Effect of ajmaline on sustained ventricular tachycardia induced by programmed electrical stimulation in conscious dogs after myocardial infarction

Summary As yet the antiarrhythmic efficacy of ajmaline with regard to suppressing the induction of sustained ventricular tachycardia after myocardial infarction has not been determined. Therefore, programmed electrical stimulation was performed in 8 conscious, chronically instrumented mongrel dogs 8–20 days after a 4-hour occlusion of the left anterior descending coronary artery. At baseline all animals responded with sustained ventricular tachycardia. Thereafter, ajmaline was administered at two consecutive ix. doses: a bolus of 0.7 mg kg^–1 followed by infusion of 2 mg kg^–1 h^–1 and infusion of 4 mg kg^–1 h^–1. The induction of sustained ventricular tachycardia was prevented in 2/8 animals by 2 mg kg^–1 h^–1 ajmaline and in 1/8 animals by 4 mg kg^–1 h^–1 ajmaline. During sinus rhythm only 4 mg kg^–1 h^–1 ajmaline significantly increased QRS-duration and intraventricular activation times, but during rapid right ventricular pacing (cycle length = 330 ms) both doses of ajmaline increased QRS duration and intraventricular conduction times. 4 mg kg^–1 h^–1 ajmaline also increased the cycle length of induced sustained ventricular tachycardia. In 3 animals induction of sustained ventricular tachycardia during infusion of 4 mg kg^–1 h^–1 ajmaline was achieved by introduction of less extrastimuli than at baseline. Furthermore the coupling intervals of extrastimuli that induced sustained ventricular tachycardia were substantially prolonged by this dose. Inhomogeneity of conduction between left ventricular normal zone and left ventricular infarct zone was significantly increased by 4 mg kg^–1 h^–1 ajmaline during rapid right ventricular pacing, but not during sinus rhythm.We conclude that ajmaline has only limited efficacy with regard to the prevention of induction of sustained ventricular tachycardia after myocardial infarction. Drug-induced increases in tachycardia cycle lengths, as observed under the higher dose of ajmaline, were associated with a rate-dependent rise in cardiac electrical instability. Correspondence to H. Todt at the above address     

Efficacy of epicardial controlled-release lidocaine for ventricular tachycardia induced by rapid ventricular pacing in dogs.

The effects of epicardial lidocaine on ventricular tachycardia (VT) induced by rapid ventricular pacing (50 Hz) were studied in dogs. Lidocaine-polyurethane (28% wt/wt) matrixes (40-50 mg, 5 x 5 mm) were placed proximal to bipolar left ventricular epicardial electrodes in open-chest anesthetized dogs (n = 9) after VT was established by rapid ventricular pacing. In the first set of experiments, matrices were removed immediately after VT had converted to sinus rhythm. Control animals underwent VT induction protocol with a nondrug-containing matrix positioned next to the epicardial electrode. In the lidocaine-treated animals, VT conversion was noted in all animals and occurred after 51.7 +/- 8.9 s (mean +/- SE), with a VT threshold current elevation of 73.5 +/- 11.2% above baseline at the time of conversion which progressed to 259 +/- 44% of the initial value by 5.4 +/- 0.5 min post-matrix placement. Lidocaine 1.4 +/- 0.1 mg was delivered to the myocardium at the time of VT conversion (0.11 +/- 0.01 mg/kg). In comparison, accelerated VT persisted for 5 min in three of five control animals, and progressed to ventricular fibrillation (VF) in the other two animals. In a separate series of eight dogs, the lidocaine-polyurethane matrixes were left in palce for 4 h so that we could study the sustained antiarrhythmic action of controlled-release lidocaine on VT induction. The results of these experiments demonstrated a maintenance of the VT threshold elevation at a level of 53.9 +/- 10.8% after 4 h, with a net lidocaine dose of 0.52 +/- 0.06 mg/kg after 4 h of controlled release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of amitriptyline on left ventricular function in conscious dogs

Amitriptyline (Am) is a frequently prescribed tricyclic antidepressant drug associated with an increased risk of sudden death that has been presumed to be arrhythmia related. Little has been known about the effects of Am on left ventricular function. We studied i.v. Am (0.5, 1.0, and 1.5 mg/kg) in 10 conscious, resting, chronically instrumented dogs. Heart rate (HR) increased up to 70%; this increase was only partially prevented by propranolol. Left ventricular end diastolic pressure (LVEDP) decreased without, but not with, propranolol. Mean arterial pressure (MAP) increased by 10-13% transiently. The maximum rate of rise of left ventricular pressure (dP/dtmax) decreased by 16-18% without propranolol and by 14-29% with propranolol, indicating a moderate decrease in myocardial contractility. Changes in stroke volume were similar to changes in dP/dt. Thus, i.v. Am, at levels similar to therapeutic blood levels, causes a moderate depression of myocardial contractility, which is accentuated by propranolol. Tricyclic antidepressants, therefore, could have adverse effects on cardiac performance in patients with underlying myocardial dysfunction.     

