Does the iontophoretic application of bretylium tosylate modulate sweating during exercise in the heat in habitually trained and untrained men?

NEW FINDINGS: What is the central question of this study? Does the administration of the adrenergic presynaptic release inhibitor bretylium tosylate modulate sweating during exercise in the heat, and does this response differ between habitually trained and untrained men? What is the main finding and its importance? Iontophoretic administration of bretylium tosylate attenuates sweating during exercise in the heat in habitually trained and untrained men. However, a greater reduction occurred in trained men. The findings demonstrate a role for cutaneous adrenergic nerves in the regulation of eccrine sweating during exercise in the heat and highlight a need to advance our understanding of neural control of human eccrine sweat gland activity. ABSTRACT: We recently reported an influence of cutaneous adrenergic nerves on eccrine sweat production in habitually trained men performing an incremental exercise bout in non-heat stress conditions. Based on an assumption that increasing heat stress induces cholinergic modulation of sweating, we evaluated the hypothesis that the contribution of cutaneous adrenergic nerves on sweating would be attenuated during exercise in the heat. Twenty young habitually trained and untrained men (n = 10/group) underwent three successive bouts of 15 min of light-, moderate- and vigorous-intensity cycling (equivalent to 30, 50, and 70% of peak oxygen uptake ( V̇O2peak ) respectively), each separated by a 15 min recovery while wearing a perfusion suit perfused with warm water (43°C). Sweat rate (ventilated capsule) was measured continuously at two bilateral forearm skin sites treated with 10 mm bretylium tosylate (an inhibitor of neurotransmitter release from adrenergic nerve terminals) and saline (control) via transdermal iontophoresis. A greater sweat rate was measured during vigorous exercise only in trained as compared to untrained men (P = 0.014). In both groups, sweating was reduced at the bretylium tosylate versus control sites, albeit the magnitude of reduction was greater in the trained men (P ≤ 0.024). These results suggest that cutaneous adrenergic nerves modulate sweating during exercise performed under a whole-body heat stress, albeit a more robust response occurs in trained men. While it is accepted that a cholinergic mechanism plays a primary role in the regulation of sweating during an exercise-heat stress, our findings highlight the need for additional studies aimed at understanding the neural control of human eccrine sweating.

Efficacy of bretylium tosylate for ventricular tachycardia.

In 20 patients with inducible ventricular tachycardia (VT), intravenous bretylium tosylate infused as a 10-mg/kg bolus followed by 2 mg/min caused no change in refractory periods and did not suppress inducibility of VT. The use of bretylium for the treatment of VT should be reexamined.

Effect of bretylium tosylate on ventricular fibrillation threshold during hypothermia in dogs.

How bretylium tosylate affected the ventricular fibrillation threshold, electrophysiological parameters, and plasma catecholamine levels during hypothermia in dogs was studied. Threshold for ventricular fibrillation was determined by programmed electrical stimulation using a stimulation protocol that involved applying a maximum of five extrastimuli at body temperatures 37, 34, 31, 28, and 25 degrees C, and at the same temperatures during rewarming. Electrocardiogram, epicardial monophasic action potentials (MAP), and electrograms were recorded, and ventricular effective refractory period (VERP) was determined at each of the above temperatures. In one group (n = 7), a bolus dosage of bretylium tosylate (BT), 6 mg/kg body wt, was administered at 25 degrees C before rewarming. Another group (n = 4) was exposed to cooling and rewarming without addition of BT. Cooling to 25 degrees C reduced ventricular fibrillation threshold linearly, reduced heart rate, increased VERP and MAP, and slowed myocardial conduction velocity in both groups. There was no overall increase in plasma catecholamine levels during cooling. Addition of BT at 25 degrees C increased ventricular fibrillation threshold during rewarming compared with cooling. Addition of BT at 25 degrees C increased VERP by +/- 32 milliseconds and the corrected JT time by 0.06 +/- 0.02 seconds. VERP and JTc increased during rewarming with BT compared with cooling with no drug. BT had no effect on conduction velocity, and plasma catecholamine levels were not reduced. The antiarrhythmic effect of BT during hypothermia was attributed to an increased wavelength of refractoriness by its increase in the refractory period. This increased wavelength of refractoriness may prevent excitable gaps or increase circuit pathway in the setting of reentry arrhythmias.

