Effects Of Bretylium Research Articles

Bretylium decreases and verapamil increases defibrillation threshold in pigs.

Patients with ischemic heart disease may require antianginal and/or antiarrhythmic regimes. These patients may also be candidates for implantable defibrillators. The effects of antiarrhythmics, such as bretylium, or calcium antagonists, such as verapamil, nifedipine, or diltiazem on internal defibrillation efficacy have been inconsistent or are unknown. The effects of bretylium and verapamil on the energy requirements for ventricular defibrillation threshold (DFT) were determined in 92 open-chest anesthetized pigs. Triplicate DFTs were determined before and after intravenous administration of saline or one of four doses of verapamil, or saline or one of three doses of bretylium, in a balanced random order. Bretylium elicited a dose dependent reduction of DFT (F = 2.72 at 3 degrees and 36 degrees of freedom). DFT was significantly reduced with the highest dose of bretylium, (from 5.9 +/- 0.6 J to 4.7 +/- 0.6 J, mean +/- S.E.M.; P < 0.01). However, cardiac massage was sometimes needed at this dose due to low blood pressure immediately after defibrillation. In contrast, there was a positive correlation between DFT and serum verapamil concentration (r = 0.54, P < 0.001). The highest dose of verapamil significantly increased DFT (from 6.3 +/- 0.6 J to 8.2 +/- 1.1 J; P < 0.05), at a serum verapamil concentration of 86.6 +/- 6.8 ng/mL. These data indicate that bretylium decreases while verapamil increases the minimum energy requirement for internal defibrillation. Caution is warranted in patients who may be hemodynamically comprised and may be candidates for bretylium therapy or in patients who have marginal DFT value who might be candidates for verapamil therapy.

Interaction of bretylium tosylate with guinea-pig myocardial Na +−K +-ATPase

1. 1. The effects of bretylium on myocardial Mg 2+-dependent, Na +−K +-ATPase (EC 3.6.1.3) activity were compared with those of ouabain in guinea-pig heart preparations. 2. 2. Both ouabain and bretylium inhibited microsomal Na +−K +-ATPase activity in a concentration-dependent fashion in the range of 0.01–100 and 1.0–4000 μM, respectively. The IC 50 values were 1.93 ± 0.27 μM for ouabain and 2.45 ± 0.17 mM for bretylium. 3. 3. In another set of experiments, the effects of bretylium on the enzyme activity were tested in combination with 2.5 or 5.0 μM ouabain. 4. 4. The combined effects of the two drugs resulted in a net reduction in the total inhibitory activities of the individual drugs, which became more marked the higher the bretylium concentration. This trend seems to suggest a competitive mode of interaction of the two drugs in their inhibitory actions on Na +−K +-ATPase activity. 5. 5. The results demonstrate therefore that bretylium is a potent inhibitor of ouabain-inhibited ATP hydrolysis by myocardial Na +−K +-ATPase. These actions may be pertinent with regard to some of its cardiac actions.

Effects of MDL 11,939 on Action Potential and Contractile Force in Cardiac Tissues: A Comparison with Bretylium, Clofilium, and Sotalol

The effect of MDL 11,939 hydrochloride [alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol HCl], a novel antiarrhythmic agent, was studied using microelectrode recording techniques. MDL 11,939 (10(-7) - 10(-6) M increased the action potential (AP) duration in both guinea pig papillary muscle and dog Purkinje fiber with a maximum effective concentration of 10(-6) to 3 x 10(-6) M. MDL 11,939 up to and including 10(-6) M did not alter upstroke velocity (Vmax) of the AP in either tissue but 10(-5) M decreased the Vmax in Purkinje fibers. Compared to the other class III antiarrhythmic agents (bretylium, clofilium, and d-sotalol), MDL 11,939 was among the most potent in increasing AP duration in the papillary muscle, while being relatively less effective in increasing AP duration in Purkinje fiber. Bretylium did not increase the AP duration in papillary muscle unless it was reserpinized. MDL 11,939, clofilium, and d-sotalol all produced negative inotropic effects in papillary muscle, whereas bretylium produced a positive inotropic effect. The positive inotropic effect of bretylium was abolished by reserpinization. In papillary muscle preparations depolarized with 22 mM K+, MDL 11,939 at concentrations greater than or equal to 10(-5) M depressed Vmax of the slow AP, suggesting that it inhibited the inward Ca2+ current, and such an effect may contribute to the negative inotropic effect of this agent. In the depolarized preparations, the slow AP duration was still increased by concentrations of MDL 11,939 greater than or equal to 10(-6) M. In conclusion, MDL 11,939 has cellular electrophysiological properties that suggest a class III antiarrhythmic activity.

