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Biomedical subjects

G E Isom

Publications and source records attributed to G E Isom.

At least 91 records · Page 5Linked to original sources
PubMed1987

Alteration of cytosolic calcium levels in PC12 cells by potassium cyanide.

The effect of KCN on cytosolic Ca2+ levels was measured in PC12 cells using Quin II/AM, a fluorometric calcium indicator. The resting cytosolic Ca2+ concentration, 115.0 +/- 4.9 nm, increased gradually and steadily over a 30-min time period following addition of 10(-4), 10(-3), or 10(-2)M KCN to the cells. After 15 min, 10(-3) and 10(-2)M KCN produced a three- and sixfold increase in the cytosolic Ca2+ concentration, respectively. In K+-depolarized cells, KCN induced a more rapid rise of intracellular calcium than in cells treated with KCN or KCI alone. KCN and/or K+-induced accumulation of cytosolic Ca2+ was blocked when the cells were pretreated with 10(-5)M diltiazem (a calcium channel blocker). These results demonstrate in a cell model that cyanide induces an accumulation of cytosolic Ca2+ and this additional cytosolic Ca2+ load appears to originate primarily from the extracellular compartment. This study supports previous reports implicating calcium as an intracellular mediator of cyanide toxicity.

Animals↗
PubMed1987

Studies of the hypotensive effect of calcium injected into lateral brain ventricles.

Calcium chloride (1-2 mumole) injected into lateral brain ventricles of pentobarbital anesthetized rats markedly decreases blood pressure. The hypotensive response is not affected by vagotomy and is characteristic calcium and barium since other polyvalent cations do not have the same effect. The calcium channel blocker, verapamil given into brain ventricles prevents the depressor effect of calcium suggesting that the hypotensive action of calcium is initiated intracellularly. The well documented lowering of blood pressure by increases in dietary intake of calcium may be mediated by increases in free calcium in cerebrospinal fluid.

Animals↗
PubMed1986

The hepatotoxic potential of combined toluene-chronic ethanol exposure.

The hepatotoxic properties of concurrent chronic oral ethanol ingestion and acute toluene inhalation were evaluated. Male rats were maintained on ethanol-containing or control liquid diets for 29 days. Animals of each group were subjected to five 20-min exposures to 10 000 ppm toluene with 30 min of room air inhalation between exposures on days 22, 24, 26, and 28 of liquid diet feeding. Some of the ethanol-fed animals were withdrawn from ethanol 14 h before exposure. Ethanol-withdrawn animals displayed an increased sensitivity to the narcotic action of toluene. Animals were sacrificed and assays performed on day 29. Stress markers (plasma corticosterone, free fatty acid, and glucose) were not affected by treatments. A modest elevation in plasma aspartate aminotransferase occurred in non-withdrawn animals receiving both ethanol and toluene. Ethanol-toluene exposure increased both relative liver weight and liver triglycerides. Toluene antagonized the hypertriglyceridemia associated with chronic ethanol ingestion. This study indicates that combined ethanol and toluene exposure has minor potential to induce acute liver injury, but results in altered deposition of hepatic triglycerides.

Animals↗
PubMed1986

Cyanide-induced neurotoxicity: role of neuronal calcium.

The effect of cyanide on whole-brain calcium levels was determined in mice administered KCN and correlated with the neurotoxic signs manifested during acute cyanide poisoning. KCN (10mg/kg, sc) significantly increased whole-brain total calcium levels from 48.1 +/- 1.8 to 66.5 +/- 3.9 micrograms/g dry wt within 15 min after administration. The levels remained elevated for 3 hr and returned to control readings after 12 hr. Dose-response studies revealed KCN, at doses of 10-15 mg/kg, produced significant elevations of whole-brain calcium 30 min after administration. No measurable effect was obtained from lower doses which suggested a threshold effect. Pretreatment 15 min before KCN with diltiazem, a calcium channel blocker, prevented the cyanide-induced rise in whole-brain total calcium. Cyanide-induced tremors, which are centrally mediated symptoms of intoxication, were quantified and correlated with the observed changes in whole-brain calcium. Tremors were detected at 10 and 12 mg/kg KCN and peak intensity was observed at 15 min postcyanide. Pretreatment with diltiazem markedly attenuated the cyanide-induced tremors. It appears that a correlation exists between cyanide-induced change in whole-brain calcium and tremors. This study suggests that intraneuronal calcium may play an important role in mediating cyanide neurotoxicity and calcium channel blocking agents may be useful in limiting the severity of the centrally mediated symptoms of acute cyanide intoxication.

