The Experts below are selected from a list of 78 Experts worldwide ranked by ideXlab platform
C.b. Ferry - One of the best experts on this subject based on the ideXlab platform.
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The origin of the effects of an anticholinesterase on the latencies of action potentials in mouse skeletal muscles
British journal of pharmacology, 1994Co-Authors: S.s. Kelly, C.b. FerryAbstract:1. Subcutaneous injection in mice of a single dose of an organophosphorous anticholinesterase, Ecothiopate (0.5 mumol kg-1), produced increased variability in the latency (jitter) of indirectly-elicited action potentials in diaphragm muscles 5 days after treatment, but there was no effect on the variability of latencies of endplate potentials. This study was designed to elucidate the mechanism(s) of the increase in action potential jitter. 2. Action potentials evoked directly by electrical stimulation at one end of muscle fibres and recording near the other end had less jitter than indirectly-evoked action potentials and Ecothiopate had no effect on directly-evoked action potentials. 3. In preparations with uncut fibres, pretreatment with Ecothiopate reduced by about 20% both muscle fibre input resistance and the amplitude of spontaneous miniature endplate potentials. Ecothiopate had no effect on muscle fibre resting membrane potential or on the threshold potential for excitation. 4. In untreated preparations, indirectly-evoked action potentials recorded at the endplate had similar jitter to action potentials recorded at the tendon when latencies were measured at 10% of peak amplitude. However, when latencies were measured at peak, there was greater jitter of action potentials at the endplate. Ecothiopate increased jitter of action potentials recorded at the endplate at 10% of peak but did not significantly increase jitter of action potentials recorded at the endplate when measured at the peak. 5. In cut-fibre preparations, the first endplate potential of trains was significantly increased after Ecothiopate but there was no effect of Ecothiopate on the amplitude of plateau endplate potentials later in the train. Analysis of plateau endplate potentials showed that 5 days after administration, Ecothiopateproduced an increase in the variance of endplate potential amplitudes and changes in the binomial parameters n and p.6. It was concluded that the increased jitter produced by Ecothiopate is not a generalized effect on the plasma membrane and that none of the above observations could explain the increased jitter. The possibility is discussed that increased jitter is produced by variability in times to threshold of endplate potentials and/or by variability in the locus of generation of the action potential in the perijunctional area.
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Protection against the effects of anticholinesterases on the latencies of action potentials in mouse skeletal muscles
British journal of pharmacology, 1992Co-Authors: S.s. Kelly, C.b. Ferry, J.p. Bamforth, S.k. DasAbstract:Abstract 1. Adult male albino mice were injected subcutaneously with an organophosphorous anticholinesterase to initiate excessive variability in the latency of indirectly elicited muscle action potentials (jitter) when assessed 5 days later. 2. Pretreatment of the mice with a single dose of pyridostigmine prevented the development of jitter after subsequent dosing with an organophosphate. 3. Treatment with one dose of pralidoxime (2PAM) prevented the development of jitter if given less than 1 h after treatment with Ecothiopate, a reactivatable inhibitor of cholinesterase. Similar treatment with 2PAM after a non-reactivatable inhibitor did not prevent the development of jitter. The repeated administration of 2PAM over 12 h did ameliorate jitter. 4. Pretreatment of mice orally with alpha-tocopherol and N-acetylcysteine, known to prevent Ecothiopate-induced myopathy, did not prevent the development of jitter after Ecothiopate. 5. It is concluded that the development of jitter was a consequence of the inhibition of acetylcholinesterase, and although jitter did not develop acutely, the potential for the full development of jitter was achieved about 1 h after intoxication with Ecothiopate. The development of jitter did not involve the generation of free radicals. Reduction of the early effects of intoxication with anticholinesterases by pyridostigmine or 2PAM prevented the development of jitter.
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Myopathic changes in indirectly stimulated mouse diaphragm after Ecothiopate in vitro.