Antiarrhythmic and Electrophysiologic Effects of MDL 11,939, a Novel Class III Antiarrhythmic Agent in Anesthetized Dogs

MDL 11,939 (alpha-phenyl-1-[2-phenylethyl]-4-piperidine-methanol) is a new class III antiarrhythmic agent that was evaluated for antiarrhythmic activity in anesthetized dogs. Intravenous (i.v.) administration of MDL 11,939 (1, 3, and 10 mg/kg) increased left ventricular effective refractory periods. Q-T interval, and Q-Tc in a dose-related way. The effects of MDL 11,939 on ventricular refractoriness were similar to those observed with administration of identical doses of d-sotalol, with the exception that those produced by MDL 11,939 lasted longer. Intraduodenal administration of 10 mg/kg MDL 11,939 also increased left ventricular effective refractory period (LV ERP). The increase in left ventricular refractoriness produced by MDL 11,939 occurred without a significant increase in QRS duration. MDL 11,939 (10 mg/kg i.v.) also protected against induction of ventricular tachycardia (VT) and ventricular fibrillation (VF) induced with programmed electrical stimulation (PES) in anesthetized dogs with chronic 4- to 7-day myocardial infarctions. In comparison, antiarrhythmic effects of bretylium (10 mg/kg i.v.) against PES-induced ventricular arrhythmias were dependent on additional administration of propranolol (0.1 mg/kg i.v.), whereas propranolol alone (0.1 mg/kg i.v.) was ineffective. The results observed with MDL 11,939 are consistent with its in vitro class III antiarrhythmic action and suggest utility for this agent in treatment of VT and VF.

Studies on the mode of action of bretylium and guanethidine in post-ganglionic sympathetic nerve fibres.

1. The effects of bretylium and guanethidine on the nerve terminal impulse and transmitter release from sympathetic postganglionic nerve terminals in the guinea-pig vas deferens have been studied in vitro using focal extracellular recording. Excitatory junction currents (EJCs) were used as a measure of transmitter release. 2. Both bretylium and guanethidine altered the configuration of the nerve terminal impulse in a manner consistent with their being local anaesthetics. 3. Bretylium (1-3 microM) only completely inhibited transmitter release when impulse propagation in the sympathetic nerve terminal was blocked. 4. In contrast, guanethidine (1-10 microM) could block transmitter release with little effect on the configuration of the nerve terminal impulse. 5. The inhibitory effects of these agents on both the nerve terminal impulse and on transmitter release were reversed by the indirectly acting sympathomimetic agent, d-amphetamine (1-10 microM). 6. Using this technique the mechanisms of action of drugs known to modify the transmitter release in sympathetic nerve terminals can be more precisely determined.

Importance of Interaction with Adrenergic Neurons for Antifibrillatory Action of Bretylium in the Dog

The present study was designed to investigate whether or not interaction with the adrenergic neurons is important for the antifibrillatory effect of bretylium. The direct action of bretylium on cardiac electrophysiological properties, as indicated by effective refractory period prolongation, was also assessed. In pentobarbital-anesthetized, open-chest dogs, bretylium, 5 mg/kg i.v., increased ventricular fibrillation threshold rapidly and markedly. The effect peaked in 1 h and was sustained for at least 3 h. Complete adrenergic neuronal blockade also occurred within 30 min. Effective refractory period lengthening was minimal and variable. When bretylium's access to the adrenergic neurons was prevented either by antagonism of the presynaptic amine transport pump with desipramine or by chemical sympathectomy with 6-hydroxydopamine, the antifibrillatory effect was absent. Furthermore, when blockade of adrenergic neurotransmission by bretylium was reversed by the administration of d-amphetamine, ventricular fibrillation threshold also decreased. Data from all groups of experiments revealed that changes in effective refractory period did not correlate, in either magnitude or direction, with changes in ventricular fibrillation threshold. Thus, it can be concluded that interaction with adrenergic neurons is important for bretylium's antifibrillatory action and that absence of sympathetic neurotransmission contributes to the elevation of ventricular fibrillation threshold.

