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Experimental Physiology Oct 2020What is the central question of this study? Does the administration of the adrenergic presynaptic release inhibitor bretylium tosylate modulate sweating during exercise...
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 ( ) 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.
Topics: Adult; Bretylium Tosylate; Eccrine Glands; Exercise; Forearm; Hot Temperature; Humans; Iontophoresis; Male; Oxygen; Skin; Sweat; Sweating; Young Adult
PubMed: 32776611
DOI: 10.1113/EP088797 -
Canadian Medical Association Journal Apr 1965The treatment of essential hypertension still consists of the judicious combination of two or more agents. The chemical nature, pharmacology, side effects and relative... (Review)
Review
The treatment of essential hypertension still consists of the judicious combination of two or more agents. The chemical nature, pharmacology, side effects and relative merits of two groups of drugs are reviewed: (1) agents interfering with the synthesis, storage and release of endogenous catecholamines and (2) oral diuretic agents. Rauwolfia compounds, bretylium tosylate, guanethidine, alpha-methyldopa and pargyline hydrochloride comprise the first group; thiazide derivatives, phthalimidine compounds and spironolactones constitute the second. Guanethidine is the most potent and most extensively used agent in the second group. While not yet fully assessed, alpha-methyldopa and pargyline hydrochloride are useful in selected cases. The intrinsic hypotensive properties of oral diuretics, their low incidence of side effects and their ability to potentiate the more potent agents make them useful adjuncts in the long-term treatment of hypertension. Attention is drawn to the potential diabetogenic and hyperuricemic effects of the thiazides and phthalimidine compounds.
Topics: Antihypertensive Agents; Bretylium Compounds; Chlorothiazide; Chlorthalidone; Diuretics; Drug Therapy; Essential Hypertension; Guanethidine; Hydralazine; Hypertension; Methyldopa; Pargyline; Rauwolfia; Spironolactone; Toxicology
PubMed: 14289140
DOI: No ID Found -
Clinical Pharmacology and Therapeutics Oct 1980To compare the oral and intravenous disposition of bretylium tosylate in man, 10 normal male subjects were randomly assigned single doses of 5 mg/kg bretylium tosylate... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
To compare the oral and intravenous disposition of bretylium tosylate in man, 10 normal male subjects were randomly assigned single doses of 5 mg/kg bretylium tosylate either orally or intravenously and crossed over 2 wk later to the opposite route (20 studies). Each experiment included sampling for drug in serum and urine over 48 hr. Bretylium tosylate was assayed by gas chromatography. Kinetic analysis provided the following mean [coefficient of variation] results: 100FPo, 22.6% [40.2%]; ClrIV, 300 ml/min [27.8%]; ClrPo, 1.268 mg/min [54.8%]; ClBIV, 299 ml/min [31.9%]; f, 101% [8.7%]; Vdss, 3.37 l/kg [30.5%]; lambda lIV 0.0510 [12.8%]; lambda lPG, 0.115 [52.7%]hr-1; elimination half-life (t 1/2) after intravenous bretylium tosylate, 13.6 hr, and after oral bretylium tosylate, 6.0 hr (harmonic means). Bretylium tosylate binding to plasma proteins in normal volunteer samples was found to be negligible. The results indicate extensive tissue binding of bretylium tosylate. Oral doses of bretylium tosylate are only partially absorbed. Bretylium tosylate is eliminated entirely by the kidneys as unchanged drug. The greater renal clearance after oral than intravenous bretylium tosylate, and the greater elimination rate constant and shorter oral bretylium tosyulate t 1/2 are of interest but no explanation is available.
Topics: Administration, Oral; Adult; Blood Pressure; Blood Proteins; Bretylium Compounds; Bretylium Tosylate; Humans; Injections, Intravenous; Kidney; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Protein Binding
PubMed: 7408407
DOI: 10.1038/clpt.1980.190 -
The American Journal of Emergency... Jul 1992The effect of bretylium tosylate on plasma catecholamines and on electrically induced arrhythmias was evaluated in anesthetized hypothermic dogs. Bretylium at a dose of...
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.