International journal of experimental pathology, 1991Co-Authors: C.b. Ferry, M. J. CullenAbstract:Mouse phrenic nerve-hemidiaphragms were stimulated in vitro in the presence of the anticholinesterase Ecothiopate iodide and prepared for light and electron microscopy at different times during and after the appearance of prolonged contractions localized at the endplate. The earliest changes were at the subsynapse, without damage to the plasma membrane, and comprised hypercontraction of the sarcomeres, dilatation and vesiculation of the sarcoplasmic reticulum and the mitochondria, and dissolution of the Z-lines. Later there was damage to the plasma membrane. Also appearing later in the junctional region, but separated from the subsynapse by apparently normal muscle, were extrasynaptic hypercontractions, with a plasma membrane initially undamaged, but which became permeable after the contractile material divided into contraction clots. A hypothesis is proposed for the formation of such hypercontractions by abnormal mechanical factors arising from different contractile states along the length of the fibre, and is discussed with the role of prolonged transmitter action in the aetiology of myopathy.
Peter G. Blain - One of the best experts on this subject based on the ideXlab platform.
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A Comparison of the Electrophysiological Effects of Two Organophosphates, Mipafox and Ecothiopate, on Mouse Limb Muscles☆
Toxicology and applied pharmacology, 1998Co-Authors: G. E. De Blaquière, Faith M. Williams, Peter G. Blain, Sean S. KellyAbstract:Adult male albino mice were given single subcutaneous injections of either mipafox (110 μmol/kg) or Ecothiopate (0.5 μmol/kg), two organophosphorus compounds (OPs). Acetylcholinesterase activity was measured in the soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch) muscles. At 7 and 28 days after dosing,in vitroelectrophysiological measurements were carried out in the soleus and EDL. Action potentials and end-plate potentials were evoked at 30 Hz and recorded intracellularly from single muscle fibers. The amplitudes, time course, and latencies of these potentials were measured and the variability (jitter) of latencies was calculated. Recordings after mipafox were also made with 3-Hz stimulation. Acetylcholinesterase activity was inhibited by mipafox (65% in the soleus; 76% in the EDL) and Ecothiopate (59% in the soleus; 42% in the EDL). Mipafox and Ecothiopate both increased postjunctional (muscle action potential) jitter in the soleus and EDL at 7 days after dosing. Organophosphates caused an increase in end-plate potential amplitudes in the soleus. Mipafox caused an increase in prejunctional (end-plate potential) jitter at 28 days after dosing in both muscles. A single dose of Ecothiopate also caused an increase in prejunctional jitter at 28 days in the soleus. The OP-induced increase in jitter was different at different frequencies of stimulation. The results show that there are electrophysiological changes in both muscles after administration of organophosphorus compounds. The slow-twitch soleus appears more sensitive to prejunctional changes caused by OPs than the fast-twitch EDL.
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The effects of multiple low doses of organophosphates on target enzymes in brain and diaphragm in the mouse.
Human & experimental toxicology, 1997Co-Authors: Faith M. Williams, C. Charlton, Gail E De Blaquière, Elaine Mutch, Sean S. Kelly, Peter G. BlainAbstract:1 Multiple low doses of the direct acting organopho sphates, Ecothiopate, paraoxon and mipafox produced persistent and additive inhibition of diaphragm acetylcholinesterase. Paraoxon and mipafox had similar effects on brain acetylcholinesterase. There was greater recovery from inhibition between doses for paraoxon and Ecothiopate than for mipafox.2 Ecothiopate did not inhibit brain acetylcholinesterase but there was a small increase in activity.3 Mipafox also had a cumulative inhibitory effect on brain neuropathy target esterase.4 These results have particular implication for the use of multiple low doses of organophosphates occupation- ally by man.
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Effects of multiple doses of organophosphates on evoked potentials in mouse diaphragm.