Effects of bretylium tosylate on inhomogeneity of refractoriness and ventricular fibrillation threshold in canine hearts with quinidine-induced long QT interval.

We studied effects of bretylium tosylate (6 mg X kg-1, injected intravenously over 60s) on ventricular refractoriness and its inhomogeneity, and ventricular fibrillation threshold (VFT) in canine hearts with quinidine-induced long QT interval. In 3 anaesthetised open chest dogs, 30 mg X kg-1 of quinidine sulphate was injected intravenously over 5 min to produce QT prolongation. Effective refractory period (ERP) was determined at 8 test points of the right ventricle using extrastimuli. Temporal dispersion as an expression of inhomogeneity of ventricular refractoriness was estimated as the difference between the longest and the shortest ERP. VFT was determined using a train of pulses, 4 ms in duration and at 10 ms intervals. Effects of bretylium were determined from 30 to 60 min after injection. Quinidine-induced long QT interval did not change after bretylium (358 +/- 37 vs 348 +/- 26 ms) when transiently elevated blood pressure returned to the pre-bretylium level. Bretylium shortened ERP slightly (278 +/- 16 vs 268 +/- 14 ms, p less than 0.02) but did not shorten ERP after premature depolarisation (209 +/- 14 vs 209 +/- 15). However, temporal dispersion was significantly decreased by bretylium. VFT, which was lowered by quinidine (14.5 +/- 5.0 vs 8.5 +/- 2.9 mA, p less than 0.01), was elevated significantly by bretylium (21.9 +/- 6.9, p less than 0.001). These effects of bretylium might be attributed to the combination of its direct electrophysiology and indirect adrenergic actions.

Bretylium opens mucosal amiloride-sensitive sodium channels

Addition of the quanternary ammonium compound, bretylium, to the outer surface of a frog skin leads to an increase in the potential difference and in the short circuit current across the skin. Bretylium does not have any effect when applied to the inside face of the frog skin. The effect of bretylium is dependent upon the presence of sodium ions in the outer medium; it is depressed when sodium is replaced by choline or potassium but not when lithium substitutes for sodium. The bretylium effect is blocked by the specific sodium channel blocker, amiloride. It is proposed that bretylium opens mucosal, amiloride-sensitive sodium channels.

Serial Electrophysiologic Effects of Bretylium in Man and Their Correlation with Plasma Concentrations

The serial electrophysiologic effects of bretylium were studied in 10 patients undergoing cardiac catheterization before giving the drug, at the end of bretylium tosylate-loading infusion (5 mg/kg/15 min), and after 1 h of intravenous drug maintenance (1.5 mg/min). Mean blood pressure increased during drug loading from 93.6 +/- 10.9 mm Hg to 121.1 +/- 16.2 mm Hg (p less than 0.01, t = 15 min) but returned toward control (100.9 +/- 18.7 mm Hg, p = NS) during drug maintenance (t = 75 min). Small changes in PR, QRS, QTc, AH, and HV intervals during spontaneous and paced rhythms were not significant. Comparison of the control electrophysiologic study with early and late postdrug studies showed no significant changes in corrected sinus node recovery times and in Wenckebach cycle lengths, but small decreases in refractory periods occurred. After drug loading, decreases in mean effective refractory periods of atrium, AV node, and right ventricle of 12, 2, and 16 ms, respectively, occurred (p = NS); during drug maintenance (t = 75 min), these refractory periods had decreased with respect to control by 21, 36, and 13 ms, respectively (p less than 0.05, 0.05, and 0.01). Functional refractory period of the AV node decreased at 75 min by 31 ms (p less than 0.01). The observed shortening of refractory periods contrasts with the direct effects of bretylium in isolated ventricular muscle and Purkinje fibers, which consist of prolongation of effective refractory periods and action potential duration. Thus, indirect (adrenergic) effects may be more important to overall clinical electrophysiologic actions not only acutely during loading but also during at least the first 60-90 min of maintenance therapy, which spans the expected time of initial clinical antifibrillatory response.

Pharmacologic reversal of hypotensive effect complicating antiarrhythmic therapy with bretylium.