[The effect of bretylium tosylate on ventricular arrhythmias in patients with acute myocardial infarction]. / Wplyw tosylanu bretylium na komorowe zaburzenia rytmu u chorych w ostrej fazie swiezego zawalu serca.

Sixty three patients with the acute myocardial infarction, aged between 34 and 85 years, admitted to the Intensive Cardiological Care Unit during the first 12 hours following the infarction were randomly divided into two groups. Patients of group I (20 subjects) were treated with nitroglycerin and additional intravenous infusions of bretylium tosylate in the dose of 5 mg/kg administered every 6 hours for 48-72 hours. Patients of group II (33 subjects) were mainly treated with intravenous nitroglycerin. A type and incidence of the ventricular arrhythmias, conduction disorders in AV node, and hemodynamic complications were analysed during the first 72 hours. It was found that bretylium tosylate reduces the incidence of ventricular arrhythmias accompanying myocardial infarction but after 2-3 hours following its administration (p < 0.05). Therefore, bretylium tosylate should be administrated to patients with the acute myocardial infarction in combination with other rapidly acting anti-arrhythmic drug. Bretylium tosylate increases also the effectiveness of electric defibrillation in patients with ventricular fibrillation or ventricular tachyarrhythmia. No evidence of the effectiveness of bretylium tosylate on atrio-ventricular conduction and hemodynamic complications of myocardial infarction was found.

Bretylium tosylate and electrically induced cardiac arrhythmias during hypothermia in dogs.

The effect of bretylium tosylate on plasma catecholamines and on electrically induced arrhythmias was evaluated in anesthetized hypothermic dogs. Bretylium at a dose of 7.5 mg/kg was administered prior to cooling from 37 degrees C to 27 degrees C. During cooling, the ventricular arrhythmia threshold (VAT) in control animals decreased from 10.1 +/- 1.9 to 4.4 +/- 1.3 impulses, while the VAT in bretylium-treated animals increased from 9.8 +/- 2.9 to 23.2 +/- 2.7 impulses. Catecholamine levels increased during cooling in all animals. In control animals, the epinephrine/norepinephrine ratio was unchanged, but in animals treated with bretylium tosylate, the ratio increased more than 10-fold (from 0.48 +/- 0.1 to 5.49 +/- 0.32 at 29.9 degrees C). The demonstrated increase in catecholamine levels during hypothermia suggests that the protection offered by bretylium tosylate against cardiac arrhythmias is not explained by modification of catecholamine levels, and is more likely due to an alteration of the electrophysiologic properties of cardiac tissues.

Implantable pharmacological defibrillator (AIPhD): preliminary investigations in animals.

The treatment of ventricular fibrillation (VF) by means of automatic implantable cardioverter defibrillators (AICD) poses many severe problems and limitations at the present time. In order to overcome these problems, we propose a totally new way to terminate VF or ventricular sustained tachycardia (VST). Our proposal consists of replacing the electric shock, which is dangerous, delayed, and sometimes ineffective, with a "chemical" shock: i.e., a chemical bolus retroperfused in the coronary sinus (CS) immediately after VF arises. The possible device is hypothesized and preliminary investigations in animals, performed to verify the theoretical assumption, are presented. In rabbits, and in larger animals (sheep and swine). Drugs were perfused in the coronary bed: lidocaine was used in 86% and bretylium tosylate in 14% of the animals. The results were: lidocaine immediately terminated VF in 100% and sinus rhythm was restored in rabbits; lidocaine terminated VF in VST in sheep; and in swine, bretylium immediately produced sinus rhythm in one case; in another one, only delayed sinus rhythm was achieved but lasted a short time; in the last case ventricular tachycardia at 128 beats/min appeared. Because new drugs, which are really "defibrillating" drugs, are available (bretylium tosylate, bethanidine, clofilium, tricyclic antidepressants, phenotiazine derivatives), we plan to investigate these defibrillating drugs in isolated hearts, found in suitable animals like dogs (sheep and swine are difficult to defibrillate) and in humans during routine electropharmacological studies.