A comparison of changes in atropine-induced tachycardia and atropine concentration in conscious dogs

In the conscious dog, after intravenous injection of 0.2 mg/kg 3H-labelled atropine the progressive decrease of the heart rate was well correlated with the disappearance of atropine from the blood. But, with atropine infusion (0.2 mg/kg/h) the tachycardia decreased progressively in spite of an increase in the blood concentration of atropine. Differences appeared between the normal animals or those pretreated with propranolol or reserpine, and the animals which had undergone bilateral thoracic sympathectomy. In the stellectomized animals atropine induced a smaller but much more lasting cardiac acceleration than under the other experimental conditions. It seems that only peripheral factors are involved in the complex interactions between the adrenergic and cholinergic nervous systems at the sinus node level.     

Nicardipine causes sympathetic activation that does not involve baroreceptor reflex tachycardia in conscious sinoaortic-denervated dogs

Nicardipine-induced tachycardia is generally attributed to the involvement of the baroreflex. The effects of nicardipine on blood pressure (BP) and heart rate (HR) as well as on plasma catecholamine levels were studied in six conscious dogs made hypertensive by sinoaortic denervation. Nicardipine (50, 100 and 200 micrograms/kg i.v.) induced both a significant decrease in mean BP and a marked increase in HR in these dogs whereas the catecholamines rose significantly. Nicardipine-induced tachycardia cannot be explained by a baroreflex mechanism only. It is suggested that nicardipine induces an increase in HR and sympathetic tone, probably by a direct action on central cardiovascular mechanisms.     

Suppression of reflex tachycardia following alpha-adrenoceptor blockade in conscious dogs: comparison of urapidil with prazosin

The effects of the alpha-adrenoceptor antagonists urapidil and prazosin were compared as to their ability to suppress or enhance baroreceptor-induced reflex changes in heart rate in conscious dogs. Bradykinin was injected as an intravenous bolus to elicit a vasodepressor response and reflex tachycardia, and angiotensin II was utilized to produce opposite effects via baroreceptor activation. Urapidil, which is an alpha 1- and alpha 2-antagonist, was infused intravenously at 2 and 5 mg/kg, and suppressed reflex tachycardia elicited by bradykinin at both dose levels. The suppression of reflex tachycardia elicited by bradykinin was not evident with intravenous prazosin (0.25 and 0.625 mg/kg), an alpha 1-antagonist. Reflex bradycardia elicited by angiotensin was not affected by urapidil but was enhanced by prazosin. Therefore, urapidil may have a selective effect in suppressing cardiac sympathetic reflexes with no apparent effect on vagal reflexes. Both urapidil and prazosin produced similar decreases in arterial blood pressure with no long-term effects on heart rate, and the degree of alpha-receptor postjunctional blockade by both agents was judged to be equivalent, as determined by intravenous phenylephrine injection. The suppression of reflex tachycardia by urapidil could be eliminated by guanethidine pretreatment, indicating that a cardiosympathoinhibitory effect by urapidil was involved.     

Worsening of ventricular tachycardia by amiodarone

The details of worsening of ventricular tachycardia in 8 (4.1%) of 194 patients receiving treatment with amiodarone are reported. Two forms of amiodarone-induced tachycardia were recognized: first, the development of new tachycardias (three patients) and second, a change in the pattern of recurrence of clinical tachycardia (five patients). In retrospect, the time from the initiation of amiodarone to the initial documentation of worsening ranged from 1 to 23 days (mean +/- SD, 9.4 +/- 8.2 days) and the time from the initiation of therapy to the recognition of worsening ranged from 6 to 26 days (14.6 +/- 10.1 days). Seven patients survived the worsening of tachycardia and one died. The total dose of amiodarone received and the duration of administration did not correlate with time to manifestation or time to resolution of worsening. This report emphasizes that worsening of ventricular tachycardia as a result of amiodarone is often difficult to differentiate from inadequate drug loading or early recurrence of 2 patient's clinical tachycardia. Further, because of the pharmacokinetics of the drug, the manifestations of worsening may be prolonged. In the cases reported, it ranged from 2 to 26 days (7.9 +/- 8.3 days), which is longer than previously reported. Because of the potential for amiodarone to cause life-threatening worsening of ventricular tachycardia and in accordance with current results, a period of in-hospital monitoring of at least 10 days at the start of therapy with amiodarone is recommended.     

