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Biomedical subjects

S D Murphy

Publications and source records attributed to S D Murphy.

At least 55 records · Page 3Linked to original sources
PubMed1982

Antinociceptive and hypothermic effects of trimethyltin.

Trimethyltin (TMT) induced a dose-dependent antinociceptive and hypothermic effect in mice. Antinociception was not attenuated by naloxone but was reversed by atropine. TMT, however, was ineffective in displacing (3H)-QNB binding in vitro and did not affect (3H)-QNB binding or acetylcholinesterase activity after in vivo administration. The ethyl ester of nipecotic acid, a specific inhibitor of synaptosomal GABA uptake, exerted a similar antinociceptive effect that could be blocked by atropine. The GABA receptor antagonist bicuculline attenuated antinociception induced by TMT and nipecotic acid ethyl ester but not by morphine or oxotremorine. Gamma-Vinyl GABA, an irreversible inhibitor of GABA metabolism, prolonged TMT but not morphine-induced antinociception. In contrast, neither the dose-response nor the time course of TMT-induced hypothermia were affected by any of the drugs tested. The findings suggest that the GABAergic system may be involved in TMT induced antinociception; however, the mechanism responsible for the hypothermic effect of TMT is not apparent.

Animals↗
PubMed1982

The role of non-critical binding proteins in the sensitivity of acetylcholinesterase from different species to diisopropyl fluorophosphate (DFP), in vitro.

In vitro studies showed that organophosphate insecticides have different IC50 values (i.e., concentration of inhibitor required to inhibit 50% enzyme activity) for acetylcholinesterases (AChE's) from different species. Since previous reports indicated that the binding of active cholinesterase inhibitors to non-critical binding proteins is an important mechanism of detoxification of organophosphate insecticides in vivo, we investigated the role of non-critical binding proteins in synaptosomal membrane preparations from monkey, rat and chicken brain tissues as a possible explanation of the differences in the IC50's. The amount of non-critical binding proteins as well as critical binding sites, AChE, were determined by 3H-DFP binding in vitro. The affinity constants (Ka) and phosphorylation constants (Kp) of DFP for AChE's from these preparations were also determined by kinetic studies. In IC50 studies, monkey brain AChE was 1.5X and 3.2X more sensitive to DFP inhibition than chicken and rat brain AChE. The observed differences in IC50's cannot be explained on the basis of differences in the amount of non-critical binding proteins, since only small amount of non-critical binding proteins were found in these preparations. However, in the kinetic studies, monkey brain AChE had 3.7X and 2.1X higher affinity than chicken and rat brain AChE, respectively; and chicken brain AChE had about 2.7X faster rate of phosphorylation than the other two. It is therefore concluded that non-critical binding proteins are relatively unimportant in terms of affecting IC50's. The differences observed in IC50's are primarily due to different affinity and/or rate of phosphorylation of AChE active sites by DFP.

Acetylcholinesterase↗
PubMed1982

Muscarinic receptor alterations following neostigmine treatment.

Male mice administered neostigmine in the drinking water a daily increasing concentrations (20-100 mg/l) for four days became tolerant to its toxicity and presented a reduced binding of [3H]quinuclidinyl benzilate ([3H]QNB) in the small intestine. An increased binding of [3H]QNB was found in the forebrains of neostigmine-treated animals. This was due to an increase in muscarinic cholinergic receptor density. Neostigmine-treated animals were also more sensitive than control to the hypothermic effect induced by oxotremorine. Dopaminergic and alpha- and beta-adrenoceptor were not affected. Administration of methylatropine together with neostigmine prevented the decrease of [3H]QNB binding in the small intestine as well as the increase in the forebrain.

Animals↗
PubMed1982

Tolerance to anticholinesterase compounds in mammals.

Administration of multiple, sublethal doses of organophosphorus insecticides induces the development of tolerance to their toxicity. Among the different hypotheses investigated to explain the mechanism of this phenomenon, the one which has received the greatest experimental support is a downregulation of the muscarinic cholinergic receptors. Subsensitivity to cholinergic agonist has been demonstrated in vivo and in vitro in isolated organ preparations. Receptor binding experiments using muscarinic antagonists and agonists revealed a decrease of cholinergic receptors in central and peripheral tissues. Tolerance to another class of acetylcholinesterase inhibitors, carbamates has also been demonstrated. Differences from and similarities to organophosphate tolerance are discussed.

