Bretylium Research Articles

Intravenous bretylium overdose

An 81.5-mg/kg intravenous overdose of bretylium tosylate was administered to a 74-year-old patient after resuscitation from inferior wall myocardial infarction and cardiac arrest. The patient exhibited prolonged neurological depression with eventual neurological recovery. This case demonstrates the central nervous system depression that can occur with bretylium overdose. The emergency physician should be aware of this effect and avoid ending lifesaving measures because of apparent brain death in patients with bretylium overdose.

Ion-channel activities regulate transmembrane signaling in thymocyte apoptosis and T-cell activation

Several examples have shown that plasma membrane ion channels (e.g., Ca 2+ and K + channels) make an important contribution to lymphocyte activation or thymocyte apoptosis. Here we report on the importance of these ion channels in the sensitivity or resistance of lymphoid cells to extracellular ATP-induced apoptosis. Thymocytes of Balb/c mice responded to extracellular ATP (ATP ex) sensitively, with an immediate increase in the intracellular calcium level and later with an increased membrane permeability to low MW markers. Mature (medullary) thymocytes showed a higher sensitivity than did cortical thymocytes. Three human lymphoma cell lines, including SUPT13, a cell line reported to be sensitive to TcR/CD3 activation-induced apoptosis, showed a high resistance to ATP ex action. These observations suggest that maturation/differentiation state-dependent activity or disappearance of early ATP-receptor operated signaling systems (including ion channels) are critical for the cells in developing towards apoptosis. Using the patch-clamp technique we demonstrated that bretylium tosylate (a particular K +-channel blocker) known as inhibitor of T-lymphocyte proliferation also influences the single-channel properties of voltage-gated K + channels through depressing wholecell K + currents. This finding is yet another example underlining the importance of K + channel activity in T-lymphocyte proliferation.

Prehospital pharmacotherapeutic interventions: Recommendations for medication administration by EMT-A and EMT-I personnel

Because many communities lack prehospital advanced life support (ALS) services, increasing public access to such care is important. The present study was completed to establish an epidemiological database defining prehospital pharmacotherapeutic interventions by ALS rescue teams, in the hope of developing recommendations for medication administration by non-ALS personnel. Data were collected on 333 patients, including indication for pharmacotherapy, patient age, ambulance field time, route of medication administration, adverse effects of pharmacotherapy, efficacy of pharmacotherapy, additional ALS interventions, and patient medication/past medical history. Medications studied included albuterol nebulizer treatments (albuterol), aminophylline, amyl nitrite, atropine, bretylium tosylate, dexamethasone sodium phosphate, dextrose 50% (D-50), diazepam, diphenhydramine, dopamine, epinephrine 1 mg 1 mL , epinephrine 1 mg 10 mL , furosemide, glucagon, ipecac, isoproterenol, lidocaine, morphine sulfate, naloxone, nitroglycerin tablets (nitroglycerin), sodium bicarbonate, and verapamil. Albuterol, D-50, and nitroglycerin were used more often than other medications, accounting for total pharmacotherapeutic interventions for 228 persons (68.47% of total patients), including 100% of all pediatric patients. Partial pharmacological needs for an additional 20 patients also were satisfied by these agents. In all, albuterol, D-50, and nitroglycerin accounted for 250 of 395 total medication interventions (63.29%). No inappropriate use, point estimate [ (0) (333) (0.00% to 0.90%)], or unmet need, point estimate [ (0) (3,613) (0.00% to 0.08%)], of care was noted. When faced with communities lacking ALS rescue services, albuterol, D-50, and nitroglycerin are recommended for administration by emergency medical technician-ambulance and intermediate level rescuers, because of the high rate of use, relative ease of administration, and high benefit/low complication rates associated with these medications.

