Properties of acebutolol in twenty patients with cardiac arrhythmias

Summary Acebutolol (M & B 17,803 A), a new cardioselective beta-adrenergic blocking agent, was given intravenously to 20 selected patients with various cardiac arrhythmias. Cumulative doses ranging from 12.5 to 50 mg were moderately or highly effective in 4 out of 4 patients with sinus tachycardia, 2 out of 3 patients with premature atrial beats, 3 out of 4 patients with premature ventricular beats, 3 out of 5 patients with atrial fibrillation (one was converted to sinus rhythm) and in 2 out of 3 patients with atrial flutter. The drug was ineffective in one patient with atrial tachycardia. Mild systolic hypotension occured in two patients with recent myocardial infarction and there was some aggravation of a preexisting bronchospasm in a patient with congestive heart failure secondary to hyperthyroidism. It was concluded that acebutolol is a cardioselective beta-blocker which by intravenous route may be useful in the treatment of selected cardiac arrhythmias.     

Efficacy of cardioselective beta-adrenergic blockade with intravenously administered metoprolol in the treatment of supraventricular tachyarrhythmias

The efficacy of intravenously administered metoprolol, a cardioselective beta-adrenergic blocking agent, was evaluated in the treatment of supraventricular tachyarrhythmias in 16 patients. The arrhythmias that were treated were atrial fibrillation (11 patients), atrial flutter (2 patients), supraventricular tachycardia (2 patients), and multifocal atrial tachycardia (1 patient). Mean dose of metoprolol was 9.5 mg (range: 2-15 mg) administered in one or two separate infusions of up to 7.5 mg each over a cumulative maximum interval of 25 minutes. In the 13 responders (81%), mean ventricular rate decreased from 134 +/- 6 to 106 +/- 7 beats/min 10 minutes after metoprolol administration and was controlled for 40 to 320 minutes without further therapy. Minimum ventricular rate (98 +/- 6 beats/min) was reached 48 minutes after initiation of metoprolol. Metoprolol reduced ventricular rate by greater than 15% (decrease of 26-60 beats/min) in 11 (69%) of 16 patients, including 9 (82%) of 11 patients with atrial fibrillation. In two other patients, one with atrial fibrillation and one with supraventricular tachycardia, ventricular rate was reduced by greater than 12%. Hypotension, occurring in five patients, was the most frequent side effect but was transient and readily managed. Cardioselective beta-adrenergic blockade by metoprolol was rapidly effective in controlling ventricular rate in a majority of patients with supraventricular tachyarrhythmias and may be of particular use in selected patients with chronic obstructive pulmonary disease in whom intravenous beta-adrenergic blockade is indicated. Hypotension is an important potential side effect.     

Influence of halothane and catecholamines on heart rate and rhythm in the horse

1. Ventricular ectopic beats were recorded in eight of thirteen conscious horses following the intravenous administration of adrenaline in doses of 3 mug/kg. Following pre-treatment with either atropine sulphate (0.1 mg/kg) or propranolol hydrochloride (0.1 mg/kg), the same dose level of adrenaline failed to produce ventricular ectopic beats.2. Halothane anaesthesia sensitized the equine heart to the arrhythmogenic actions of adrenaline; the incidence and duration of ventricular arrhythmias being greater than in conscious animals. In comparison with the findings in conscious horses, ether anaesthesia appeared to protect the heart against adrenaline-induced arrhythmias.3. From a comparison of the arrhythmogenic, chronotropic and pressor actions of adrenaline, noradrenaline and isoprenaline during halothane anaesthesia, it was concluded that sensitization to the arrhythmogenic actions of catecholamines resulted primarily from the action of halothane on the ventricle. The results also indicated that the pressor responses to catecholamines during halothane anaesthesia probably played some part in the genesis of arrhythmias.4. No "spontaneous" ventricular arrhythmias were recorded in twenty-four horses anaesthetized with halothane or in sixteen animals under ether anaesthesia.5. The available evidence indicates that a moderate to fairly severe degree of hypercapnia produced little increase in sympathetic control of the myocardium during halothane anaesthesia; the absence of irregularities in ventricular rhythm during halothane anaesthesia were attributed to this factor.     