Animals↗
PubMed1982

Trimethyltin inhibits uptake of neurotransmitters into mouse forebrain synaptosomes.

Trimethyltin (TMT), in a concentration dependent manner, inhibits in vitro uptake of gamma-aminobutyric acid (GABA), norepinephrine and serotonin by mouse forebrain synaptosomes with IC50S of 75, 43 and 24 microM, respectively. At 2 h and 14 h following in vivo administration of TMT (4.26 mg/kg; i.p.) to mice, GABA and serotonin uptake by forebrain synaptosomes are decreased, although norepinephrine uptake was not significantly affected. In vitro kinetic analyses of TMT inhibition of forebrain synaptosomal uptake of GABA, norepinephrine and serotonin indicated that the inhibition was not of the competitive type. This inhibition of uptake of neurotransmitters could be responsible, at least in part, for altered neurotransmitter levels in the synaptic cleft and may contribute to altered nervous system function during TMT intoxication.

Animals↗
PubMed1982

Effect of trimethyltin on chemically-induced seizures.

The effect of trimethyltin (TMT; 4.26 mg/kg i.p.), at 1 and 14 h following administration, on chemically-induced seizures in mice is reported. At 1 h following administration, TMT decreased seizure responsiveness and protected animals from bicuculline, isonicotinic acid hydrazide (INH) and pentylenetetrazol (PTZ) induced seizures. At 14 h following administration, TMT provided little protection against bicuculline, INH or PTZ induced seizures. Only slight decreases in seizure responsiveness were observed with strychnine induced seizures at either 1 or 14 h. By 16 h following administration, animals exhibited spontaneous tremors and convulsions. The results indicate that TMT exerts a biphasic effect on central nervous system excitability.

Animals↗
PubMed1982

Filtration surgery in the treatment of neovascular glaucoma.

The disappointing visual acuity results following cyclocryotherapy for neovascular glaucoma have prompted us to consider filtration surgery as a reasonable alternative in the treatment of selected patients. All cases of surgically treated neovascular glaucoma were reviewed. There were 26 operations in 24 eyes with a follow-up ranging from six months to seven years and a mean of 22.8 months. Adequate pressure control was obtained in 16 of the 24 eyes (67%). In the eyes with successful control of intraocular pressure, vision was 20/400 or better in eight of the 16 eyes (50%). Four patients (17%) lost light perception. Approximately one half of the operations were trabeculectomies, and the others were posterior lip sclerectomies. There seemed to be no significant difference in the final intraocular pressure levels, number or degree of complications, or successes within the two subgroups. Panretinal photocoagulation, topical steroids, cycloplegics, and time for these measures to have their effect are important preoperative adjuncts to surgical treatment. We are encouraged by the long-term preservation of vision and control of intraocular pressure in many of these eyes.

Adult↗
PubMed1981

Potentiation by triorthotolyl phosphate of acrylate ester-induced alterations in respiration.

The purpose of this study was to determine whether triorthotolyl phosphate (TOTP), an inhibitor of carboxylesterases, would enhance the inhibitory effects of acrylate esters on respiration. Respiratory frequency was measured and the calculated decreases in respiratory frequency were used as an index of respiratory irritancy due to acrylate compounds. Tidal volume, minute ventilation, and rectal temperature were also measured. Dose-dependent decreases in frequency were found in rats inhaling methyl acrylate, ethyl acrylate and acrylic acid. Tidal volume was also reduced in rats exposed to acrylate compounds and, as a result, the percentage change in minute ventilation was greater than the percentage change in frequency or tidal volume alone. Pretreatment with TOTP (125 mg/kg) enhanced the decreases in frequency and minute ventilation caused by acrylate esters but not those resulting from exposure to acrylic acid. Exposure to ethyl acrylate and acrylic acid also resulted in dose-dependent reductions in rectal temperature. TOTP potentiated ethyl acrylate-induced decreases in rectal temperature but not those caused by acrylic acid. The results suggest that inhibition of carboxylesterases can result in enhanced irritant action of acrylate esters on the upper respiratory tract, and provide support for a local role of carboxylesterases in the detoxification of these irritant esters.