The κ agonist fedotozine modulates colonic distention-induced inhibition of gastric motility and emptying in dogs

Background/Aims: Gastric motor disturbances, associated with a delay in gastric emptying, occur in patients with the irritable bowel syndrome. The influence of fedotozine and κ agonists on the cologastric reflex produced by nonpainful colonic distention was evaluated in conscious dogs. Methods: Colonic distention was applied in dogs fitted with either strain gauges or gastric cannula to assess its influence on gastrointestinal motility and gastric emptying, respectively. Results: Colonic distention delayed the occurrence of gastric migrating motor complex by 141%, an effect blocked by intravenous fedotozine, U 50 488 (25 and 50 μg/ kg), and hexamethonium (0.5 mg/kg) but not by d-Ala2, N-methyl, Phe4, Gly5-ol enkephalin (1, 5, and 10 μg/ kg), granisetron (50 and 100 μg/kg), or bretylium to-sylate (5 mg/kg). Nor-binaltorphimine hydrochloride (1 mg/kg intravenously) eliminated the suppressive action of fedotozine. Colonic distention reduced the 1-hour gastric emptying of solids by 40.1%, an effect blocked by fedotozine and U 50 488 (50 and 100 μg/ kg); nor-binaltorphimine hydrochloride (1 mg/kg) antagonized the blocking effect of fedotozine. Conclusions: Fedotozine acts through κ receptors to block the colonic distention-induced delay on gastric motility and emptying. The cologastric reflex involves nicotinic ganglionic receptors but not adrenergic pathway and 5-hydroxytryptamine 3 receptors.

Effect of pregnancy on pressure-volume relationships in circulation of rabbits

Mean circulatory filling pressure (MCFP) has been measured after vagally induced cardiac arrest in 11 nonpregnant and 10 near-term pregnant rabbits, anesthetized with pentobarbital sodium. MCFP was 6.1 +/- 0.4 (SD) mmHg in the nonpregnant and 7.2 +/- 0.4 mmHg in the pregnant animals. The difference of 1.1 mmHg was significant (P < 0.001). Sympathetic blockade with bretylium tosylate (10 mg/kg) reduced MCFP by 0.4 mmHg in both nonpregnant and pregnant rabbits. Vascular capacitance was examined in the two groups. Unstressed vascular volume and vascular compliance were derived from measurements of MCFP after increasing blood volume by 8 and 16% or reducing it by 8%. The unstressed vascular volumes, 33.9 +/- 3.9 (SD) ml/kg in the nonpregnant and 35.1 +/- 3.2 ml/kg in the pregnant group, were not significantly different, but compliance in the pregnant group (4.0 +/- 0.6 ml.kg-1.mmHg-1) was significantly greater than in the nonpregnant rabbits (3.4 +/- 0.6 ml.kg-1.mmHg-1) (P < 0.05). We conclude that there are changes in vascular capacitance in rabbit pregnancy, probably not related to alterations in vasomotor activity, but these are insufficient to fully compensate for the increase in blood volume, thus leading to the rise in MCFP.

The effect of distension of the stomach on coronary blood flow in anaesthetized pigs

The present study was undertaken in anaesthetized pigs to determine whether distension of the stomach reflexly affects coronary blood flow. Experiments were performed on 17 pigs anaesthetized with ketamine and sodium pentobarbitone and artificially ventilated. Coronary blood flow was measured with an electromagnetic flowmeter positioned around the origin of the left circumflex coronary artery. The stomach was distended by injecting 0.8l warm Ringer solution into a balloon positioned within the stomach (mean gastric transmural pressure of about 13 mm Hg). Changes in aortic blood pressure and heart rate were prevented by a pressurized reservoir connected to the left femoral artery and by atrial pacing respectively. Distension of the stomach always caused a decrease in mean coronary blood flow. In five pigs, the magnitude of the decrease in coronary blood flow was graded by step increments in the gastric distending volume from 0.6l to 1l. The response of coronary blood flow was not affected by the administration of atropine (12 pigs), while it was abolished by the administration of bretylium tosylate (eight pigs) and by bilateral vagotomy (eight pigs; four cervical, four subdiaphragmatic vagotomy). These results show that innocuous distension of the stomach in anaesthetized pigs reflexly decreases coronary blood flow. This reflex response is mediated by sympathetic effects and its afferent limb involves the vagal nerves.