Human & experimental toxicology, 1997Co-Authors: Sean S. Kelly, Faith M. Williams, Gail E De Blaquière, Peter G. BlainAbstract:1. Male albino mice were injected s.c. with an organophosphate (mipafox, Ecothiopate or paraoxon). Treatments were either a single injection or multiple daily injections with lower doses for 5 or 8 days. At 3 h after injection the activity of brain and diaphragm acetylcholinesterase and of brain neuropathy target esterase (NTE) was measured. Also measured in the diaphragm at 3 h post dose was the duration of spontaneous miniature endplate potentials (eMEPPs), recorded extracellularly. 2. At 7 and 28 days after dosing action potentials and evoked endplate potentials, produced by stimulating the phrenic nerve at 30 Hz, were recorded in diaphragm muscle. The amplitudes, time-course and latencies of these potentials were measured and the variability of latencies (jitter) was calculated. 3. Single doses of mipafox (20 mg/kg), Ecothiopate (0.192 mg/kg) or paraoxon (0.415 mg/kg) in the mouse produced ca. 70% inhibition of diaphragm acetylcholinesterase at 3 h after dosing. All three OPs produced a prolongation of the half-decay times of eMEPPs. 4. All three OPs in the above single doses produced increased muscle action potential (postjunctional) jitter but only mipafox produced an increase in endplate potential (prejunctional) jitter. Mipafox in a slightly reduced single dose (17.5 mg/kg) had no effect on prejunctional or postjunctional jitter. 5. Multiple dosing with mipafox (8 mg/kg daily for 5 days) increased both postjunctional and prejunctional jitter at both 7 and 28 days after the end of dosing. After multiple dosing with mipafox (5 mg/kg daily for 5 days) postjunctional (but not prejunctional) jitter was increased. Multiple doses of paraoxon (0.166 mg/kg daily for 5 days) or Ecothiopate (0.76 mg/kg daily for 5 days) increased prejunctional and postjunctional jitter. 6. Depending on the dosing regime, all three OPs tested were capable of increasing both prejunctional and postjunctional jitter. Neither Ecothiopate nor paraoxon inhibited NTE, so this prejunctional effect is not likely to be related to 'classical' OP-induced delayed neuropathy. The prejunctional effects may be related to long-term inhibition of acetylcholinesterase and the triggering mechanism for increase in prejunctional jitter may involve a relationship between the inhibition of acetylcholinesterase and the time for which it is inhibited. The differences between the time-courses of increases in prejunctional and postjunctional jitter and the differential effects of the different multiple dosing regimes indicate that it is likely that the triggering relationship between enzyme inhibition and time is different for prejunctional and postjunctional effects.
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Comparative studies of two organophosphorus compounds in the mouse.
Toxicology letters, 1995Co-Authors: Elaine Mutch, Sean S. Kelly, Peter G. Blain, Faith M. WilliamsAbstract:A rodent model, the albino mouse, was used to investigate the in vitro and in vivo capacity of 2 organophosphate (OP) compounds, mipafox and Ecothiopate, to inhibit enzymes considered to be involved in the mechanisms of OP toxicity. Mipafox and Ecothiopate were chosen as model compounds because the former can produce a delayed neuropathy whereas the latter does not. Mipafox (110 mumol/kg, s.c.) inhibited brain acetylcholinesterase (AChE), neuropathy target esterase (NTE) and phenylvalerate hydrolases by 58, 64 and 65%, while diaphragm AChE and phenylvalerate hydrolases were inhibited by 66 and 80%, respectively. In contrast, Ecothiopate (0.5 mumol/kg) had no effect on brain NTE or on brain or diaphragm phenylvalerate hydrolases. At the same time, diaphragm AChE was inhibited by 60% while brain AChE activity had increased by 15% of control. Mipafox was a potent inhibitor of AChE and NTE in vitro. Although Ecothiopate was a highly potent anti-ChE in vitro, it had no inhibitory effect on NTE.
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Electrophysiological and biochemical effects following single doses of organophosphates in the mouse
Archives of Toxicology, 1994Co-Authors: Sean S. Kelly, Faith M. Williams, Elaine Mutch, Peter G. BlainAbstract:Single doses of organophosphates (mipafox or Ecothiopate) were given subcutaneously to mice. At intervals up to 77 days after dosing animals were killed and muscle action potentials and endplate potentials were recorded intracellularly in mouse phrenic-nerve/hemidiaphragm preparations. Activities of acetylcholinesterase and neuropathy target esterase in brain and acetylcholinesterase in diaphragm were also measured. Mipafox (0.11 mmol/kg), a neurotoxic organophosphate, produced an increase in prejunctional jitter (i. e. the variabilities of the latencies) of endplate potentials. This increase began 14–21 days after administration and lasted more than 23 days. No clinical signs of neuropathy were observed during this study. Mipafox also produced an increase in postjunctional (muscle action potential) jitter. Mipafox inhibited brain and diaphragm acetylcholinesterase and brain neuropathy target esterase. By comparison, a non-neurotoxic organophosphate, Ecothiopate (0.5 μmol/kg), was a potent inhibitor of diaphragm acetylcholinesterase and produced a large increase in postjunctional jitter but Ecothiopate did not inhibit brain neuropathy target esterase and had no effect on prejunctional jitter. Doses were chosen so that the inhibition of diaphragm acetylcholinesterase by each of the two organophosphates was similar. It is concluded that the neurotoxic organophosphate, mipafox, produced measurable changes in nerve function. These long-term changes may represent a new phenomenon, unrelated to the classical organophosphate induced delayed neuropathy. Alternatively, they may represent a neuropathic process which precedes or is below the threshold for clinical signs.
