by intracoronary glucose infusion (Group 3). ET-1 infusion induced prolongation of the QT-time and frequency-adjusted QT-time in all groups. Other electrophysiological parameters were comparable between the groups. This was followed by the occurence of ventricular premature beats, coupled extra-beats and later sustained ventricular tachycardia. Most of the experiments were terminated by ventricular fibrillation. The onset of arrhythmias was shorter in diabetic dogs as compared with control and locally hyperglycemic animals (18 +/- 8 minutes versus 24 +/- 8 minutes and 30 +/- 28 minutes, P < 0.05). However, there was no difference in the number of ventricular fibrillations, and the total elapsed time until the termination of the experiments. Therefore, the diabetic heart seems to be more prone to ET-1-induced arrhythmias and this is probably not a result of locally high glucose concentrations.     

Minocycline attenuates ischemia-induced ventricular arrhythmias in rats

Minocycline has been shown to protect against myocardial ischemia–reperfusion injury. This study investigated the effects of minocycline on ischemia-induced ventricular arrhythmias in rats. Anesthetized male rats were once treated with minocycline (45 mg/kg, i.p.) 1 h before ischemia in the absence and/or presence of 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002, 0.3 mg/kg, i.v., a PI3K inhibitor) and 5-hydroxydecanoic acid [5-HD, 10 mg/kg, i.v., a specific inhibitor of mitochondrial ATP-sensitive potassium (K_ATP) channels] which were once injected 10 min before ischemia and then subjected to ischemia for 30 min. Ventricular arrhythmias were assessed. L-type Ca²⁺ current was measured by the patch-clamp technique. During the 30-minute ischemia, minocycline significantly reduced the incidence of ventricular fibrillation (VF) (P < 0.05). The duration of VT + VF, the number of VT + VF episodes and the severity of arrhythmias were all significantly reduced by minocycline compared to those in myocardial ischemia group (P < 0.05 for all). Administration of LY294002 or 5-HD abolished the protective effects of minocycline on VF incidence, the duration of VT + VF, the number of VT + VF episodes and the severity of arrhythmias (P < 0.05 for all). In addition, minocycline inhibited L-type Ca²⁺ currents of normal myocardial cell membrane in a dose-dependent manner. This study suggested that minocycline could attenuate ischemia-induced ventricular arrhythmias in rats in which PI3K/Akt signaling pathway, mitochondrial K_ATP channels and L-type Ca²⁺ channels may be involved_.