Regulation of central vascular blood flow in the turtle.

The purpose of this study was to determine the effects of vagal nerve stimulation on the pulmonary and systemic circulations in the turtle Pseudemys scripta. The heart rate (HR), systemic vascular resistance (Rsys), pulmonary vascular resistance (Rpul), total pulmonary blood flow (Qpul), and total systemic blood flow (Qsys) were measured during electrical stimulation of the vagal efferent and the vagal afferent nerves. Vagal efferent nerve stimulation resulted in a bradycardia, increased Rsys and Rpul, and a 60% reduction in the Qpul and Qsys. These cardiovascular changes were eliminated after an intravenous injection of atropine. In contrast, vagal afferent nerve stimulation resulted in a tachycardia, a twofold increase in Rsys, a reduction in Rpul, and an 85% increase in Qpul. These changes were eliminated after pretreating the animals with bretylium tosylate (10 mg/kg). An intravenous infusion of epinephrine (0.1 micrograms/kg) produced cardiovascular changes similar to vagal afferent stimulation. The cardiovascular changes resulting from afferent and efferent nerve stimulation were similar to the cardiovascular adjustments often associated with intermittent lung ventilation in reptiles. The results of our study suggest that such cardiovascular changes are under cholinergic and adrenergic control.

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°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°C before rewarming. Another group (n = 4) was exposed to cooling and rewarming without addition of BT. Cooling to 25°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°C increased ventricular fibrillation threshold during rewarming compared with cooling. Addition of BT at 25°C increased VERP by ±32 milliseconds and the corrected JT time by 0.06 ± 0.02 seconds. VERP and JT c 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.

A new function for lactate in the toad Bufo marinus.

In the amphibian Bufo marinus, progressive hypoxia below a critical PO2 elicits a transient 50% increase in O2 consumption that coincides with the onset of lactate formation. The present study was designed to test the hypothesis that lactate causes the observed rise in metabolic rate. Arterial bolus infusions of pH-neutral sodium lactate solutions (4 mmol/kg body wt) in toads maintained under hypoxia actually elicit a similar increase in metabolic rate. The application of adrenergic antagonists (bretylium tosylate, phentolamine, propranolol, and reserpine) inhibits this response, suggesting that catecholamines are involved. Moreover, animals injected with lactate move to a cooler environment (behavioral hypothermia), a behavioral response that is beneficial during hypoxia. We hypothesize that, in accordance with Cannon's concept of an emergency response, lactate may function as an alarm signal during hypoxia. However, the signal function of lactate is observed in animals both under hypoxia and under normoxia and should thus be considered in future studies whenever elevated lactate levels are present, e.g., during and after exercise.

Reflex control of active cutaneous vasodilation by skin temperature in humans

The purpose of this study was to examine whether reflex effects of changes in whole body skin temperature (Tsk) on cutaneous vasculature are mediated through the vasoconstrictor or the active vasodilator arm of the sympathetic nervous system. In six subjects, reflex responses in forearm skin blood flow (SkBF) to changes in Tsk were monitored by laser-Doppler flowmetry. SkBF was monitored at a control site and at a 0.6-cm2 site where bretylium (BT) had been iontophoretically applied to abolish sympathetic vasoconstrictor control. Reflex control of SkBF at BT-treated sites is solely through active vasodilator activity. An index of cutaneous vascular conductance (CVC) was calculated from the blood flow signal and mean arterial pressure, measured noninvasively. Data are expressed relative to maximum CVC (CVCmax) achieved by local warming of measurement sites to 42 degrees C at the end of each study. Tsk was controlled with a water-perfused suit covering the entire body except for the head and arms. Esophageal temperature (Tes) was measured as an index of internal temperature. In part A (rest), raising Tsk at rest from 31.9 +/- 0.3 to 36.7 +/- 0.2 degrees C increased CVC at control sites from 3 +/- 0.2 to 5 +/- 0.6% of CVCmax. CVC did not change at BT-treated sites, suggesting that at rest, with a normal internal temperature, reflex effects of raising Tsk on SkBF are mediated through vasoconstrictor withdrawal. In part B (exercise), exercise at a low Tsk increased Tes to 37.49 +/- 0.1 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