Acrylates↗
PubMed1981

Tolerance to the carbamate insecticide propoxur.

Male mice were given the carbamate insecticide propoxur (2-isopropoxy phenyl methylcarbamate; Baygon) in the drinking water at weekly increasing concentrations (from 50 to 2000 ppm), for a period of 6 weeks. At the end of the treatment the LD50 for propoxur was significantly higher in the treated animals as compared with controls. Propoxur-treated animals were also resistant to the hypothermic effect of an acute administration of the same compound. Groups of mice were challenged with the cholinergic agonist carbachol at intervals during the drinking water dosing and at its end. No differences in sensitivity to carbachol acute toxicity were found between control and treated animals. Propoxur-tolerant animals were also not resistant to the hypothermic effect of oxotremorine, another cholinergic agonist. [3H]Quinuclidinyl benzilate ([3H]QNB) binding (a measure of muscarinic receptor density and affinity) in forebrain, hindbrain and ileum never differed in control and treated mice. The possibility that repeated administrations of propoxur induced increased metabolic inactivation was tested by measuring hexobarbital sleeping time and carboxylesterase activity in treated and control mice. No changes in tissue carboxylesterase activities occurred but hexobarbital sleeping time was significantly reduced in propoxur treated animals suggesting an induction of hepatic microsomal enzymes. These results suggest that tolerance to propoxur is not mediated by a decrease of cholinergic receptors, as reported for other acetylcholinesterase inhibitors, but possibly by an enhancement of its metabolism.

Animals↗
PubMed1981

Reduced muscarinic receptor binding in tissues of rats tolerant to the insecticide disulfoton.

Tolerance to the toxic effects of exposure to the organophosphate acetylcholinesterase inhibitor, disulfoton, was induced by giving multiple, sublethal doses of the compound to male rats. Tolerance was judged to have been induced when toxic signs of exposure, including weight loss, were reversed or diminished. Binding of the specific muscarinic radioligand, [3H] quinuclidinyl benzilate ([3H] QNB) to ileal muscle, forebrain, and hindbrain from treated animals was significantly less than the amount bound to tissue from the control animals. Binding of [3H] QNB to heart tissue from tolerant animals was not different from control values. After a typical tolerance-inducing regimen of 7 doses of 2 mg/kg/day disulfoton followed by 4 doses of 3 mg/kg/day, [3H] QNB binding to heart from treated animals was 104% of controls, while binding to ileal muscle, forebrain, and hindbrain was 67, 69, and 77% of control values (p less than .001, .001 and .01), respectively. [3H] QNB binding was not decreased due to competition for binding sites with excess acetylcholine. Neither were decreases due to displacement by disulfoton, as an acute dose of disulfoton (which caused marked inhibition of acetylcholinesterase) did not result in decreased binding. The maximal binding (Bmax) to forebrain of tolerant animals was 56% of control (1.06 vs 1.88 pmol [3H] QNB mg protein-1, p less than 0.01), but no statistically significant change could be seen in equilibrium dissociation constants (Kd, 0.35 vs 0.36 nM). No changes in [3H] QNB binding constants occurred in hearts form tolerant animals. Differences between tolerant and control groups could be seen in [3H] QNB binding to striatum, but no alterations occurred in this brain area in the binding of dopaminergic or gabaergic radiolabels. The data presented in consistent with the hypothesis that cholinergic receptors are involved in organophosphate tolerance.

Animals↗
PubMed1979

Some concepts in toxicology.

Toxicology seeks to understand and quantify injurious chemico-biological interactions. The application of this understanding is prediction of the likelihood of occurrence of injury to human health or to undesirable alteration of ecological balance. The key to understanding chemical induced biological injury is development of improved methods of measuring changes in cellular function and structure and the application of these methods to elucidate the mechanisms and factors that modulate chemical injuries. The key to application of this understanding is appropriately designed dose-response and time-response studies which will, with appropriate consideration of biological mechanisms, allow prediction of conditions of exposure (and their confidence limits) that represent finite levels of risk of injury. The underlying data base required is extensive and will be drawn from traditional studies as well as new methods of testing and risk assessment.

Animals↗