Sean S. Kelly - One of the best experts on this subject based on the ideXlab platform.
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A Comparison of the Electrophysiological Effects of Two Organophosphates, Mipafox and Ecothiopate, on Mouse Limb Muscles☆
Toxicology and applied pharmacology, 1998Co-Authors: G. E. De Blaquière, Faith M. Williams, Peter G. Blain, Sean S. KellyAbstract:Adult male albino mice were given single subcutaneous injections of either mipafox (110 μmol/kg) or Ecothiopate (0.5 μmol/kg), two organophosphorus compounds (OPs). Acetylcholinesterase activity was measured in the soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch) muscles. At 7 and 28 days after dosing,in vitroelectrophysiological measurements were carried out in the soleus and EDL. Action potentials and end-plate potentials were evoked at 30 Hz and recorded intracellularly from single muscle fibers. The amplitudes, time course, and latencies of these potentials were measured and the variability (jitter) of latencies was calculated. Recordings after mipafox were also made with 3-Hz stimulation. Acetylcholinesterase activity was inhibited by mipafox (65% in the soleus; 76% in the EDL) and Ecothiopate (59% in the soleus; 42% in the EDL). Mipafox and Ecothiopate both increased postjunctional (muscle action potential) jitter in the soleus and EDL at 7 days after dosing. Organophosphates caused an increase in end-plate potential amplitudes in the soleus. Mipafox caused an increase in prejunctional (end-plate potential) jitter at 28 days after dosing in both muscles. A single dose of Ecothiopate also caused an increase in prejunctional jitter at 28 days in the soleus. The OP-induced increase in jitter was different at different frequencies of stimulation. The results show that there are electrophysiological changes in both muscles after administration of organophosphorus compounds. The slow-twitch soleus appears more sensitive to prejunctional changes caused by OPs than the fast-twitch EDL.
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The effects of multiple low doses of organophosphates on target enzymes in brain and diaphragm in the mouse.
Human & experimental toxicology, 1997Co-Authors: Faith M. Williams, C. Charlton, Gail E De Blaquière, Elaine Mutch, Sean S. Kelly, Peter G. BlainAbstract:1 Multiple low doses of the direct acting organopho sphates, Ecothiopate, paraoxon and mipafox produced persistent and additive inhibition of diaphragm acetylcholinesterase. Paraoxon and mipafox had similar effects on brain acetylcholinesterase. There was greater recovery from inhibition between doses for paraoxon and Ecothiopate than for mipafox.2 Ecothiopate did not inhibit brain acetylcholinesterase but there was a small increase in activity.3 Mipafox also had a cumulative inhibitory effect on brain neuropathy target esterase.4 These results have particular implication for the use of multiple low doses of organophosphates occupation- ally by man.
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Effects of multiple doses of organophosphates on evoked potentials in mouse diaphragm.