Topics: Animals; Arrhythmias, Cardiac; Bretylium Tosylate; Dogs; Dopamine; Electric Stimulation; Electrophysiology; Epinephrine; Heart; Hemodynamics; Hypothermia; Male; Norepinephrine
PubMed: 1616517
DOI: 10.1016/0735-6757(92)90008-l -
Journal of the American College of... Aug 1983Electrophysiologic effects of bretylium tosylate on transmembrane action potentials of canine Purkinje fibers were studied by microelectrode methods. Perfusion of this...
Electrophysiologic effects of bretylium tosylate on transmembrane action potentials of canine Purkinje fibers were studied by microelectrode methods. Perfusion of this agent (20 mg/liter) prolonged the action potential duration and the effective refractory period, but did not alter the maximal diastolic potential, upstroke phase of the action potential and membrane responsiveness curve under normal oxygenation. With a hypoxic superfusion, the action potential amplitude, maximal diastolic potential, maximal rate of depolarization and action potential duration were all decreased. Subsequent addition of bretylium antagonized all these effects of hypoxia and restored the action potential variables to control values. However, similar effects of hypoxia observed in Purkinje fibers pretreated with reserpine were not reversed by bretylium except for a prolongation of repolarization. These results suggest that antiarrhythmic effects of bretylium in hypoxic or depressed myocardium are probably due to: 1) increased maximal rate of depolarization (and conduction velocity) caused by membrane hyperpolarization, and 2) prolongation of the effective refractory period. The first electrophysiologic action appears to depend on catecholamine release by bretylium, as hyperpolarization was not observed in reserpine-pretreated Purkinje fibers. The second effect may represent a direct membrane action.
Topics: Action Potentials; Animals; Bretylium Compounds; Bretylium Tosylate; Catecholamines; Diastole; Dogs; Heart Conduction System; Microelectrodes; Oxygen; Purkinje Fibers; Reserpine; Time Factors
PubMed: 6863763
DOI: 10.1016/s0735-1097(83)80165-x -
Journal of Applied Physiology... Aug 2007Hypoxia and hypercapnia represent special challenges to homeostasis because of their effects on sympathetic outflow and vascular smooth muscle. In the cutaneous...
Hypoxia and hypercapnia represent special challenges to homeostasis because of their effects on sympathetic outflow and vascular smooth muscle. In the cutaneous vasculature, even small changes in perfusion can shift considerable blood volume to the periphery and thereby impact both blood pressure regulation and thermoregulation. However, little is known about the influence of hypoxia and hypercapnia on this circulation. In the present study, 35 healthy subjects were instrumented with two microdialysis fibers in the ventral forearm. Each site was continuously perfused with saline (control) or bretylium tosylate (10 mM) to prevent sympathetically mediated vasoconstriction. Skin blood flow was assessed at each site (laser-Doppler flowmetry), and cutaneous vascular conductance (CVC) was calculated as red blood cell flux/mean arterial pressure and normalized to baseline. In 13 subjects, isocapnic hypoxia (85 and 80% O(2) saturation) increased CVC to 120 +/- 10 and 126 +/- 7% baseline in the control site (both P < 0.05) and 113 +/- 3 (P = 0.087) and 121 +/- 4% baseline (P < 0.05) in the bretylium site. Adrenergic blockade did not affect the magnitude of this response (P > 0.05). In nine subjects, hyperpnea (matching hypoxic increases in tidal volume) caused no change in CVC in either site (both P > 0.05). In 13 subjects, hypercapnia (+5 and +9 Torr) increased CVC to 111 +/- 4 and 111 +/- 4% baseline, respectively, in the control site (both P < 0.05), whereas the bretylium site remained unchanged (both P > 0.05). Thus both hypoxia and hypercapnia cause modest vasodilation in nonacral skin. Adrenergic vasoconstriction of neural origin does not restrain hypoxic vasodilation, but may be important in hypercapnic vasodilation.
Topics: Adult; Cell Hypoxia; Female; Humans; Hypercapnia; Male; Oxygen; Regional Blood Flow; Skin; Vasoconstriction; Vasodilation
PubMed: 17510298
DOI: 10.1152/japplphysiol.01443.2006 -
British Journal of Pharmacology Apr 19711. The actions of bretylium tosylate on neuromuscular transmission in the rat phrenic nerve diaphragm preparation have been investigated by electrophysiological methods....