The value of bretylium for long-term therapy of arrhythmias is slight because of the almost universal development of orthostatic hypotension induced by adrenergic neuron blockade. Blockade of neurotransmission by bretylium depends on its uptake into adrenergic neurons by the norepinephrine pump. The effects of inhibiting the pump with protriptyline were evaluated in jive patients with ventricular tachycardia (VT) resistant to conventional therapy but responsive to bretylium. Adrenergic blockade was assessed by measuring the venous rejex response (VRR) and change in blood pressure on standing. Before bretylium, VRR was present and standing blood pressure was normal. The patients received intravenous bretylium in increasing doses until VT was suppressed, at which time the VRR was blocked and all patients were bedridden due to orthostatic hypotension. The dosage of bretylium was tapered as oral treatment was begun and the dosage gradually increased to maintain VT suppression. Protriptyline was then given orally in slowly increasing doses in an attempt to reverse intolerable orthostatic hypotension. Five to 7 days later the VRR was restored and the blood pressure in the standing position returned toward normal, enabling the patients to become ambulatory. In these patients the antiarrhythmic efficacy of bretylium was not altered by protriptyline and was therefore not dependent on adrenergic neuron blockade. As bretylium was withdrawn and protriptyline continued, recurrence of arrhythmia established that protriptyline did not contribute to bretylium's antiarrhythrnic efficacy. These findings do not, however, constitute sujjicient evidence to support the routine application of this approach to therapy. Rather, it provides a pharmacologic rationale for more extensive evaluation of the safety and efficacy of the combination. The demonstration of dissociation between the antiarrhythmic and adrenergic effects of bretylium in man suggests that structural modiJication of the molecule might yield an antiarrhythmic drug free of undesirable effects on the adrenergic nervous system. Raymond

Effect of Bretylium on Neuromuscular Transmission

The effect of bretylium on the response of an isolated muscle (guinea pig lumbrical) to direct and indirect stimulation was examined. An initial increase in twitch response to both indirect and direct stimulation was followed at higher concentrations of bretylium by block of the indirect response only. The ED50 for this latter effect was 106.9 +/- 9.25 microM. However, in the presence of subthreshold levels of d-tubocurarine the ED50 was markedly reduced to 1.31 +/- 1.11 microM, a concentration that could occur during clinical use of bretylium. Thus, the physician is cautioned to consider the possibility that neuromuscular block may be produced when bretylium is administered in close temporal proximity to neuromuscular blocking agents.

Pharmacokinetics of bretylium in man after intravenous administration.

The pharmacokinetic profile of bretylium was studied in four normal male volunteers using a new sensitive EC-GC procedure for its quantitative in biological fluids. The plasma concentrations and urinary excretion rates following the constant i.v. infusion of a single 4 mg/kg dose of bretylium tosylate declined biexponentially and the data were fitted to a two-compartment model with a renal and a nonrenal route of elimination. The drug had a mean half-life (t1/2 beta) of 7.8 hr and apparent volume of distribution (Vd, beta) of 8.18 liters/kg. The renal clearance, which was 6 times that of the glomerular filtration rate, accounted for almost 84% of the total body clearance and correlated linearly with the subjects' creatinine clearance. The observed side effects of bretylium were mild and similar to those of other adrenergic blocking agents.

Kinetics of antiarrhythmic effects of bretylium: Correlation with myocardial drug concentrations

Kinetics of antiarrhythmic effects of bretylium: Correlation with myocardial drug concentrations

Bretylium tosylate: A review

The chemistry, pharmacology, pharmacokinetics, clinical uses, adverse effects, drug interactions and dosage of bretylium tosylate, a recently approved antiarrhythmic agent, are reviewed. Bretylium tosylate is used to treat life-threatening ventricular arrhythmias, principally ventricular fibrillation and ventricular tachycardia, that have not responded to treatment with first-line antiarrhythmic agents. The drug has a direct positive inotropic effect on the myocardium and blocking effect on postganglionic sympathetic nerve transmission. The drug is poorly absorbed orally, requiring either i.m. or i.v. administration. Drug excretion occurs primarily through the kidney, necessitating dosage modification in renal disease. Hypotension is the most commonly observed adverse reaction to bretylium tosylate. Rapid i.v. administration may cause severe nausea and vomiting, and i.m. injection at the same site may cause atrophy and necrosis of muscle tissue. Quinidine and procainamide may potentiate the hypotensive effects of bretylium. Bretylium will aggravate digitalis-induced arrhythmias. Bretylium's use in resistant ventricular tachyarrhythmias requires close clinical monitoring.