Human & experimental toxicology, 1997Co-Authors: Sean S. Kelly, Faith M. Williams, Gail E De Blaquière, Peter G. BlainAbstract:1. Male albino mice were injected s.c. with an organophosphate (mipafox, Ecothiopate or paraoxon). Treatments were either a single injection or multiple daily injections with lower doses for 5 or 8 days. At 3 h after injection the activity of brain and diaphragm acetylcholinesterase and of brain neuropathy target esterase (NTE) was measured. Also measured in the diaphragm at 3 h post dose was the duration of spontaneous miniature endplate potentials (eMEPPs), recorded extracellularly. 2. At 7 and 28 days after dosing action potentials and evoked endplate potentials, produced by stimulating the phrenic nerve at 30 Hz, were recorded in diaphragm muscle. The amplitudes, time-course and latencies of these potentials were measured and the variability of latencies (jitter) was calculated. 3. Single doses of mipafox (20 mg/kg), Ecothiopate (0.192 mg/kg) or paraoxon (0.415 mg/kg) in the mouse produced ca. 70% inhibition of diaphragm acetylcholinesterase at 3 h after dosing. All three OPs produced a prolongation of the half-decay times of eMEPPs. 4. All three OPs in the above single doses produced increased muscle action potential (postjunctional) jitter but only mipafox produced an increase in endplate potential (prejunctional) jitter. Mipafox in a slightly reduced single dose (17.5 mg/kg) had no effect on prejunctional or postjunctional jitter. 5. Multiple dosing with mipafox (8 mg/kg daily for 5 days) increased both postjunctional and prejunctional jitter at both 7 and 28 days after the end of dosing. After multiple dosing with mipafox (5 mg/kg daily for 5 days) postjunctional (but not prejunctional) jitter was increased. Multiple doses of paraoxon (0.166 mg/kg daily for 5 days) or Ecothiopate (0.76 mg/kg daily for 5 days) increased prejunctional and postjunctional jitter. 6. Depending on the dosing regime, all three OPs tested were capable of increasing both prejunctional and postjunctional jitter. Neither Ecothiopate nor paraoxon inhibited NTE, so this prejunctional effect is not likely to be related to 'classical' OP-induced delayed neuropathy. The prejunctional effects may be related to long-term inhibition of acetylcholinesterase and the triggering mechanism for increase in prejunctional jitter may involve a relationship between the inhibition of acetylcholinesterase and the time for which it is inhibited. The differences between the time-courses of increases in prejunctional and postjunctional jitter and the differential effects of the different multiple dosing regimes indicate that it is likely that the triggering relationship between enzyme inhibition and time is different for prejunctional and postjunctional effects.
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Comparative studies of two organophosphorus compounds in the mouse.
Toxicology letters, 1995Co-Authors: Elaine Mutch, Sean S. Kelly, Peter G. Blain, Faith M. WilliamsAbstract:A rodent model, the albino mouse, was used to investigate the in vitro and in vivo capacity of 2 organophosphate (OP) compounds, mipafox and Ecothiopate, to inhibit enzymes considered to be involved in the mechanisms of OP toxicity. Mipafox and Ecothiopate were chosen as model compounds because the former can produce a delayed neuropathy whereas the latter does not. Mipafox (110 mumol/kg, s.c.) inhibited brain acetylcholinesterase (AChE), neuropathy target esterase (NTE) and phenylvalerate hydrolases by 58, 64 and 65%, while diaphragm AChE and phenylvalerate hydrolases were inhibited by 66 and 80%, respectively. In contrast, Ecothiopate (0.5 mumol/kg) had no effect on brain NTE or on brain or diaphragm phenylvalerate hydrolases. At the same time, diaphragm AChE was inhibited by 60% while brain AChE activity had increased by 15% of control. Mipafox was a potent inhibitor of AChE and NTE in vitro. Although Ecothiopate was a highly potent anti-ChE in vitro, it had no inhibitory effect on NTE.
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Electrophysiological and biochemical effects following single doses of organophosphates in the mouse
Archives of Toxicology, 1994Co-Authors: Sean S. Kelly, Faith M. Williams, Elaine Mutch, Peter G. BlainAbstract:Single doses of organophosphates (mipafox or Ecothiopate) were given subcutaneously to mice. At intervals up to 77 days after dosing animals were killed and muscle action potentials and endplate potentials were recorded intracellularly in mouse phrenic-nerve/hemidiaphragm preparations. Activities of acetylcholinesterase and neuropathy target esterase in brain and acetylcholinesterase in diaphragm were also measured. Mipafox (0.11 mmol/kg), a neurotoxic organophosphate, produced an increase in prejunctional jitter (i. e. the variabilities of the latencies) of endplate potentials. This increase began 14–21 days after administration and lasted more than 23 days. No clinical signs of neuropathy were observed during this study. Mipafox also produced an increase in postjunctional (muscle action potential) jitter. Mipafox inhibited brain and diaphragm acetylcholinesterase and brain neuropathy target esterase. By comparison, a non-neurotoxic organophosphate, Ecothiopate (0.5 μmol/kg), was a potent inhibitor of diaphragm acetylcholinesterase and produced a large increase in postjunctional jitter but Ecothiopate did not inhibit brain neuropathy target esterase and had no effect on prejunctional jitter. Doses were chosen so that the inhibition of diaphragm acetylcholinesterase by each of the two organophosphates was similar. It is concluded that the neurotoxic organophosphate, mipafox, produced measurable changes in nerve function. These long-term changes may represent a new phenomenon, unrelated to the classical organophosphate induced delayed neuropathy. Alternatively, they may represent a neuropathic process which precedes or is below the threshold for clinical signs.