Electrophysiological actions of amrinone in dogs with cardiac lesions

We examined the actions of amrinone in five models using dogs to determine under what circumstances intravenous amrinone might exert arrhythmogenic or antiarrhythmic properties. In dogs with 24-h post-coronary artery ligation arrhythmias, amrinone, given at incrementally increasing doses of 1.5, 3.0, and 6.0 mg/kg at 30-min intervals, produced significant increases of cardiac contractility without altering the severity of the arrhythmia. In dogs with 2- to 6-day-old ischemic lesions and 90-100% sinus beats, a bolus dose of 3.0 mg/kg amrinone was followed by an increased incidence of abnormal beats (p = 0.013); neither 1.5 nor 6.0 mg/kg caused a significant incidence of arrhythmias. Acute occlusion of the left anterior descending coronary artery followed by reperfusion caused fibrillation in nine of 15 control dogs and two of 14 dogs treated with 2.3 mg/kg amrinone. This difference was significant at the level p less than 0.05. In ouabain-intoxicated dogs, amrinone at 1.0 and 3.0 mg/kg neither worsened nor improved the arrhythmias. In the atrial circus flutter arrhythmia, amrinone increased ventricular heart rate by a significantly greater amount than it increased atrial rate, suggesting that amrinone facilitates atrioventricular conduction.     

Effects of the phenothiazine analog,EN-313, on ventricular arrhythmias in the dog

Effects of the phenothiazine analog, EN-313, on ventricular electrical activity were studied using isolated blood-superfused canine Purkinje fibers and conscious dogs with sustained ventricular arrhythmias following a 2-stage ligation of the left anterior descending coronary artery. EN-313, < 3 mg/kg, i.v., had no significant effect on transmembrane potentials of Purkinje fibers. At 3 mg/kg, EN-313 significantly decreased maximum upstroke velocity of phase 0 depolarization and action potential duration. In conscious dogs, EN-313 (1–3 mg/kg i.v.; 10–20 mg/kg p.o.) reduced arrhythmias that occurred ? 24 h after coronary artery ligation. No excessive changes in electrocardiographic parameters were observed following EN-313. These studies demonstrate that EN-313 suppresses ventricular arrhythias in doses which have little effect on cellular electrophysiologic properties of normal Purkinje fibers and suggest that EN-313 should be useful in treating cardiac arrhythmias arising as a result of coronary occlusion.     

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.     

The treatment of cardiac arrhythmias with sotalol

Summary Sotalol, at a fixed dose of 20 mg was given intravenously to 34 patients with cardiac arrhythmias of varying aetiology. It was effective in the treatment of supraventricular tachycardias, acute onset atrial and ventricular ectopics and acute onset atrial fibrillation. In chronic arrhythmias sinus rhythm was not restored, but in 77% there was slowing of the cardiac rate. Side effects were seen in only one patient who developed moderate bronchospasm.     

二(二甲氨基)-二苯甲烷的抗心律失常作用

碘杂环化合物(IHC-64,IHC-65,IHC-66)有抗心律失常、降血压,并表现钙拮抗效应。4,4′-二(二甲氨基)-二苯甲烷[4,4′-bis(dimethyl amino)-diphenyl methane,BDDM]是合成碘杂环化合物的前体物,与抗心律失常药利多卡因、安博律定(aprindine)等在化学结构上有相近之处,如苯环和碱性氨基。本实验观察了碘杂环前体物BDDM的抗实验性心律失常作用。并进一步探讨本系列合成物的构效关系。     

The effect of reserpine on the pressor responses to angiotensin in the conscious cat

1. Blood pressure recordings have been made in conscious cats in an attempt to reveal a possible indirect component to the angiotensin pressor response.2. Reserpine (50 to 250 mug/kg per day) caused a maximal reduction of about 50% in the pressor response to angiotensin whilst virtually abolishing the responses to tyramine and McN-A-343. Responses to noradrenaline were only slightly and transiently reduced.3. Syrosingopine (0.5 mg/kg) and reserpine (250 mug/kg) reduced the responses to angiotensin, McN-A-343 and tyramine to much the same extent, but tetrabenazine only reduced the responses to all these agents in a dose (25 mg/kg) which probably had effects on the catecholamine stores of smooth muscle.4. The reduction in the responses to angiotensin, tyramine and McN-A-343 by reserpine was partly reversed by tranylcypromine. Noradrenaline and (+/-)-dopa infusions were ineffective by themselves, but increased the effects of tranylcypromine in restoring the responses to angiotensin, tyramine and McN-A-343 after reserpine.5. Infusion of alpha-methyldopa markedly increased the responses to angiotensin, tyramine and McN-A-343 after these had been reduced by reserpine.6. The results suggest that the pressor response to angiotensin in the conscious cat is partly mediated by release of noradrenaline from peripheral neuronal stores.     