Bretylium tosylate versus lidocaine in experimental cardiac arrest.

Bretylium tosylate has been shown effective in the treatment of ventricular fibrillation and in the prevention of its recurrence. However, lidocaine is generally preferred because bretylium could have adverse hemodynamic effects related to its antiadrenergic action. To explore further the differences between these two antiarrhythmic agents, the authors compared the effects of bretylium, lidocaine, and saline on a standardized dog model of ventricular fibrillation followed by electromechanical dissociation (EMD). The protocol included three successive episodes of cardiac arrest in each animal. Three minutes before each episode of ventricular fibrillation, 5 mg/kg of bretylium tosylate (n = 11), 1 mg/kg of lidocaine (n = 9) or saline (n = 12) were administered blindly. There was no difference in the duration of cardiac arrest (bretylium, 8 min 18 sec; lidocaine, 7 min 54 sec; saline, 8 min 20 sec) or the total doses of epinephrine required to resuscitate the animals. Both bretylium and lidocaine appeared to preserve cardiac function 5 minutes after recovery, as stroke volume increased from 17.8 +/- 6.7 to 18.7 +/- 6.7 mL (NS) after bretylium and from 17.7 +/- 7.7 to 19.0 +/- 7.0 mL (NS) after lidocaine, but decreased from 19.0 +/- 5.3 to 14.6 +/- 6.0 mL (P less than .05) after saline. During the first 10 minutes of EMD, ventricular fibrillation or ventricular tachycardia recurred in 4 dogs treated with lidocaine, 3 dogs treated with saline, but no dog treated with bretylium (P less than .05 between bretylium and saline).(ABSTRACT TRUNCATED AT 250 WORDS)

[Pathophysiologic characteristics of the reactive toxic stage of acute suppurative peritonitis and ways to enhance the effectiveness of intensive therapy]. / Patofiziologicheskie osobennosti reaktivno-toksicheskoi stadii ostrogo gnoinogo peritonita i puti povysheniia éffektivnosti intensivnoi terapii.

The oxygen regimen, circulation, and metabolism were studied in 95 patients in the reactive-toxic stage of diffuse purulent peritonitis. The results of cluster analysis made it possible to determine the clinical and pathophysiological features of the phases of the disease. The phase of compensation was characterized by disorders of mass exchange of plasma water which led to increased index of transcapillary exchange and increased excess of lactate. These parameters of tissue metabolism were grouped into one cluster together with the oxygen regimen value and mean arterial pressure. The other cluster was formed of the values of oxygen consumption and the values of oxygen systemic and vascular tissue transport and the hemodynamic parameters. In the phase of decompensation the homeostasis parameters were grouped into another 2 clusters. The first contained the indices of transcapillary exchange of oxygen and water, the other--those of the intensity of blood oxygen transport function and metabolism. Surgical treatment and inclusion of the sympatholytic agent ornid and the beta-adrenergic agonist alupent in the complex of intensive therapy from the stages of preoperative and anesthesiological management brought homeostasis to a level characteristic of the phase of compensation, as a result of which fatal outcomes were absolutely excluded.

Use of bretylium tosylate as prophylaxis and treatment in hypothermic ventricular fibrillation in the canine model.

