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At least 19 recordsLinked to original sources
PubMed1988

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.

Amphetamine↗
PubMed1975

The influence of bretylium tosylate on the intraocular pressure of the rabbit.

Bretylium tosylate was applied topically and intravitreously to rabbit eyes. The topical application of 1, 2, 5 and 10% bretylium tosylate gave a small but significant decrease of the intraocular pressure 6 hrs after treatment. The effects had disappeared, when the eyes were re-examined after 24 hrs. The intravitreous injection of 200 mug of bretylium tosylate caused a more pronounced and prolonged pressure decrease. The results are interpreted in the light of chemical sympathectomy.

Animals↗
PubMed1979

Cardiac arrhythmias produced by bretylium in cats anesthetized with halothane.

Bretylium given by rapid intravenous injection into cats anesthetized solely with halothane precipitates severe and unusually long-lasting ventricular arrhythmias. They are observed 20-70 sec following doses of bretylium ranging from 0.8 mg/kg to 15 mg/kg and last for 60 sec to just over half an hour. Bretylium also manifests signs of sympathetic involvement since it raises blood pressure and heart rate just prior to the onset of arrhythmias. Propranolol pretreatment prevents bretylium arrhythmias. From these results and from those of other investigations, it is concluded that bretylium arrhythmias are mediated through the release of endogenous noradrenaline stored in adrenergic neurons of the heart. These results call attention to the arrhythmogenic potential of bretylium in the presence of halothane anesthesia.

Anesthesia↗
PubMed1989

Bretylium tosylate binds preferentially to muscarinic receptors labelled with [3H]oxotremorine M (SH or 'high affinity' receptors) in rat heart and brain cortex.

Bretylium tosylate is an antiarrhythmic agent. In guinea pig atria it showed the properties of a competitive muscarinic (cholinergic) antagonist and could distinguish between two muscarinic receptor classes or states in cardiac membranes. We decided to further investigate its binding properties at muscarinic cholinergic receptors of the rat heart and brain (cortex), keeping in mind the recently discovered heterogeneity of muscarinic receptor protein. Bretylium tosylate recognized two receptor classes or states in the heart with Ki values of 0.9 and 11 microM. All cardiac membrane receptors showed a homogeneous (11 microM) Ki value for the drug in the presence of GTP in the incubation medium, or after in vivo pretreatment with islet activating protein (IAP). Bretylium tosylate was able (but only at a high concentration, 1 mM) to slow the dissociation kinetics of the tracer, which suggests that it also bound to an allosteric site on the muscarinic receptor, or that it affected the receptor environment. In the brain cortex, as in the heart, bretylium tosylate displayed a high affinity for receptors labelled with the agonist [3H]oxotremorine M (Ki value: 0.8 microM for the SH-or cardiac-type high-affinity receptors), and a 8- to 10-fold lower affinity for cortex M and L receptors. These data suggest that the antagonist bretylium tosylate had binding properties in rat cardiac membranes analogous to those of the partial agonist pilocarpine and that it interacted with a single type of receptor.

Animals↗
PubMed1988

Sympatho-endocrine and metabolic responses to exercise under post-ganglionic blockade in rats.

The purpose of this study was to further document the role of locally released norepinephrine (NE) in the control of metabolic and endocrine responses to exercise in rats. Post-ganglionic blockade with bretylium (20 mg.kg-1, i.v.) reduced NE release from sympathetic nerve endings and triggered a compensatory increase in epinephrine (E) release from the adrenal medulla, as reflected by plasma NE and E concentrations at rest and exercise (E/NE ratio = 2.92 +/- 0.53 and 2.48 +/- 0.51 vs 0.62 +/- 0.15 and 1.48 +/- 0.18 in control rats; mean +/- SE). Following bretylium administration a reduction in running time to exhaustion (28 m.min-1, 8% slope: 33 +/- 2 min vs 74 +/- 10 min) was associated with 1) a faster decrease in blood glucose concentration (3.58 +/- 0.80 mM vs 8.09 +/- 0.38 mM in control rats exercised for 33 min); and 2) an increased glycogen store utilization in fast-twitch muscles (superficial vastus lateralis and gastrocnemius lateralis). Glycogen utilization was not modified in soleus muscle and in the liver. Taken together these results suggest that post-ganglionic blockade increased carbohydrate store and peripheral blood glucose utilization. This could reflect an impairment in fat mobilization and utilization which might be secondary to a reduction of NE release in the adipose tissue and/or in the endocrine pancreas.