Faith M. Williams - One of the best experts on this subject based on the ideXlab platform.
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A Comparison of the Electrophysiological Effects of Two Organophosphates, Mipafox and Ecothiopate, on Mouse Limb Muscles☆
Toxicology and applied pharmacology, 1998Co-Authors: G. E. De Blaquière, Faith M. Williams, Peter G. Blain, Sean S. KellyAbstract:Adult male albino mice were given single subcutaneous injections of either mipafox (110 μmol/kg) or Ecothiopate (0.5 μmol/kg), two organophosphorus compounds (OPs). Acetylcholinesterase activity was measured in the soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch) muscles. At 7 and 28 days after dosing,in vitroelectrophysiological measurements were carried out in the soleus and EDL. Action potentials and end-plate potentials were evoked at 30 Hz and recorded intracellularly from single muscle fibers. The amplitudes, time course, and latencies of these potentials were measured and the variability (jitter) of latencies was calculated. Recordings after mipafox were also made with 3-Hz stimulation. Acetylcholinesterase activity was inhibited by mipafox (65% in the soleus; 76% in the EDL) and Ecothiopate (59% in the soleus; 42% in the EDL). Mipafox and Ecothiopate both increased postjunctional (muscle action potential) jitter in the soleus and EDL at 7 days after dosing. Organophosphates caused an increase in end-plate potential amplitudes in the soleus. Mipafox caused an increase in prejunctional (end-plate potential) jitter at 28 days after dosing in both muscles. A single dose of Ecothiopate also caused an increase in prejunctional jitter at 28 days in the soleus. The OP-induced increase in jitter was different at different frequencies of stimulation. The results show that there are electrophysiological changes in both muscles after administration of organophosphorus compounds. The slow-twitch soleus appears more sensitive to prejunctional changes caused by OPs than the fast-twitch EDL.
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The effects of multiple low doses of organophosphates on target enzymes in brain and diaphragm in the mouse.
Human & experimental toxicology, 1997Co-Authors: Faith M. Williams, C. Charlton, Gail E De Blaquière, Elaine Mutch, Sean S. Kelly, Peter G. BlainAbstract:1 Multiple low doses of the direct acting organopho sphates, Ecothiopate, paraoxon and mipafox produced persistent and additive inhibition of diaphragm acetylcholinesterase. Paraoxon and mipafox had similar effects on brain acetylcholinesterase. There was greater recovery from inhibition between doses for paraoxon and Ecothiopate than for mipafox.2 Ecothiopate did not inhibit brain acetylcholinesterase but there was a small increase in activity.3 Mipafox also had a cumulative inhibitory effect on brain neuropathy target esterase.4 These results have particular implication for the use of multiple low doses of organophosphates occupation- ally by man.
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Effects of multiple doses of organophosphates on evoked potentials in mouse diaphragm.