Effect of alinidine on experimental cardiac arrhythmias

Alinidine (2.9 +/- 0.7 mg/kg) prevented an adrenaline-induced ventricular arrhythmia in dogs respired with halothane. In ouabain-induced ventricular tachycardia, a cumulative dose of alinidine (15.5 mg/kg) reduced the number of ventricular beats by 91.6 +/- 1.9%. The drug was much less effective in abolishing the ventricular tachycardia 24 h after ligation of a coronary artery, with only a 36 +/- 15% reduction in ventricular ectopic beats after 15.5 mg/kg. The administration of alinidine (0.5-1.0 mg/kg) to anaesthetized dogs with no cardiac arrhythmia reduced sinus node rate with little effect on the response of the node to vagal stimulation.     

碘杂环化合物的抗心律失常作用

碘杂环-64能防治乌头碱、氯化钡和结扎冠状动脉诱发的大鼠心律失常,推迟肾上腺素—氯仿诱发家兔心律失常的发作和缩短心律失常持续期,提高哇巴因诱发豚鼠心律失常的剂量,显著降低乙酰胆碱(Ach)—氯化钙诱发小鼠房颤(扑)的发生率。碘杂环-64减慢心率与迷走神经兴奋和β受体阻滞无关。     

Electrocardiographic effects of intravenous cocaine: an experimental study in a canine model

Cocaine abuse causes cardiac dysfunction. Acute intravenous administration of cocaine may lead to development of severe arrhythmias, conduction abnormalities, ST-T changes, and sudden death. Understanding arrhythmogenesis due to cocaine may provide a therapeutic approach to reduce morbidity and mortality. We studied the arrhythmogenic activity and other electrocardiographic abnormalities resulting from an intravenous bolus of cocaine. Baseline and postanesthetic electrocardiographic findings were compared with those after administration of intravenous bolus of various doses of cocaine hydrochloride in 20 dogs. The study was done in three phases (phase I: low dose of cocaine [1 mg/kg, 15 experiments]; phase II: medium dose [2 mg/kg, 30 experiments]; and phase III: high dose [5-7 mg/kg, 10 experiments]). Plasma levels of cocaine were estimated. The low dose induced sinus bradycardia, sinus arrhythmia, atrial ectopic, wandering pacemaker, unifocal ventricular premature contractions, and ventricular couplets. The medium dose generated moderately severe arrhythmias that were of supraventricular origin. Atrial flutter and atrial fibrillation were observed in two experiments each. Ventricular arrhythmias were manifested as unifocal, multifocal, interpolated ventricular premature contractions as well as bigeminy, trigeminy, couplets, and salvos. The high dose of 5-7 mg/kg increased electrocardiographic intervals and caused ST-segment elevation as well as serious life-threatening arrhythmias. Three of the dogs developed sustained ventricular tachycardia followed by ventricular flutter-fibrillation and death.     

Effects of lidocaine, disopyramide and verapamil on the in vivo triggered ventricular arrhythmia in digitalized canine heart

Triggered activity due to delayed after depolarization has been postulated to be one of the generation mechanisms of some arrhythmias, especially that due to digitalis toxicity. The present experiment demonstrates an in vivo canine model of ventricular arrhythmias that were triggered by ventricular stimulation during administration of low doses of ouabain. Ventricular ectopic beats could be induced by stimulation before the occurrence of spontaneous ventricular arrhythmia, and the coupling interval of the first ectopic beat was shortened as the stimulation rate increased. Verapamil (0.2 mg/kg, i.v.) was ineffective in suppressing the occurrence of the triggered ventricular ectopic beats, but lidocaine (1 and 3 mg/kg, i.v.) and disopyramide (0.3 and 1 mg/kg, i.v.) were effective in suppressing these digitalis-induced triggered ventricular ectopic beats in a dose-dependent fashion.     