Excretion and metabolism of flunarizine in rats and dogs

The excretion and metabolism of (E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl)piperazine dihydrochloride (flunarizine hydrochloride, R 14 950, Sibelium) were studied after single oral doses in rats and dogs, using tritium-labelled as well as 14C-labelled drug. Flunarizine was well absorbed in both species. The mass balance for the unchanged drug and its major metabolites in urine, bile and faeces, as estimated with radio-HPLC, ALLOWED an explanation of the differences observed for the excretion pattern of the radioactivity in flunarizine-14C and flunarizine-3H dosed rats, and in male and female rats. Main metabolic pathway in male rats was the oxidative N-dealkylation resulting in bis(4-fluorophenyl)methanol and a number of complementary metabolites of the cinnamylpiperazine moiety, of which hippuric acid was the main one. In female rats and male dogs, however, hydroxy-flunarizine was the main metabolite, resulting from the aromatic hydroxylation of the phenyl ring of the cinnamyl moiety. Enterohepatic circulation of bis(4-fluorophenyl)methanol and hydroxy-flunarizine was proved by "donor-acceptor" coupling in rats; in bile and urine, these two metabolites were present mainly as glucuronides. The glucuronide of hydroxy-flunarizine was also the main plasma metabolite in dogs.     

Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs

Summary The aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 g/kg/min (i.v.). During 80 g/kg/min lidocaine (mean plasma level 3.5 g/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 g/kg/min and 4 of 8 to 120 g/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p<0.05), 67.7 ms (p<0.05), 70.0 ms (p<0.01) respectively.In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting. Send offprint requests to K. Krejcy at the above address     

Eugenol delays the onset of ouabain-induced ventricular cardiac arrhythmias in guinea pigs

Eugenol is an aromatic compound used in the manufacture of medicines, perfumes, cosmetics and as an anaesthetic due to the ability of the drug to block the neuronal isoform of voltage-gated Na⁺ channels (Na_V). Some arrhythmias are associated with gain of function in the sodium current (I_Na) found in cardiomyocytes, and antiarrhythmic sodium channel blockers are commonly used in the clinical practice. This study sought to elucidate the potential mechanisms of eugenol's protection in the arrhythmic model of ouabain-induced arrhythmias in guinea pig heart. Ex vivo arrhythmias were induced using 50 μM of ouabain. The antiarrhythmic properties of eugenol were evaluated in the ex vivo heart preparation and isolated ventricular cardiomyocytes. The compound's effects on cardiac sodium current and action potential using the patch-clamp technique were evaluated. In all, eugenol decreased the ex vivo cardiac arrhythmias induced by ouabain. Furthermore, eugenol showed concentration dependent effect upon peak I_Na, left-shifted the stationary inactivation curve and delayed the recovery from inactivation of the I_Na. All these aspects are considered to be antiarrhythmic. Our findings demonstrate that eugenol has antiarrhythmic activity, which may be partially explained by the ability of eugenol to change de biophysical properties of I_Na of cardiomyocytes.     

Lack of protection of ischemic myocardium by verapamil in conscious dogs

To determine whether coronary dilation and decreased myocardial oxygen requirements resulting from administration of verapamil, a calcium and slow current antagonist, protect ischemic myocardium in conscious dogs, we studied 15 treated and 15 control animals after coronary occlusion. Verapamil (0.2–0.7 mg/kg/h) was given by continoous infusion for 17 h beginning 5 h after the initial plasma creatine kinase (CK) elevation after coronary occlusion. Observed infarct size and infarct size predicted before verapamil were estimated from hourly plasma CK values and infarct size was estimated also from myocardial CK depletion measured directly, 24 h after occlusion. Changes in heart rate, blood pressure, and frequency of premature ventricular complexes (recorded every 30 min) after occlusion were similar in treated and control dogs. Coronary flow after verapamil, measured with radioactively labeled microspheres, did not increase in ischemic zones but increased by 90% in normal myocardium (p < 0.05). The differences between observed and predicted infarct size estimated from plasma CK changes in treated and controls were similar (3.0±2.2 (S.E.) and 2.0±1.4 CK-g-eq), and myocardial CK depletion was also comparable in the two groups (25 ± 2% and 23 ±2%). Thus although verapamil, administered five hours after the initial plasma CK elevation, increased coronary flow in normal myocardium, it did not augment flow in ischemic tissue or limit the extent of infarction.     