Animals↗
PubMed1986

A new method for quantification of tremors in mice.

A procedure for quantifying whole-body tremors in mice was developed. Displacement of a free-floating platform by animal movement created a change in resistance across a strain gauge. The resulting resistive changes were assessed as voltage fluctuations by a wheatstone bridge and converted into an intensity-frequency profile by a series of calculations involving Fourier transformations. Movement profiles of normal mice were characterized by high-intensity, low-frequency peaks. Administration of oxotremorine, 2.5 mg/kg, ip, produced numerous high-frequency, high-intensity peaks within 5 min of administration. The peak frequency at 5 min after oxotremorine was approximately 15 Hz, and within 30 min the intensity-frequency profile had returned to control levels. In dose-response studies, a slight decrease in exploratory activity and initiation of low-level tremors was observed after 0.5 mg/kg. The most severe tremors were detected after a dose of 1.0 mg/kg. The peak frequency remained at approximately 15 Hz at 1.0 to 5.0 mg/kg, but varied greatly in intensity. This study describes an inexpensive, quantitative, sensitive, and rapid technique for quantifying tremors in mice.

Animals↗
PubMed1985

Anti-morphine anti-idiotypic antibodies. Opiate receptor binding and isolated tissue responses.

Anti-idiotypic antibodies which recognize the opiate receptor were generated in guinea pigs following immunization against purified rabbit anti-morphine antibodies. The anti-idiotypic antibodies produced a concentration-dependent inhibition of [3H]naloxone binding to opiate receptors in a membranous mouse brain preparation. Saturation analysis indicated that the antibodies produced a non-competitive inhibition of naloxone binding. The ability of the antibodies to interact with biological systems was investigated in in vitro systems. In both the isolated guinea pig ileal longitudinal muscle and mouse vas deferens, the antibodies produced a concentration-dependent, opiate agonist-like action. The anti-morphine anti-idiotypic antibodies appear to interact specifically with the opiate receptor and may serve as useful tools in characterization of this receptor system.

Animals↗
PubMed1985

Presence of dynorphin-like immunoreactivity but not opiate binding in Walker-256 tumors.

Walker-256 tumor tissue was removed from rats on day 8 of tumor growth. An acidified methanol extract of the tumor tissue was assayed for immunoreactive (ir) dynorphin-A 1-17 (DYN-17) and ir-dynorphin-A (DYN-8). Levels of ir-DYN-17 and ir-DYN-8 were nearly 4-and 8-fold higher, respectively, in tumors versus normal muscle. However, tumor homogenates did not exhibit specific 3H-naloxone binding. These results indicate that although the Walker-256 carcinosarcoma may produce opioids, it is unlikely that these ectopic substances have direct opioid actions on the tumor itself.

Animals↗
PubMed1985

The oxidative disposition of potassium cyanide in mice.

The role of oxidative metabolism in the disposition of potassium cyanide (KCN), was investigated in mice administered KCN, (4.6 mg/kg, s.c.) containing 4.5 microCi [14C]KCN. The expired pulmonary metabolites, [14C]hydrocyanic acid (HCN) and 14CO2, were collected and analyzed. Approximately 1% and 2% of the KCN dose was expired as [14C]HCN and 14CO2, respectively. Expiration of the pulmonary metabolites was decreased following pretreatment with sodium nitrite, sodium thiosulfate, oxygen, or a combination of cyanide antidotes. Treatment with hydrogen peroxide lowered the amount of [14C]HCN expired and did not alter the expiration of 14CO2. Treatment with 3-amino-1,2,4-triazole (catalase inhibitor), superoxide dismutase, or diethyldithiocarbamic acid (superoxide dismutase inhibitor) did not change the amount of [14C]HCN expired. However, superoxide dismutase significantly increased the amount of 14CO2 expired, whereas diethyldithiocarbamic acid decreased 14CO2 expiration. The results from these studies suggest that in vivo cyanide can be oxidized to CO2 and treatment with agents that alter the availability of endogenous superoxide and/or hydrogen peroxide can alter the rate of cyanide oxidation.

Amitrole↗
PubMed1984

Binding of antimorphine anti-idiotypic antibodies to opiate receptors.