Effects of cromakalim, pinacidil and nicorandil on cardiac refractoriness and arterial pressure in open-chest dogs

The cardiac electrophysiologic effects of the potassium channel activators cromakalim, pinacidil and nicorandil were determined in anesthetized open-chest normotensive dogs using conventional surface electrogram recording techniques. Intravenous administration of cromakalim (0.025-0.5 mg/kg), pinacidil (0.1-2.0 mg/kg) and nicorandil (0.1-2.5 mg/kg) produced large dose-dependent decreases in arterial blood pressure accompanied by smaller reductions of atrial and ventricular effective refractory periods. The shortening of refractoriness was more pronounced in the atrium than in the ventricle and was similar for all three compounds at a given level of hypotension. Effects on other electrophysiological parameters were minimal. Atrial arrhythmias could be induced during electrical pacing at doses of cromakalim and pinacidil producing excessive (greater than or equal to 40%) decreases in mean arterial pressure. No arrhythmias were observed with nicorandil. Induction of the arrhythmias appeared to be closely coupled to the extrastimuli (S2) used to determine refractory periods and was associated with a significant reduction in atrial refractory period (greater than or equal to 30%). No ventricular arrhythmias were observed in this study with any of the compounds tested. Although the plasma levels reached in this study are likely to be higher than those seen clinically, the results nevertheless suggest the potential for cardiac electrophysiologic effects by these agents.     

Ranbezolid, a novel oxazolidinone antibacterial: in vivo characterisation of monoamine oxidase inhibitory potential in conscious rats

Ranbezolid, a novel oxazolidinone antibacterial, competitively inhibits monoamine oxidase-A (MAO-A), in vitro. The consequences of MAO-A inhibition was evaluated in vivo, by testing interaction of Ranbezolid with tyramine (in solution or mixed with feed), and amine containing cold remedies on pressor response in conscious rats. Single and repeat doses of Ranbezolid (50 mg/kg, p.o.) did not affect pressor response to tyramine (5 or 15 mg/kg), but potentiated the same after a single dose of 100 mg/kg. Co-administration of Ranbezolid with tyramine in feed or with cold remedies also did not potentiate the respective pressor responses. These results suggest that Ranbezolid exhibits minimal cardiovascular liability associated with MAO-A inhibition.     

Cardiovascular effects of acebutolol following coronary artery occlusion and reperfusion in anaesthetized dog.

1 The effects of 5 mg/kg acebutolol given intravenously were investigated in anaesthetized dogs after (a) ligation of the left anterior descending coronary artery and (b) coronary reperfusion following 60 min of ligation of the anterior descending coronary artery. 2 Coronary artery ligation produced, after 4 to 6 h, persistent multiple ventricular ectopic beats and abnormalities of R and T waves and of the S-T segment. Administration of acebutolol, after the development of persistent ventricular arrhythmias, restored normal sinus rhythm within 5 min of injection. Electrocardiographic abnormalities were also reduced. 3 Coronary artery reperfusion (following 60 min of ligation) resulted in multiple ventricular ectopic beats, ventricular tachycardia and/or ventricular fibrillation. Pretreatment with acebutolol, 15 min before starting reperfusion, markedly reduced the arrhythmias. 4 Acebutolol did not affect peak inspiratory airway pressure. 5 Acebutolol produced significant bradycardia and slight, transient, hypotension. It was without effect on left ventricular systolic pressure, left ventricular end-diastolic pressure, cardiac output or pulmonary arterial pressure. 6 These results suggest beneficial effects of acebutolol in myocardial ischaemia and coronary reperfusion, without any significant risk of cardiodepression or bronchospasm.     