Blunted central bromocriptine-induced tachycardia in conscious,malnourished rats

Bromocriptine-induced tachycardia, persisting after adrenalectomy, is mediated by central dopamine D2 receptor stimulation through activation of the sympathetic outflow to the heart. The present study investigated the effects of malnutrition during pregnancy on bromocriptine-induced tachycardia in adult conscious rats. Malnourished rats were obtained by feeding dams a multideficient diet (providing 8% protein) during mating and pregnancy. Birth weight was significantly reduced in malnourished rats when compared to control rats born to dams fed standard commercially diet (23% protein) during mating and pregnancy. Baseline mean aortic pressure and heart rate in malnourished rats were comparable to those of well-nourished rats. Tachycardia (33+/-9 beats/min.), but not the hypotensive response to intravenous bromocriptine (150 microg/kg) was significantly reduced in malnourished rats, compared with control rats (70+/-10 beats/min.). In malnourished rats, pretreatment with intravenous domperidone (500 microg/kg) blocked the bromocriptine-induced hypotension, without affecting the tachycardia. Neither cardiac vagal (40+/-6 beats/min.) nor sympathetic tone (76+/-6 beats/min.) was significantly altered by multideficient diet-induced malnutrition (51+/-6 and 67+/-10 beats/min., respectively). In isolated perfused heart preparations from malnourished rats, positive inotropic response to isoproterenol (10-8 to 10-4 M) was not significantly different compared to that in control rats. In summary, malnutrition during foetal life blunted the bromocriptine-induced tachycardia, an effect that could be related to central dopamine D2 receptor desensitization rather than to impairment of autonomic regulation of the heart or cardiac beta-adrenoceptor desensitization.     

特发性室性心动过速伴发心律失常的临床分析

目的 分析特发性室性心动过速(室速)伴发心律失常的临床特点和体表心电图特征,以及药物终止心动过速中出现的心律失常特征.方法 收集特发性室性心动过速16例患者的临床资料进行回顾性分析,并对典型患者的临床特点和心电图资料结合文献进行分析.结果 16例患者中右心室室速6例,左心室室速8例,左心室游离后壁近心尖部2例.室性心动过速的心电图特点:室速发作的频率为125～250次/min,波动范围较大,右心室流出道室速额面QRS波平均心电轴为+(81.86±26.08)°,左心室后间隔室速额面QRS波平均心电轴为-(89.25±40.37)°.特发性室性心动过速可伴发窦性和房性心律失常,在应用药物终止心动过速时可出现窦房抑制,继而出现逸搏,逸搏心律,心房扑动和逸搏反复搏动各1例,3例有电张调整性T波改变.结论 特发性室速伴其他心律失常虽较少见,但在药物终止过程中可出现一过性心律失常,应重视心电监护并及时描记心电图,并及时做相应处理.     

Effects in conscious dogs of ajmaline,propranolol, amiodarone and verapamil on right ventricular anodal strength-interval curves

We studied the effect of antiarrhythmic drugs on the right ventricular anodal strenth-interval curve in the conscious dog. The anodal strenth-interval curve differs from its cathodal homologue by a shorter refractory period, a higher late diastolic threshold and the existence of a dip corresponding to a period of rhythmic vulnerability. The dogs were equipped with permanent ventricular electrodes; the heart was driven at a constant frequency by left ventricular stimulation and the anodal extra-stimulus was delivered on the right ventricle. This technique allowed us to determine the variations in the effective refractory period, the interventricular conduction (IVC) and the specific curve thresholds (late diastolic threshold, LDT, minimal dip level, Sm, maximal post dip threshold, SM). Ajmaline, a quinidine-like drug, significantly increased IVC and all the thresholds. Only high doses lengthened the effective refractory period. Propranolol, a β-blocking agent significantly increased Sm. The intrinsic effect of amiodarone, a non-specific anti-adrenergic drug and a potent anti-anginal substance seemed to result in a significant increase in LDT, Sm, SM. Verapamil, a calcium antagonist only caused a significant increase in SM. Therefore, each of the four drugs studied, belonging to a different group of teh Vaughan Williams classification, acted in a different way on the anodal strengh-interval curve. This study clarified the mechanisms by which these drugs exert their antiarrhythmic effect.