Reactive oxygen species produced in metal-catalyzed oxidation of bis(trifluoromethyl)disulfide and protection by ZE.

Bis(trifluoromethyl)disulfide (TFD), used as an industrial fumigant, was found to generate a thiyl free radical as seen by EPR/spin trapping. Oxygen appears to be an absolute requirement for radical production. The results obtained in this investigation implicate the production of thiyl and reactive oxygen species (ROS), superoxide radical anion and hydroxyl radicals, during TFD autoxidation. The rate of production of these free radical intermediates was found to increase in the presence of iron(III) and copper(II). In addition, the metal ion chelator DETAPAC and ROS scavengers ethanol, mannitol, and PEG-SOD/catalase were found to inhibit free radical production. Reactive oxygen species were not formed when a high-potency zinc plus antioxidant, ZE caps, was present. These results provide support for the pro-oxidation of TFD and a protective role for zinc.

Autoionization reaction of phosgene (OCCl2) studied by electron paramagnetic resonance/spin trapping techniques.

The reaction of phosgene with nitrone spin traps was investigated using electron paramagnetic resonance (EPR)/spin trapping techniques. Evidence for the intermediacy of a carbamoyl monochloride intermediate was obtained. Isotopic substitution of 13C-phosgene was employed to verify the hyperfine coupling constant assignments. The implications of these observations on pulmonary damage caused by inhalation of phosgene are mentioned.

Pyridostigmine used as a nerve agent pretreatment under wartime conditions.

OBJECTIVE: To determine the adverse effects of pretreatment with pyridostigmine bromide for nerve agent exposure during wartime. DESIGN: A retrospective study. SETTING: Southwest Asia. PARTICIPANTS: Personnel who provided medical support to the XVIII Airborne Corps. These medical officers supplied information pertaining to symptoms and disposition of 41,650 soldiers who received pyridostigmine at the onset of hostilities of Operation Desert Storm. INTERVENTION: Pyridostigmine bromide, 30 mg orally, was self-administered every 8 hours while under the threat of nerve agent attack (for 1 to 7 days). MAIN OUTCOME MEASURE: Physiologic changes attributable to pyridostigmine that resulted in need for medical attention, discontinuation of the drug, hospitalization, and/or evacuation from Southwest Asia. RESULTS: About half of the population noted physiologic changes that were not incapacitating, such as increased flatus, abdominal cramps, soft stools, and urinary urgency. Approximately 1% of the soldiers believed they had effects that warranted medical attention, but fewer than 0.1% had effects sufficient to discontinue the drug. Nonincapacitating symptoms often occurred; however, military mission performance was not impaired. CONCLUSION: While under the threat of nerve agent attack, pyridostigmine can be administered to virtually all soldiers.

Interactions between nerve agent pretreatment and drugs commonly used in combat anesthesia.

Pyridostigmine is a drug stockpiled for oral pretreatment of nerve agent exposure; however, the soldier is still vulnerable to conventional warfare injuries, which are commonly associated with the need for anesthesia and surgery. In order to determine if we should be concerned about pyridostigmine-drug interactions, a comprehensive search of existing literature on pyridostigmine and selected drugs contained in the Defense Medical Standardization Board D-Day Items list was completed. It appears that the most significant interaction might be with the neuromuscular blocking drugs used in anesthesia, which in turn could pose the greatest casualty management concerns. Other potential interactions are discussed, along with a review of the pharmacology of pyridostigmine.

Estimation of the LCt50 of phosgene in sheep.

In all species previously studied, inhalation of toxic doses of phosgene results in varying degrees of pulmonary edema, often after a symptom-free period. The sheep is an anatomically unique animal in which to study the development of pulmonary edema by monitoring the effluent from a catheterized caudal mediastinal lymph node. In addition, the size of the sheep is sufficient to permit placement of vascular monitoring devices and withdrawal of multiple biologic samples for analyses. In spite of this, there appear to be no published reports of sheep having ever been exposed to phosgene. This study was undertaken as a dose-ranging study, in order to permit subsequent studies of phosgene inhalation toxicity in a sheep lung lymph preparation. Accordingly, the LCt50 (24 hours) was estimated to be 13,300 mg.min/m3 (3325 ppm) by "up and down" subsequent dosage selection and moving average interpolation methods.

Thyrotropin-releasing hormone-immunoreactive neurons project from the ventral medulla to the intermediolateral cell column: partial coexistence with serotonin.

Projections from medullary thyrotropin-releasing hormone (TRH) containing neurons to the intermediolateral cell column (IML) of the thoracic spinal cord were studied in the rat. Lesions of the ventral medullary reticular formation nuclei, nucleus paragigantocellularis lateralis and nucleus interfascicularis hypoglossi, decreased the thyrotropin-releasing hormone immunoreactivity in the IML. The ventral horn and dorsal horn contents of TRH were also reduced in rats with nucleus paragigantocellularis lateralis lesions. Coexistence of spinal cord TRH and serotonin was evaluated and quantified in 5,7-dihydroxytryptamine-treated rats. Treatment with the serotonin neurotoxin reduced the TRH content of the IML by 45% and of the ventral horn by 92%. These data show that TRH containing neurons project from the ventral medulla to IML and that approximately one-half of these TRH neurons are also serotonergic. Comparisons of the effects of the same lesions on the substance P and TRH content of the IML show that neither the origin of the SP and TRH neuronal projections to the IML, nor their coexistence with serotonin, are identical.

Cardiovascular effects of spinal cord substance P: studies with a stable receptor agonist.