Animals↗
PubMed1978

Porcine malignant hyperthermia. VI: the effects of bilateral adrenalectomy and pretreatment with bretylium on the halothane-induced response.

The effects of bilateral adrenalectomy, together with the i.v. administration of bretylium tosylate 20 mg kg-1 on halothane-induced malignant hyperthermia (MH), were investigated in six Pietrain pigs. All six animals survived the halothane challenge, and failed to show any signs of increased muscle metabolism. Bilateral adrenalectomy alone prevented halothane-induced MH in three out of four Pietrain pigs, whereas the i.v. administration of bretylium alone protected only one pig out of an additional four animals studied. The results show that complete adrenergic blockade inhibits the susceptibility of Pietrain skeletal muscle to halothane and that the adrenal medulla makes an important contribution to this response.

Adrenalectomy↗
PubMedDate not supplied

Competitive inhibition of acetylcholinesterase by bretylium: possible mechanism for its induction of norepinephrine release.

The antiarrhythmic drug bretylium tosylate competitively inhibits acetylcholinesterase activity. The Ki values for the inhibition of the purified enzyme (from electric eel), and acetylcholinesterase activity of crude rat ventricular and cortical homogenates were 6 X 10(-5), 3 X 10(-5), and 8 X 10(-5) M respectively. These values are close to the concentrations of the drug known to induce norepinephrine release from cardiac adrenergic presynaptic vesicles. It is suggested that inhibition of acetylcholinesterase activity by bretylium induces norepinephrine release through the effect of accumulated acetylcholine on nicotinic receptors in adrenergic nerve terminals.

Acetylcholinesterase↗
PubMed1989

Ischemia-induced conduction delay and ventricular arrhythmias: comparative electropharmacology of bethanidine sulfate and bretylium tosylate.

Bretylium tosylate and bethanidine sulfate were studied in two models of experimental myocardial ischemia. In anesthetized dogs, left anterior descending coronary artery occlusion during rapid atrial pacing (180-200 min-1) produced ventricular tachycardia and fibrillation within 5 min in 9 of 11 dogs studied. In all cases, arrhythmias were preceded by and appeared to be temporally related to progressive fractionation and delay of electrograms recorded from the ischemic zone. In four dogs, bretylium (10 mg/kg) did not alter the time course of electrogram changes nor the time to onset of arrhythmia. However, in five dogs bethanidine (10 mg/kg) markedly exacerbated conduction changes in the ischemic zone and decreased the time to onset of ventricular arrhythmias (173 +/- 35 vs. 262 +/- 34 s control, mean +/- SEM, p less than 0.05). Bethanidine administration also facilitated ischemia-induced ventricular tachycardia and fibrillation in two dogs that did not exhibit ischemia-induced arrhythmias before receiving the drug. In isolated perfused rabbit hearts, global ischemia produced conduction slowing, depolarization of resting membrane potential, and decreases in amplitude and Vmax that were reproducible in serial 10 min ischemic episodes. Bretylium (10 mg/L) did not affect these parameters under either perfused or ischemic conditions. Although bethanidine (10 mg/L) also did not affect these parameters during perfusion, conduction slowing and depression of Vmax during ischemia were accelerated without affecting the time course of change in resting membrane potential. Both bretylium and bethanidine prolonged action potential duration under perfused conditions, but after 10 min of ischemia this effect was no longer evident. The results demonstrate that differences in the electrophysiologic effects of bretylium and bethanidine are markedly accentuated in the setting of acute ischemia. Although both these agents have been demonstrated to have antifibrillatory effects in other experimental settings, under the conditions of this study, bretylium failed to protect against ischemia-induced arrhythmias and acute bethanidine administration produced a proarrhythmic effect in association with an exacerbation of ischemia-induced conduction changes.

Action Potentials↗
PubMed1976

Effect of adrenergic neuron inhibitors on the vascular response to sympathetic nerve stimulation.

In anesthetized cats, the lumbar sympathetic trunk was stimulated, and the responses of the resistance and capacitance vessels of the hindlimb were recorded (by resistography and plethysmography, respectively). The drugs used were reserpine, methyldopa and bretylium tosylate. It was found that reserpine and methyldopa inhibit the response of the resistance vessels to a greater extent than that of the capacitance vessels, while bretylium tosylate has a greater effect on the transmission of constrictor impulses to the capacitance vessels. Reserpine mainly suppresses responses to low-frequency stimulation and bretylium tosylate--those to high-frequency stimulation, while methyldopa affects them to the same degree at all frequencies.