Effect of bretylium on cardiovascular changes induced by coronary occlusion in the cat

The influence of bretylium pretreatment on the heart rats, blood pressure, contractile force and cardiac rhythm changes produced by occlusion of the anterior descending coronary artery was evaluated in chloralose-anesthetized cats. Bretylium pretreatment shortened the duration of the ventricular arrhythmia. This drug however had no effect on the other cardiovascular changes evoked by coronary occlusion. These results suggest that the sympathetic nervous system has a role in maintaining electrical instability after experimentally induced myocardial infarction.

Bretylium Tosylate

The effects of bretylium tosylate in managing acute myocardial infarction were studied in 16 patients within 24 hours from the onset of symptoms and were compared to those of lidocaine in a comparable group of 15 patients. Both drugs were equally effective in preventing cardiac arrhythmias during the 48 hours of trial. No deleterious hemodynamic effects were associated with lidocaine treatment. However, marked supine hypotension developed in seven patients treated with bretylium. No changes occurred simultaneously in heart rate, left ventricular ejection time, or central venous pressure. The occurrence of hypotension correlated with a poor initial hemodynamic state. The substantial and unpredictable circulatory effects of bretylium in acute myocardial infarction contraindicates its routine use in the prevention of infarction arrhythmias.

COCAINE-LIKE EFFECT OF KETAMINE ON VASCULAR ADRENERGIC NEURONES

The influence of ketamine on adrenergic and cholinergic responses was studied in the rabbit pulmonary artery in vitro. Ketamine and cocaine potentiated smooth muscle contractions elicited by nonadrenaline, adrenaline and transmural electrical stimulation of adrenergic neurone terminals. Arterial contractions elicited by tyramine were enhanced by ketamine, while cocaine blocked them. Ketamine moved the concentration-response curve of carbachol slightly to the right. Nicotine-induced contractions were blocked by ketamine and cocaine. The adrenergic neurone blocking effect of bretylium and dimethylphenylpiperazinium on the response to transmural stimulation was prevented by ketamine. The uptake of 3H-noradrenaline by rabbit isolated aorta was inhibited by ketamine and cocaine. It is concluded that ketamine inhibits the membrane amine pump in the terminals of postganglionic adrenergic neurones in a cocaine-like manner.

Effect of bretylium on adrenergic neurons and its relation to sodium

Effect of bretylium on adrenergic neurons and its relation to sodium

The effects of bretylium on the subcellular distribution of noradrenaline and on adrenergic nerve function in rat heart.

1. The effects of bretylium were investigated on the content and subcellular distribution of noradrenaline in the rat heart and on the response to stimulation of the sympathetic nerves supplying the heart.2. In most experiments bretylium produced no change in the total noradrenaline content of the heart but significant changes were produced in the subcellular distribution of noradrenaline.3. Treatment with amphetamine both prevented and antagonized the bretylium-induced adrenergic neurone blockade and most of the accompanying changes in the subcellular distribution of noradrenaline.4. There was a temporal correlation between the bretylium-induced depletion of noradrenaline from the microsomal (P(2)) fraction and adrenergic neurone blockade.5. The onset of adrenergic neurone blockade was also accompanied by an elevation of the noradrenaline content in the low-speed coarse (P(1A)) fraction and in the mitochondrial (P(1B)) fraction; this elevation was prevented by pretreatment with alpha-methyl-p-tyrosine.6. It is concluded that although the elevation of the noradrenaline content of the P(1A) and P(1B) fractions and a depletion of amine from the P(2) fraction are associated with the onset of adrenergic neurone blockade only the depletion from the P(2) fraction is required for its maintenance. This conclusion supports the hypothesis that only a small portion of the noradrenaline content of an adrenergically-innervated organ is associated with the release of transmitter, for when this small ;store' is depleted, by agents like bretylium, the nerves fail to function.

Effect of Bretylium on the Pulmonary and Systemic Circulation in Patients with Mitral Valve Disease after Cardiopulmonary Bypass

Effect of Bretylium on the Pulmonary and Systemic Circulation in Patients with Mitral Valve Disease after Cardiopulmonary Bypass