Antibodies that specifically recognize and bind opiate receptors were developed by the anti-idiotypic method. Antimorphine antibodies were generated in rabbits and showed selective binding to various opiate ligands. Guinea pigs were immunized with antimorphine antibodies to produce anti-idiotypic antibodies that cross-reacted with opiate receptors. Guinea pig antiserum inhibited binding of naloxone (0.6 nmol) to mouse brain homogenate. In isolated mouse vas deferens, contraction of electrically stimulated tissue was inhibited by the antiserum. The results indicate that anti-idiotypic antibodies which interact with opiate receptors were developed without isolating receptors.

Animals↗
PubMed1984

Effects of oxygen on the antagonism of cyanide intoxication: cytochrome oxidase, in vitro.

Since oxygen was reported to be an effective cyanide antagonist in vivo, particularly in the presence of the classic antidotal combination of sodium nitrite and sodium thiosulfate, in vitro studies were initiated in an attempt to investigate the mechanism of oxygen-mediated cyanide antagonism. The effect of oxygen on cyanide-inhibited cytochrome oxidase with and without cyanide antagonist(s) was investigated in a purified membraneous enzyme system prepared from rat liver mitochondria. Cyanide produced a concentration dependent inhibition of cytochrome oxidase, and 100% oxygen did not alter the inhibition produced by KCN either in the presence or absence of sodium thiosulfate. However, the addition of sodium thiosulfate and rhodanese to the assay reactivated the cyanide-inhibited cytochrome oxidase. Kinetic analysis indicated rhodanese competes with cytochrome oxidase for cyanide, and oxygen had no effect on this coupled reaction. In conclusion, the in vivo antidotal properties of oxygen cannot be attributed to oxygen-mediated reactivation of cyanide-inhibited cytochrome oxidase or an oxygen-mediated acceleration of rhodanese detoxification.

Animals↗
PubMed1984

Recent perspectives on the toxicodynamic basis of cyanide antagonism.

The mechanism of action of nitrite-thiosulfate (Chen et al., 1933a ,b; Hug , 1933) in the antagonism of the lethal effects of cyanide is much more complex than proposed 50 years ago. Some of the recent findings concerning the mechanism of nitrite action have conceptual theoretical and practical significance, as the development of newer cyanide antagonists are dependent on the elucidation of the basic mechanism of antidotal action. There are preliminary evidence which suggest a vasogenic action rather than methemoglobin formation is the primary action of nitrite, as a cyanide antagonist. Various vasogenic compounds have been uncovered and they may play an important role in the future development of a new class of cyanide antagonists. Also recent development in thiol detoxication of cyanide suggest that rhodanese may play a more complex role. The detoxification of cyanide may be viewed from a considerably more complex perspective with the elucidation of recent mechanisms. It also may provide a newer conceptual basis for a more rational development of future compounds to antagonize the lethal effects of cyanide.

Animals↗
PubMed1983

Local application of cyclic AMP in the rat brain: characterization of the cardiovascular response.

Previous studies have demonstrated that central administration of dibutyryl cyclic AMP (DBcAMP) produces a dose-dependent rise in blood pressure accompanied by tachycardia. In an attempt to delineate brain sites that mediate these cardiovascular responses, DBcAMP was stereotaxically injected into local brain areas. Injections of 100 micrograms into the right lateral, third, and fourth ventricles produced pressor responses. Perfusion of the brain from the lateral ventricle to the cisterna magna with 15 micrograms/25 microliters per min induced a rise in blood pressure and significant bradycardia. The cyclic nucleotide was injected unilaterally in doses of 10, 25, and 50 micrograms into the posterior hypothalamic nucleus (PHN), anterior hypothalamic area (AHA), locus coeruleus (LC), and nucleus tractus solitarii (NTS). PHN injections induced tachycardia with minimal changes in blood pressure. Bradycardia and a depressor response were observed following injection of the 10 micrograms dose into the LC. Within the AHA, DBcAMP (10 micrograms) did not induce significant changes in cardiovascular function. Additionally, injections into the NTS initiated a biphasic depressor-pressor effect. Within these sites, cardiovascular responses to the 10 micrograms dose of DBcAMP paralleled those observed after adrenergic activation. These results strongly suggest that cyclic AMP functions as a second messenger within select central cardiovascular regulatory sites and plays an important role in cardiovascular regulation.

Animals↗
PubMed1983

Effect of chlorpromazine on cyanide intoxication.