We conducted a study to determine if bretylium tosylate (BT) is effective in the prophylaxis and treatment of hypothermic ventricular fibrillation (VF) in the setting of various maneuvers thought to induce this lethal arrhythmia. Twenty-two mongrel dogs were cooled to 24 C after being placed in a cold room. At 24 C, a double-blinded placebo or BT solution was infused. The dogs then were removed from the cold. They underwent the following sequential maneuvers: oral endotracheal extubation and intubation, central line and nasogastric tube placement, vigorous movement, and Swan-Ganz catheter insertion. If VF ensued, arterial blood gases were drawn, and BT was given only if refractory to countershock and epinephrine. Of the dogs that were given placebo, six of 11 (55%) fibrillated with manipulation, as compared with one of 11 (9%) dogs pretreated with BT (P = .067). Three of the 11 dogs that received BT fibrillated within minutes of its infusion. In the placebo dogs that fibrillated, four required BT and two defibrillated with countershock alone or with epinephrine prior to achieving stable rhythms.

Vagally-mediated atrial fibrillation in dogs: conversion with bretylium tosylate.

We developed a stable, reproducible model of acute atrial fibrillation (sustained for up to 90 min) in open-chest, anesthetized dogs utilizing continuous bilateral stimulation of the cervical vagi and transient rapid atrial pacing. This model was then used to study the defibrillatory effects of bretylium tosylate. In five dogs, sequential runs of atrial fibrillation lasting 1-60 minutes were induced. A single, rapid, intravenous bolus of bretylium caused conversion of all episodes of atrial fibrillation (n = 31) after a mean of 33 seconds (range 15-151 sec). In 28 of 31 episodes (90%) conversion occurred within 40 seconds. The dose of bretylium was 2.5 mg/kg in all but one episode in which 5.0 mg/kg was given. We conclude that bilateral vagal stimulation produces a stable canine model of acute atrial fibrillation and that the arrhythmia is rapidly converted with intravenous bretylium.

Experimental and clinical pharmacology of bretylium tosylate in acute myocardial infarction: a 15-year journey.

Experimental and clinical studies demonstrate the antifibrillatory effectiveness of bretylium tosylate: Experimental ventricular fibrillation induced either by electrical stimulation or by ischemia is prevented by bretylium. In 2,000 acute myocardial infarction patients who received bretylium prophylactically primary ventricular fibrillation occurred in less than 1% of cases. In a randomized hemodynamic study in acute myocardial infarction patients bretylium induced a significant decrease in heart rate, systolic and mean left ventricular pressures, and in systolic and mean aortic pressures. In addition, a parallel and significant decrease in total pulmonary and systemic resistances was seen, accompanied by decreases in tension time and left ventricular (delta P/delta V) indexes. Bretylium tosylate induces stabilization of electrical systole duration (QTc) in acute myocardial infarction patients. The conclusions of the present review strongly support those of the United States Food and Drug Administration, approving bretylium for prophylaxis and treatment of ventricular fibrillation.

Effect of quinidine and bretylium on defibrillation energy requirements.

We examined the effect of bretylium and quinidine on the energy requirements for internal defibrillation in 14 pentobarbital-anesthetized dogs. Bretylium, 6 or 10 mg/kg (n = 6), did not affect the relation between energy and the likelihood of successful defibrillation. The mean energy required to achieve 50% success (E50) or 90% success (E90) in defibrillation was not significantly altered; E50 was 5.3 +/- 1.9 J (X +/- s.d) before and 6.1 +/- 3.5 J after bretylium (n.s.), and E90 was 7.2 +/- 2.1 J before and 8.6 +/- 3.3 J after drug (n.s.). Quinidine was administered in a series of two loading and maintenance infusions to achieve mean plasma concentrations of 2.4 +/- 0.63 and 2.95 +/- 0.88 microgram/ml, respectively (n = 8). No significant effect on defibrillation energy requirement was observed; mean E50 before and after treatment was 6.3 +/- 3.3 J and 6.2 +/- 2.9 J, respectively, and mean E90 was 8.3 +/- 4.4 J and 8.3 +/- 4.1 J, respectively. Similarly, saline administration to control dogs (n = 12) resulted in no change in E50 or E90. At concentrations or doses similar to those in patients with serious arrhythmias, neither quinidine nor bretylium appears to have consistent effects on the energy requirements for internal defibrillation in our dog model.