Human & experimental toxicology, 1997Co-Authors: Sean S. Kelly, Faith M. Williams, Gail E De Blaquière, Peter G. BlainAbstract:1. Male albino mice were injected s.c. with an organophosphate (mipafox, Ecothiopate or paraoxon). Treatments were either a single injection or multiple daily injections with lower doses for 5 or 8 days. At 3 h after injection the activity of brain and diaphragm acetylcholinesterase and of brain neuropathy target esterase (NTE) was measured. Also measured in the diaphragm at 3 h post dose was the duration of spontaneous miniature endplate potentials (eMEPPs), recorded extracellularly. 2. At 7 and 28 days after dosing action potentials and evoked endplate potentials, produced by stimulating the phrenic nerve at 30 Hz, were recorded in diaphragm muscle. The amplitudes, time-course and latencies of these potentials were measured and the variability of latencies (jitter) was calculated. 3. Single doses of mipafox (20 mg/kg), Ecothiopate (0.192 mg/kg) or paraoxon (0.415 mg/kg) in the mouse produced ca. 70% inhibition of diaphragm acetylcholinesterase at 3 h after dosing. All three OPs produced a prolongation of the half-decay times of eMEPPs. 4. All three OPs in the above single doses produced increased muscle action potential (postjunctional) jitter but only mipafox produced an increase in endplate potential (prejunctional) jitter. Mipafox in a slightly reduced single dose (17.5 mg/kg) had no effect on prejunctional or postjunctional jitter. 5. Multiple dosing with mipafox (8 mg/kg daily for 5 days) increased both postjunctional and prejunctional jitter at both 7 and 28 days after the end of dosing. After multiple dosing with mipafox (5 mg/kg daily for 5 days) postjunctional (but not prejunctional) jitter was increased. Multiple doses of paraoxon (0.166 mg/kg daily for 5 days) or Ecothiopate (0.76 mg/kg daily for 5 days) increased prejunctional and postjunctional jitter. 6. Depending on the dosing regime, all three OPs tested were capable of increasing both prejunctional and postjunctional jitter. Neither Ecothiopate nor paraoxon inhibited NTE, so this prejunctional effect is not likely to be related to 'classical' OP-induced delayed neuropathy. The prejunctional effects may be related to long-term inhibition of acetylcholinesterase and the triggering mechanism for increase in prejunctional jitter may involve a relationship between the inhibition of acetylcholinesterase and the time for which it is inhibited. The differences between the time-courses of increases in prejunctional and postjunctional jitter and the differential effects of the different multiple dosing regimes indicate that it is likely that the triggering relationship between enzyme inhibition and time is different for prejunctional and postjunctional effects.
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Comparative studies of two organophosphorus compounds in the mouse.
Toxicology letters, 1995Co-Authors: Elaine Mutch, Sean S. Kelly, Peter G. Blain, Faith M. WilliamsAbstract:A rodent model, the albino mouse, was used to investigate the in vitro and in vivo capacity of 2 organophosphate (OP) compounds, mipafox and Ecothiopate, to inhibit enzymes considered to be involved in the mechanisms of OP toxicity. Mipafox and Ecothiopate were chosen as model compounds because the former can produce a delayed neuropathy whereas the latter does not. Mipafox (110 mumol/kg, s.c.) inhibited brain acetylcholinesterase (AChE), neuropathy target esterase (NTE) and phenylvalerate hydrolases by 58, 64 and 65%, while diaphragm AChE and phenylvalerate hydrolases were inhibited by 66 and 80%, respectively. In contrast, Ecothiopate (0.5 mumol/kg) had no effect on brain NTE or on brain or diaphragm phenylvalerate hydrolases. At the same time, diaphragm AChE was inhibited by 60% while brain AChE activity had increased by 15% of control. Mipafox was a potent inhibitor of AChE and NTE in vitro. Although Ecothiopate was a highly potent anti-ChE in vitro, it had no inhibitory effect on NTE.
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Electrophysiological and biochemical effects following single doses of organophosphates in the mouse
Archives of Toxicology, 1994Co-Authors: Sean S. Kelly, Faith M. Williams, Elaine Mutch, Peter G. BlainAbstract:Single doses of organophosphates (mipafox or Ecothiopate) were given subcutaneously to mice. At intervals up to 77 days after dosing animals were killed and muscle action potentials and endplate potentials were recorded intracellularly in mouse phrenic-nerve/hemidiaphragm preparations. Activities of acetylcholinesterase and neuropathy target esterase in brain and acetylcholinesterase in diaphragm were also measured. Mipafox (0.11 mmol/kg), a neurotoxic organophosphate, produced an increase in prejunctional jitter (i. e. the variabilities of the latencies) of endplate potentials. This increase began 14–21 days after administration and lasted more than 23 days. No clinical signs of neuropathy were observed during this study. Mipafox also produced an increase in postjunctional (muscle action potential) jitter. Mipafox inhibited brain and diaphragm acetylcholinesterase and brain neuropathy target esterase. By comparison, a non-neurotoxic organophosphate, Ecothiopate (0.5 μmol/kg), was a potent inhibitor of diaphragm acetylcholinesterase and produced a large increase in postjunctional jitter but Ecothiopate did not inhibit brain neuropathy target esterase and had no effect on prejunctional jitter. Doses were chosen so that the inhibition of diaphragm acetylcholinesterase by each of the two organophosphates was similar. It is concluded that the neurotoxic organophosphate, mipafox, produced measurable changes in nerve function. These long-term changes may represent a new phenomenon, unrelated to the classical organophosphate induced delayed neuropathy. Alternatively, they may represent a neuropathic process which precedes or is below the threshold for clinical signs.