The role of spinal cord substance P (SP) in regulating sympathetic outflow to the cardiovascular system was assessed with the stable active analog [pGlu5,MePhE8,MeGly9]-SP(5-11) (DiME-SP). The interaction of DiME-SP with spinal cord SP receptors was evaluated initially in binding studies. Saturable, high-affinity binding of [125I]Bolton-Hunter-SP to rat spinal cord membranes was dose-dependently inhibited by DiME-SP (IC50 = 1.5 microM). Intrathecal (i.t.) injections of DiME-SP (1.0-33 nmol) in anesthetized rats produced dose-dependent increases in blood pressure and heart rate that were accompanied by increases in plasma epinephrine and norepinephrine. Intravenous injections of the ganglionic blocker pentolinium blocked the cardiovascular and plasma catecholamine responses to i.t. injections of DiME-SP. Bulbospinal sympathoexcitatory pathways originating in the ventral medulla and their mediation by SP were also assessed. As demonstrated previously, application of bicuculline, the gamma-aminobutyric acid receptor antagonist, to the ventral surface of the medulla produced sympathetic mediated increases in blood pressure and these effects were blocked by i.t. injection of the SP receptor antagonist [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-SP. In this study, we studied the specificity of the SP antagonist for SP receptors by attempting to alter the actions of the SP antagonist with a SP agonist. Administration of DiME-SP (33 nmol i.t.) blocked the effects of [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-SP (3.3 nmol i.t.). Specifically, the SP agonist countered the SP antagonist-mediated 1) hypotensive response and 2) inhibitory effect on bicuculline-induced sympathoexcitatory responses elicited from the ventral surface of the medulla. These data provide further evidence that SP transmits excitatory information to the cardiovascular system via spinal sympathetic pathways.

Spinal cord substance P mediates bicuculline-induced activation of cardiovascular responses from the ventral medulla.

Substance P (SP) and serotonin are contained in ventral medullary projections to the intermediolateral cell column (IML) of the spinal cord, and both neurotransmitters excite sympathetic preganglionic neurons upon injection into the IML. Since gamma-aminobutyric acid (GABA) in the ventral medulla inhibits, and GABA-receptor antagonists excite sympathetic outflow to the cardiovascular system, experiments were done to determine if SP and serotonin in the spinal cord were responsible for mediating these GABAergic effects. Anesthetized rats were either given intrathecal injections of SP antagonists acutely, or pretreated with intrathecal injections of the serotonin neurotoxin, 5,7-dihydroxytryptamine. The effects of these drugs on mean arterial pressure (MAP) and heart rate (HR), as well as their ability to block the responses to topical application of GABA or the GABA antagonist, bicuculline, at the ventral medulla were assessed. Three SP antagonists (50 micrograms) decreased MAP to 2/3 baseline values, but did not change HR. They also blocked the characteristic increases in MAP and HR elicited by application of bicuculline to the ventral medulla. A lower dose (5 micrograms) of a SP antagonist also decreased MAP and blocked the bicuculline-induced increases in MAP and HR, an effect which was reversed in 1-2 h. Neonatal capsaicin treatment reduced the SP content in the dorsal horns of the thoracic spinal cord, but did not affect the cardiovascular responses to intrathecal injection of SP antagonist nor the blockade of bicuculline-induced responses. Intrathecal injection of 5,7-dihydroxytryptamine two weeks prior to the experiments resulted in 56% depletion of serotonin in the thoracic spinal cord, but did not change either basal MAP and HR, nor the responses to bicuculline and GABA applied to the ventral surface of the medulla. These data provide evidence for a role of spinal cord SP in cardiovascular regulation.

Bulbospinal substance P and sympathetic regulation of the cardiovascular system: a review.

The neurotransmitter role of substance P in mediating sympathoexcitatory effects in the spinal cord and cardiovascular effects elicited from the ventral medulla is presented. SP neurons located in the ventral medulla project to the intermediolateral cell column (IML) of the thoracic spinal cord. Intrathecal administration of a SP analog excites sympathetic outflow to the cardiovascular system. Likewise, activation of the ventral medulla results in sympathetically mediated increases in blood pressure and heart rate which are blocked with SP antagonists. The IML contained a high density of SP binding sites through which the peptide likely exerts its sympathoexcitatory influence on the cardiovascular system.

The ventral surface of the medulla in the rat: pharmacologic and autoradiographic localization of GABA-induced cardiovascular effects.

Experiments were done to evaluate a rat model for studying the cardiovascular effects of pharmacological manipulations of the ventral surface of the medulla. GABAergic drugs were used because of their well-characterized actions at the ventral surface of the medulla in the cat. GABA and muscimol, applied to the exposed ventral surface with filter paper pledgets, produced dose-dependent decreases in heart rate (HR) and mean arterial pressure (MAP) which were reversed with bicuculline but not with strychnine. Bicuculline alone raised HR and MAP. The GABA- or bicuculline-induced cardiovascular effects were mediated primarily by inhibition of sympathetic outflow. The most sensitive site was localized to an intermediate area on the ventral surface of the medulla, between the trapezoid body and exits of the hypoglossal nerves and just lateral to the pyramids. Topical application of [3H]GABA to the intermediate area resulted in labeling that was concentrated at the site of application, and which penetrated the parenchyma 1 mm dorsally. The heaviest labeling was found primarily in the ventral halves of the lateral paragigantocellular nuclei. No tritium was detected in peripheral blood. These data provide evidence for a neuronal system at the ventral medullary surface of the rat which influences sympathetic outflow and is modulated by GABA.