Previous reports from our laboratory indicated that prophylactic protection against cyanide intoxication in mice can be enhanced by administration of chlorpromazine when it is given with sodium thiosulfate. The mechanism of potentiation of sodium thiosulfate by chlorpromazine was studied alone and in combination with sodium nitrite. Although chlorpromazine was found to induce a hypothermic response, the mechanism of enhancement of the antagonism of cyanide by chlorpromazine does not correlate with the hypothermia produced. Various other possible mechanisms were investigated, such as rate of methemoglobin formation, enzymatic activity of rhodanese and cytochrome oxidase, and alpha-adrenergic blockade. The alpha-adrenergic blocking properties of chlorpromazine may provide a basis for its antidotal effect, since this protective effect can be reversed with an alpha-agonist, methoxamine.

Animals↗
PubMed1983

Reversal of acetaminophen intoxication with an N-acetylcysteine-liposome preparation.

An N-acetyl-l-cysteine (NAC)-liposome drug delivery system was assessed for its ability to reverse acetaminophen toxicity. Positively charged NAC-liposomes, as compared to neutral and negatively charged preparations, were highly effective in reversing acetaminophen-induced lethality in mice. The positively charged liposome preparation, when administered at a dose equivalent to 50 mg/kg NAC, increased the LD50 of acetaminophen from 840 to 1507 mg/kg; free NAC (50 mg/kg) did not significantly alter the LD50 (829 mg/kg). At this dose, only the liposome entrapped NAC protects against acetaminophen-induced lethality suggesting that positively charged liposomes enhance the delivery of NAC to hepatic parenchymal cells, the site of acetaminophen-induced necrosis.

Acetaminophen↗
PubMed1982

Naloxone-induced enhancement of carbon dioxide stimulated respiration.

In unanesthetized rats, naloxone (5 mg/kg, s.c.) produced an increase in both respiratory frequency and tidal volume as compared to saline administered animals. Maximal respiratory stimulation was observed within 5 minutes after naloxone injection and duration of the response was greater than 30 minutes. Exposure to different atmospheres of carbon dioxide potentiated the increase in ventilation in a step-wise manner as the carbon dioxide concentration was increased. Pretreatment with low doses of morphine sulfate (2 mg/kg daily for 2 days) or naloxone HCl (5 mg/kg daily for 5 days) enhanced respiratory stimulation induced by naloxone. It was concluded that naloxone increases the sensitivity of central ventilatory response to carbon dioxide as a result of displacement of endogenous endorphins from central opioid receptors.

Animals↗
PubMed1982

Interaction of acute and chronic stress with respiration: modification by naloxone.

Rats exposed to inescapable foot shock displayed an increase in respiratory rate, tidal volume and minute volume. Naloxone HCl (5 mg/kg, SC) potentiated the foot shock-induced increase in ventilation. Inhalation of high (5% and 10%) concentrations of carbon dioxide enhanced the stimulation of ventilation observed in both the acute stressed animals and the acute stress-naloxone treated group. Chronic daily foot shock sessions (11 days) attenuated the respiratory stimulation produced by acute foot shock and the potentiation induced by naloxone. The appearance of foot shock-induced stimulation of respiration paralleled the production of acute foot shock-induced analgesia. On the other hand, chronic foot shock attenuated both stress-related analgesia and respiratory stimulation. These results strongly suggest stress can influence respiratory function through activation or release of the endogenous opioids. It is postulated that the endorphinergic system functions as a compensatory system which prevents excessive stimulation of respiration by stress.

Animals↗
PubMed1982

Effect of antagonists on the physiologic disposition of sodium cyanide.

Attempts were made to evaluate the effects of pretreatment with air and oxygen either alone or in various combinations with sodium nitrite and/or sodium thiosulfate on the physiological disposition of 14C-labeled sodium cyanide in mice. The radioactive respiratory excretion was studied by radiorespirometry, and the effects of various combinations of cyanide antagonists were compared. Oxygen either alone or in combination with sodium thiosulfate significantly enhanced the respiratory excretion when compared with air. Sodium thiosulfate accelerated the initial rate, but not the total amount of radioactivity excreted. The cumulative recovery of radioactive gases was significantly greater with groups receiving oxygen either alone or with sodium thiosulfate. When sodium nitrite was employed as an antidote either alone or with sodium thiosulfate, no difference in the respiratory excretion was noted between air and oxygen. The use of the sodium nitrite-sodium thiosulfate combination either with air or oxygen resulted in a marked decrease in the initial rate as well as the total amount of respiratory radioactivity excreted. No significant differences between various experimental groups were noted in the total amount of urinary radioactivity excreted or the total body retention of radioactivity.

Animals↗