The primary reflex effects of distension of the stomach on heart rate, arterial pressure and left ventricular contractility in the anaesthetized pig

The present study was planned to investigate whether distension of the stomach primarily affects the heart rate, arterial blood pressure and left ventricular inotropic state and to explore the reflex mechanisms involved. In 16 anaesthetized pigs, distension of gastric balloons with 0.81 of Ringer solution (gastric transmural pressure of about 13 mmHg) without controlling any haemodynamic variable caused an increase in arterial blood pressure. When this response was prevented, an increase in heart rate was obtained in each animal. In five pigs, the increase in heart rate was graded by step increments of distension. No significant changes in maximum rate of change of left ventricular pressure were observed in the sixteen pigs during gastric distensions performed whilst preventing changes in heart rate and arterial blood pressure. The responses of arterial blood pressure and heart rate were not influenced by the administration of atropine (four and six pigs respectively), while they were abolished by the administration of bretylium tosylate (ten pigs) and by bilateral vagotomy (six pigs; three cervical, three subdiaphragmatic). The present study showed that gastric distension which was likely to be innocuous in the anaesthetized pig reflexly increased arterial blood pressure and heart rate. The afferent limb of the reflex was in the vagal nerves and the efferent limb involved sympathetic pathways.

Role of sympathetic nerves in the vascular effects of local temperature in human forearm skin.

The role of adrenergic nerve function in the cutaneous vascular response to changes in local skin temperature in the human forearm was examined using three protocols: 1) blocking release of norepinephrine presynaptically by local iontophoresis of bretylium (BT), 2) altering background adrenergic tone by changing whole body skin temperature, and 3) blocking cutaneous nerves by proximal infiltration of local anesthetic. Forearm skin blood flow was measured by laser-Doppler flowmetry (LDF) and cutaneous vascular conductance (CVC) was calculated as LDF/blood pressure. In protocol 1, local cooling (29 degrees C) elicited a rapid and sustained fall in CVC at control sites (-43 +/- 8%) in contrast to a biphasic response at BT-treated sites, consisting of an initial vasodilation followed by a vasoconstriction (percent change CVC = 28 +/- 13 and -34 +/- 18, respectively). Local warming (39 degrees C) increased CVC at control and at BT-treated sites by 331 +/- 46 and 139 +/- 31%, respectively. In protocol 2, at a neutral, cool, or warm whole body skin temperature, local cooling (29 degrees C) elicited similar reductions in CVC (-34 +/- 8, -29 +/- 5, and -30 +/- 4%, respectively), and local warming (38 degrees C) produced similar increases in CVC (89 +/- 15, 85 +/- 21, and 74 +/- 22%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of ventricular end-diastolic and systolic pressures on action potential and duration in anaesthetized dogs.

1. Although it is known that mechanical events in the heart influence the duration of the cardiac action potential, there is no quantitative information on the effects of independent changes in ventricular end-diastolic and systolic pressures. 2. Experiments were carried out on open-chest anaesthetized dogs in which the autonomic nervous influences on the heart were prevented and monophasic action potentials were recorded form the epicardial surface of the left ventricle. The duration of these action potentials was taken as the interval from the upstroke to the point of 90% repolarization. 3. Elevation of left ventricular peak systolic pressure, at constant end-diastolic pressure, significantly shortened the monophasic action potential. 4. Elevation of end-diastolic pressure at constant peak systolic pressure significantly lengthened the monophasic action potential. 5. Responses were not dependent on release of noradrenaline from sympathetic nerve terminals because they persisted after administration of bretylium tosylate. They were also not due to myocardial ischaemia because they persisted when coronary perfusion pressure was maintained at a constant high level. 6. Simultaneous recordings of changes in myocardial segment length showed the expected responses to changes in ventricular pressures: increases in shortening in response to increases in diastolic pressure and no consistent effect from changes in systolic pressure. 7. These investigations demonstrate the independent effects of changes in systolic and end-diastolic pressures on cardiac action potential duration. This effect is likely to be an effect of the mechanical events, i.e. contraction-excitation feedback. This response may be mediated through changes in myocardial fibre tension, the consequent changes in fibre shortening, or both.