1. The actions of bretylium tosylate on neuromuscular transmission in the rat phrenic nerve diaphragm preparation have been investigated by electrophysiological methods. Additional experiments have been made on the effect of the drug on the frog rectus preparation and on the acetylcholinesterase of erythrocytes.2. After bretylium, there was a reduction in the amplitudes of miniature end-plate potentials (mepps), endplate potentials (epps) and acetylcholine potentials recorded in the diaphragm, and also in the contractures of the rectus in response to acetylcholine (ACh) and to carbachol.3. After bretylium, there was a prolongation of the time courses of epps and ACh potentials. Under certain circumstances there was enhancement of the amplitudes of epps and ACh potentials and of the contractile responses to ACh but not to carbachol.4. Bretylium reduced the velocity of hydrolysis of ACh by erythrocyte ghosts. This inhibition was competitive and the Ki of bretylium was 0.053 mM.5. Bretylium did not cause a reduction in the mean quantal content of the epp in junctions blocked with Mg(++).6. It is concluded that bretylium exerts both facilitatory and inhibitory influences on neuromuscular transmission, which, exerted simultaneously, may give the false appearance that the drug has little action at this synapse.
Topics: Acetylcholine; Acetylcholinesterase; Animals; Bretylium Compounds; Carbachol; Diaphragm; Electrophysiology; Erythrocytes; Female; In Vitro Techniques; Magnesium; Male; Membrane Potentials; Muscle Contraction; Muscles; Neuromuscular Junction; Phrenic Nerve; Rats; Receptors, Cholinergic; Receptors, Drug
PubMed: 5103906
DOI: 10.1111/j.1476-5381.1971.tb07069.x -
British Journal of Pharmacology Jul 19691. The vasoconstrictor actions of tyramine, methylamphetamine and ephedrine on the blood vessels of the human hand have been found to be potentiated by administration...
1. The vasoconstrictor actions of tyramine, methylamphetamine and ephedrine on the blood vessels of the human hand have been found to be potentiated by administration intra-arterially of the adrenergic neurone blocking agent, bretylium tosylate.2. One mechanism suggested for the enhancement of vasoconstriction is that bretylium possesses monoamine oxidase inhibiting activity, which, in the case of tyramine, is protective both to the sympathomimetic agent and the intra-neuronal transmitter which it releases. In the case of methylamphetamine and ephedrine, which are not substrates for the enzyme, protection of the intra-neuronal transmitter alone might occur, accounting for the lesser degree of potentiation of the effect of these amines by bretylium.3. Comparison of the influences of bretylium and the monoamine oxidase inhibitor, tranylcypromine, on the vasoconstrictor action of the sympathomimetic agents shows a similar pattern of enhancement in the presence of both these drugs.4. Tranylcypromine caused enhancement of the response of the hand vessels to noradrenaline, and this action could contribute to its potentiation of the effect of the sympathomimetic amines.5. For a monoamine oxidase inhibiting action of bretylium to be effective in potentiating the constrictor actions of the sympathomimetic agents on the hand blood vessels at a time when reflex sympathetic activity is blocked it is necessary to postulate that these drugs and reflex nerve activity act either on different compartments of the transmitter store or by different release mechanisms.
Topics: Bretylium Compounds; Ephedrine; Hand; Humans; Injections, Intra-Arterial; Methamphetamine; Plethysmography; Regional Blood Flow; Sympathomimetics; Tranylcypromine; Tyramine
PubMed: 5789812
DOI: 10.1111/j.1476-5381.1969.tb08015.x -
The Journal of Physiology Jun 2014The time-dependent contributions of active vasodilation (e.g. nitric oxide) and noradrenergic vasoconstriction to the postexercise suppression of cutaneous perfusion...