Animals↗
PubMed1977

Experience with bretylium tosylate by a hospital cardiac arrest team.

The effect of bretylium tosylate (BT) was determined in 27 consecutive cases of resistant ventricular fibrillation (VF) encountered by a hospital cardiac arrest team. The VF was sustained and completely resistant to multiple injections of lidocaine, sequential DC shocks at 400 watt-sec and one or a combination of intravenous propranolol, diphenylhydantoin or procainamide. Following 30 min of sustained cardiac massage, BT (5 mg/kg i.v.) was administered. In 20 patients, VF was terminated within 9-12 min after DC shock. Eight of these patients failed to recover while 12 (44%) of all patients resuscitated survived to be discharged from hospital. Eleven out of 20 (55%) of all patients who had a cardiac arrest outside the CCU were survivors; only one out of seven in the CCU were successfully resuscitated. While receiving maintanance BT post-resuscitation (5 mg/kg i.m. q 8-12 hrs x 48 hrs), half the patients developed hypotension and three required vasopressors and/or fluid replacement. The data indicate that BT is a useful agent in patients with sustained VF refractory to repeated lidocaine injections, some other antiarrhythmic agents, and multiple DC shocks.

Bretylium Compounds↗
PubMed1990

Cerebroventricular calcitonin gene-related peptide inhibits rat duodenal bicarbonate secretion by release of norepinephrine and vasopressin.

Proximal duodenal bicarbonate secretion is an important factor in humans and animals protecting the mucosa against acid-peptic damage. This study examined the mechanisms responsible for the central nervous system regulation of duodenal bicarbonate secretion by calcitonin gene-related peptide (CGRP) in unrestrained rats. Cerebroventricular administration of rat CGRP significantly inhibited basal duodenal bicarbonate secretion as well as the stimulatory effects of vasoactive intestinal peptide, neurotensin, a luminal PGE1 analogue, misoprostol, and hydrochloric acid. The inhibitory effects of cerebroventricular CGRP were abolished by ganglionic blockade with chlorisondamine, significantly attenuated by noradrenergic blockade with bretylium, and enhanced by vagotomy. Inhibition of duodenal bicarbonate secretion induced by CGRP coincided with significant increases in plasma norepinephrine (NE) and vasopressin concentrations. The alpha adrenergic receptor antagonist, phentolamine, and the vasopressin V1 receptor antagonist, (1-deaminopenicillamine, 2-[O-methyl]Tyr, 8-Arg)-vasopressin, given intravenously reversed the central inhibitory effect of CGRP by approximately 50% each. Pretreatment of the animals with both phentolamine and the vasopressin antagonist completely abolished the central inhibitory effect of CGRP. Peripheral vasopressin and NE significantly decreased duodenal bicarbonate secretion, and their inhibitory effects were additive and prevented by phentolamine and the vasopressin antagonist, respectively. We conclude that cerebroventricular CGRP inhibits rat duodenal bicarbonate secretion by activation of sympathetic efferents and subsequent release of NE and vasopressin that act on alpha adrenergic and vasopressin receptors, respectively.

Adrenalectomy↗
PubMed1979

Bretylium tosylate: a newly available antiarrhythmic drug for ventricular arrhythmias.

Bretylium tosylate (Bretylol) has recently been approved for parenteral use against resistant ventricular arrhythmias. The pharmacologic action of bretylium is complex, and its antiarrhythmic action differs significantly from other drugs. Bretylium is an adrenergic neuronal blocking agent taken up selectively at peripheral adrenergic nerve terminals, where it initially releases norepinephrine (sympathomimetic effect) and then produces adrenergic neuronal blockade. It has direct cardiac membrane effect to prolong action potential duration and effective refractory period but, unlike other membrane active antiarrhythmic agents, does not depress conduction velocity or automaticity. Bretylium increases ventricular fibrillation threshold and prevents the decrease in ventricular fibrillation threshold associated with myocardial ischemia. It does not depress myocardial contractility. Clinical studies have shown parenteral bretylium to be effective in suppressing ventricular arrhythmias, particularly recurrent, drug resistant ventricular tachycardia or ventricular fibrillation.

Action Potentials↗