Bretylium-induced voltage-gated sodium current in human lymphocytes

Using the whole-cell variation of the patch-clamp technique it has been determined that 0.25–3 mM bretylium tosylate (BT) exerts a repolarizing effect on partially depolarized human lymphocytes. The repolarizing effect was ouabain (40 μM)-sensitive, and was inhibited by the removal of external Na + or by the Na +-channel-blocker amiloride (10–44 μM), but K +-channel-blockers 4-aminopyridine (0.1–5 mM) and quinine (100 μM) had no effect. The drug induced a sodium dependent, amiloride-sensitive transient inward current reaching its maximum value approx. 20–30 s after the administration of BT and lasting for 6–10 min. This current was activated by depolarization within 25 ms at around −42 mV, its inactivation took about 2 s and its reversal potential was + 24 ±5 mV. An increase in the intracellular sodium concentration (1.8–3.2 mM) has been observed upon the addition of BT by monitoring the SBFI fluorescence of the dye-loaded cells. It has been shown that whole-cell K + currents are significantly decreased by BT. The existence of voltage and ligand (BT)-gated sodium channels has been postulated in human lymphocytes. These channels are thought to participate in the initiation of membrane repolarization in human lymphocytes, and thereby influence mitogenic or antigen-induced cell-activation processes.

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°C to 27°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°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.

New Sensitive Method for the Analysis of Some Non UV Absorbing Quaternised Compounds

Abstract A rapid first derivative spectrophotometric assay of bretylium tosylate, hyoscine butylbromide, oxyphenonium bromide, cetrimide and benzalkonium chloride in pure and in pharmaceutical formulation is developed, The assay depends upon extracting the picrate salt of these quaternised compounds into chloroform from aqueous medium and measurement of peak amplitude at 430 nm or peak - trough amplitude at 365/330 nm. Linear correlation over the concentration range of 5–20 ug ml−1 of the investigated compounds is obtained. The recovery percentage of the pure compound varied from 99.5 to 100.6%. The developed method is simple, sensitive, accurate and suitable for routine analysis of these quaternised compounds in bulk powder and in pharmaceutical formulations.

A sodium channel opener inhibits stimulation of human peripheral blood mononuclear cells

The role of membrane potential changes in T cell activation was studied on human peripheral blood lymphocytes stimulated with phytohemagglutinin. Addition of bretylium tosylate, a sodium channels opener, to PHA treated lymphocytes modified the membrane potential and consequently blocked cell activation in a dose-dependent fashion. BT was non-toxic even in long-term (72 hr) incubations. It was reversibly removable, and the removal restored the stimulatory effect of PHA. 3H-thymidine incorporation was blocked if BT was present during the first 20–24 hr of the mitogenic activation. The later BT was added after PHA, the less inhibition of proliferation was observed. BT hyperpolarized the lymphocytes also in the presence of PHA. BT hindered the depolarizing effect of high extracellular potassium concns. The sustained polarized state of the lymphocytes did not influence the intracellular calcium increase upon PHA treatment. IL-2 and transferrin receptor expression was not hindered by BT during PHA stimulation of lymphocytes. Addition of rIL-2 did not abolish the inhibitory effect of BT. According to cell-cycle analysis BT arrested the majority of the cells in G 1 phase. It is suggested that cell activation demands the flexible maintenance of a relatively narrow membrane potential “window”. Any sustained and significant hyper-, or depolarization, may dramatically decrease the effectivity of transmembrane signalling.