Studies on the anti-arrhythmic effect of dextro-alprenolol

Summary The anti-arrhythmic properties of the dextro-isomer of the beta-blocking agent alprenolol have been investigated in 15 patients with different cardiac arrhythmias. The frequency of extrasystoles and other arrhythmias has been expressed quantitatively by counting the total number of arrhythmic episodes from continuous ECG-recordings on magnetic tape. The drug was given as single i.v. injections of 30 mg to 150 mg, or, as i.v. infusions of 0.5 to 3.5 mg/min. After d-alprenolol there was a mean reduction of 95% in the frequency of ventricular extrasystoles in all six patients with this type of arrhythmia. In five of the six patients with atrial fibrillation, the ventricular rate fell considerably, and one of the patients regained sinus rhythm. In six patients with paroxysmal ventricular and supraventricular tachycardias, the arrhythmic attacks were prevented by d-alprenolol. In two cases repeated episodes of ventricular fibrillation were suppressed by d-alprenolol. The drug produced a fall in systolic blood pressure in all patients, ranging from 5% to 46%. Three patients with acute myocardial infarction had symptoms of clinical shock, which disappeared during treatment with i.v. infusion of noradrenaline.     

Relationship between an arrhythmogenic action of lidocaine and its effects on excitation patterns in acutely ischemic porcine myocardium

To investigate the relationship between the effects of lidocaine on excitation patterns and its effects on the incidence of arrhythmias, the left anterior descending coronary artery was occluded for 6-min periods separated by 30 min of reperfusion, under control conditions and after injection of lidocaine, at a dose of either 2.5, 5.0, or 10.0 mg/kg i.v., in 29 open-chest anesthetized pigs. Sixty-three unipolar electrograms and a surface lead electrocardiogram were continuously recorded during atrial pacing and spontaneous ventricular arrhythmias. Ventricular fibrillation (VF) occurred only in four of a total of 45 control occlusions. VF occurred in two of five pigs following injection of lidocaine 2.5 mg/kg, in 15 or 17 pigs following injection of a 5 mg/kg dose, and in all three preparations following injection of a 10 mg/kg dose. Just prior to VF during occlusions preceded by injections of lidocaine 5 mg/kg, activation time of ischemic myocardium in atrial-paced beats was delayed by only 30 +/- 17 ms beyond preocclusion values, compared with 18 +/- 11 ms at a similar time during control occlusions and 33 +/- 18 ms at the end of control occlusions (mean +/- SD; n = 8). As ventricular tachycardia (VT) developed in the presence of lidocaine, conduction was further slowed or blocked in ischemic areas, and slowed in nonischemic regions; at the transition from VT to VF, excitation patterns displayed circus movement involving nonischemic regions.     

Effects of ergotamine on cardiovascular catecholamine receptors in the pithed rat

1. Ergotamine (3-10 micrograms/kg) inhibited the electrical stimulation-induced pressor and cardiac responses without modifying pressor responses of noradrenaline and tyramine in the pithed rat. 2. Yohimbine (0.3 mg/kg) partially prevented the ergotamine cardiac and vascular inhibitory effects but sulpiride (0.3 mg/kg) only prevented it at vascular level. Both antagonists together abolished the ergotamine inhibition of electrical stimulation-induced pressor responses. 3. The cumulative dose-response curve of ergotamine (1-100 micrograms/kg) vasoconstrictor effects was partially inhibited to the same extent by prazosin (1 mg/kg) and yohimbine (0.3 mg/kg). A greater inhibition was observed with both antagonists administered together. 4. Ergotamine (30 micrograms/kg), in presence of yohimbine, inhibited the pressor responses of methoxamine, without any effect on xylazine pressor responses. 5. These data indicate that ergotamine acts as an agonist of both the presynaptic dopamine receptors and alpha 2-adrenoceptors, of alpha 1 and alpha 2-postsynaptic adrenoceptors, and also as an antagonist of the postsynaptic alpha 1-adrenoceptors.     

烟浪丁的抗心律失常作用

NICO 100 mg/kg iv,可明显对抗乌头碱和BaCl₂诱发大鼠及氯仿-肾上腺素引起兔的心律失常;降低CaCl₂所致的大鼠室颤率;提高豚鼠心脏哇巴因中毒时的耐量。50 mg/kg iv,也可预防结扎大鼠左冠状动脉引起的心律失常。50～100 mg/kg ip,能降低氯仿或ACh—CaCl₂引起的小鼠室颤率或房颤(扑)率。NICO可减慢豚鼠心率,且可拮抗异丙肾上腺素的正性变率作用。