The time-dependent contributions of active vasodilation (e.g. nitric oxide) and noradrenergic vasoconstriction to the postexercise suppression of cutaneous perfusion despite persistent hyperthermia remain unknown. Moreover, adenosine receptors have been shown to mediate the decrease in cutaneous perfusion following passive heating. We examined the time-dependent modulation of nitric oxide synthase, noradrenergic vasoconstriction and adenosine receptors on postexercise cutaneous perfusion. Eight males performed 15 min of high-intensity (85% VO2 max) cycling followed by 60 min of recovery in temperate ambient conditions (25°C). Four microdialysis probes were inserted into the forearm skin and continuously infused with: (1) lactated Ringer solution (Control); (2) 10 mm N(G)-nitro-l-arginine methyl ester (l-NAME; nitric oxide synthase inhibitor); (3) 10 mm bretylium tosylate (BT; inhibitor of noradrenergic vasoconstriction); or (4) 4 mm theophylline (THEO; adenosine receptor inhibitor). Cutaneous vascular conductance (CVC) was expressed as a percentage of maximum and was calculated as perfusion units (laser Doppler) divided by mean arterial pressure. End-exercise CVC was similar in Control, THEO and BT (P > 0.1), but CVC with l-NAME (39 ± 4%) was lower than Control (59 ± 4%, P < 0.01). At 20 min of recovery, Control CVC (22 ± 3%) returned to baseline levels (19 ± 2%, P = 0.11). Relative to Control, CVC was reduced by l-NAME for the first 10 min of recovery whereas CVC was increased with BT for the first 30 min of recovery (P < 0.03). In contrast, CVC with THEO was elevated throughout the 60 min recovery period (P ≤ 0.01) compared to Control. We show that adenosine receptors appear to have a major role in postexercise cutaneous perfusion whereas nitric oxide synthase and noradrenergic vasoconstriction are involved only earlier during recovery.
Topics: Adult; Body Temperature; Exercise; Humans; Male; Nitric Oxide Synthase; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Regional Blood Flow; Skin; Theophylline; Vasoconstriction; Young Adult
PubMed: 24687586
DOI: 10.1113/jphysiol.2014.274068 -
Journal of Applied Physiology... Sep 2003The hypothesis that exercise causes an increase in the postexercise esophageal temperature threshold for onset of cutaneous vasodilation through an alteration of active...
The hypothesis that exercise causes an increase in the postexercise esophageal temperature threshold for onset of cutaneous vasodilation through an alteration of active vasodilator activity was tested in nine subjects. Increases in forearm skin blood flow and arterial blood pressure were measured and used to calculate cutaneous vascular conductance at two superficial forearm sites: one with intact alpha-adrenergic vasoconstrictor activity (untreated) and one infused with bretylium tosylate (bretylium treated). Subjects remained seated resting for 15 min (no-exercise) or performed 15 min of treadmill running at either 55, 70, or 85% of peak oxygen consumption followed by 20 min of seated recovery. A liquid-conditioned suit was used to increase mean skin temperature ( approximately 4.0 degrees C/h), while local forearm temperature was clamped at 34 degrees C, until cutaneous vasodilation. No differences in the postexercise threshold for cutaneous vasodilation between untreated and bretylium-treated sites were observed for either the no-exercise or exercise trials. Exercise resulted in an increase in the postexercise threshold for cutaneous vasodilation of 0.19 +/- 0.01, 0.39 +/- 0.02, and 0.53 +/- 0.02 degrees C above those of the no-exercise resting values for the untreated site (P < 0.05). Similarly, there was an increase of 0.20 +/- 0.01, 0.37 +/- 0.02, and 0.53 +/- 0.02 degrees C for the treated site for the 55, 70, and 85% exercise trials, respectively (P < 0.05). It is concluded that reflex activity associated with the postexercise increase in the onset threshold for cutaneous vasodilation is more likely mediated through an alteration of active vasodilator activity rather than through adrenergic vasoconstrictor activity.
Topics: Adrenergic Agents; Adrenergic alpha-Antagonists; Adult; Anaerobic Threshold; Blood Pressure; Body Composition; Body Temperature; Bretylium Tosylate; Exercise; Female; Hot Temperature; Humans; Laser-Doppler Flowmetry; Male; Oxygen Consumption; Pressoreceptors; Regional Blood Flow; Skin; Skin Temperature; Vasodilation
PubMed: 12777407
DOI: 10.1152/japplphysiol.00361.2003