Aging impairs membrane potential responsiveness as well as opening of voltage and ligand gated Na + channels in human lymphocytes

Depolarizing effects of increasing concentrations of extracellular K +, as well as the repolarizing effect of bretylium tosylate (BT) were evaluated in human lymphocytes from young and elderly volunteers. Cells from elderly volunteers were less responsive to depolarization induced by increased extracellular potassium concentrations than those from young volunteers. Upon a near complete depolarization induced by 140 mM K + in the extracellular space, a significant amount of non-responding cells were found in samples from elderly volunteers. BT, which opens the otherwise silent Na + channels of partially depolarized cells, with subsequent activation of the Na +-K + pump (Pieri et al., 1989). repolarized both young and old lymphocytes. However, the degree of the repolarization was only 40% in the case of lymphocytes from elderly volunteers than from that of the young. It is suggested that an increase of membrane microviscosity, characteristic of old cells, may be at least partially responsible for the decreased responsiveness of plasma membrane functions which were observed.

Haemodynamic effects of distension of the descending colon in anaesthetized dogs.

1. This study was undertaken to determine whether distension of the descending colon in anaesthetized dogs reflexly affects the heart rate, arterial blood pressure or the left ventricular inotropic state. 2. Experiments were performed on twenty-six dogs, which were anaesthetized with sodium pentobarbitone and artificially ventilated. A segment of the distal descending colon was isolated and was distended with warm Ringer solution at a steady intraluminal pressure. 3. In each animal, distension of the colon caused an increase in heart rate and aortic blood pressure. The response of an increase in heart rate was augmented by preventing changes in aortic blood pressure, and was graded in seven dogs by step increments in the distending pressure. In the same animals, distension of the colon always caused a small increase in left ventricular (dP/dt)max at constant heart rate and aortic blood pressure. 4. In four of the twenty-six dogs, cutting the pelvic nerves did not abolish the observed responses to the distension. In seven of the twenty-six dogs, which included the four animals with sectioned pelvic nerves, cutting the hypogastric nerves completely abolished all the observed responses. 5. In thirteen of the twenty-six dogs, propranolol or bretylium tosylate completely abolished the reflex increases in heart rate and left ventricular (dP/dt)max, and phentolamine or bretylium tosylate abolished the reflex increase in aortic blood pressure. 6. These results showed that distension of the colon reflexly increased the heart rate, arterial blood pressure and left ventricular inotropic state. These reflex responses were mediated by sympathetic effects and their afferent limb involved the hypogastric nerves.

Control of internal temperature threshold for active cutaneous vasodilation by dynamic exercise

Exercise induces shifts in the internal temperature threshold at which cutaneous vasodilation begins. To find whether this shift is accomplished through the vasoconstrictor system or the cutaneous active vasodilator system, two forearm sites (0.64 cm2) in each of 11 subjects were iontophoretically treated with bretylium tosylate to locally block adrenergic vasoconstrictor control. Skin blood flow was monitored by laser-Doppler flowmetry (LDF) at those sites and at two adjacent untreated sites. Mean arterial pressure (MAP) was measured noninvasively. Cutaneous vascular conductance was calculated as LDF/MAP. Forearm sweat rate was also measured in seven of the subjects by dew point hygrometry. Whole body skin temperature was raised to 38 degrees C, and supine bicycle ergometer exercise was then performed for 7-10 min. The internal temperature at which cutaneous vasodilation began was recorded for all sites, as was the temperature at which sweating began. The same subjects also participated in studies of heat stress without exercise to obtain vasodilator and sudomotor thresholds from rest. The internal temperature thresholds for cutaneous vasodilation were higher during exercise at both bretylium-treated (36.95 +/- 0.07 degrees C rest, 37.20 +/- 0.04 degrees C exercise, P less than 0.05) and untreated sites (36.95 +/- 0.06 degrees C rest, 37.23 +/- 0.05 degrees C exercise, P less than 0.05). The thresholds for cutaneous vasodilation during rest or during exercise were not statistically different between untreated and bretylium-treated sites (P greater than 0.05). The threshold for the onset of sweating was not affected by exercise (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)