Paul M. Vanhoutte - One of the best experts on this subject based on the ideXlab platform.
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Mediation by M3‐muscarinic receptors of both endothelium‐dependent contraction and relaxation to acetylcholine in the aorta of the spontaneously hypertensive rat
British journal of pharmacology, 1994Co-Authors: Chantal M. Boulanger, Keith J. Morrison, Paul M. VanhoutteAbstract:1. Experiments were designed to characterize the subtype(s) of endothelial muscarinic receptor that mediate(s) endothelium-dependent relaxation and contraction in the aorta of spontaneously hypertensive rats (SHR). 2. Rings of SHR aorta with endothelium were suspended in organ baths for the measurement of isometric force. Ecothiopate (an inhibitor of acetylcholinesterase) was present throughout the experiments. Endothelium-dependent contraction to acetylcholine was studied in quiescent aortic rings in the presence of NG-nitro-L-arginine (to prevent the formation of nitric oxide). Endothelium-dependent relaxation to acetylcholine was obtained during contraction to phenylephrine and in the presence of indomethacin (to inhibit cyclo-oxygenase activity). Responses to acetylcholine were assessed against the non-preferential muscarinic receptor antagonist, atropine, and the preferential antagonists pirenzepine (M1), methoctramine (M2) and 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP; M3). 3. The potency of acetylcholine in inducing endothelium-dependent contraction was 6.54 +/- 0.07 (EC50). Atropine, pirenzepine, methoctramine and 4-DAMP displayed competitive antagonism towards the endothelium-dependent contraction to acetylcholine. The pA2 values for these muscarinic receptor antagonists were estimated from Arunlakshana-Schild plots to be (-log M) 9.48 +/- 0.07, 6.74 +/- 0.22, 6.30 +/- 0.20 and 9.39 +/- 0.22 respectively. The potency of acetylcholine in inducing endothelium-dependent relaxation was 7.82 +/- 0.09 (IC50). Atropine, pirenzepine and 4-DAMP displayed competitive antagonism towards the endothelium-dependent relaxation to acetylcholine but methoctramine had no effect. The pA2 values for atropine and 4-DAMP for the relaxation to acetylcholine were estimated from Arunlakshana-Schild plots to be (-log M) 9.15 +/- 0.23 and 9.63 +/- 0.28, respectively. These results suggest that the muscarinic M3 receptor subtype mediates both endothelium-dependent relaxation and contraction to acetylcholine in SHR aorta.
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Mediation by M3-muscarinic receptors of both endothelium-dependent contraction and relaxation to acetylcholine in the aorta of the spontaneously hypertensive rat
'Wiley', 1994Co-Authors: Kj Morrison, Paul M. Vanhoutte, Cm BoulangerAbstract:Experiments were designed to characterize the subtype(s) of endothelial muscarinic receptor that mediate(s} endothelium-dependent relaxation and contraction in the aorta of spontaneously hypertensive rats (SHR). Rings of SHR aorta with endothelium were suspended in organ baths for the measurement of isometric force. Ecothiopate (an inhibitor of acetylcholinesterase) was present throughout the experiments. Endothelium-dependent contraction to acetylcholine was studied in quiescent aortic rings in the presence of N(G)-nitro-L-arginine (to prevent the formation of nitric oxide). Endothelium-dependent relaxation to acetylcholine was obtained during contraction to phenylephrine and in the presence of indomethacin (to inhibit cyclo-oxygenase activity). Responses to acetylcholine were assessed against the non-preferential muscarinic receptor antagonist, atropine, and the preferential antagonists pirenzepine (M1), methoctramine (M2) and 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP; M3). The potency of acetylcholine in inducing endothelium-dependent contraction was 6.54 ± 0.07 (EC50). Atropine, pirenzepine, methoctramine and 4-DAMP displayed competitive antagonism towards the endothelium-dependent contraction to acetylcholine. The pA2 values for these muscarinic receptor antagonists were estimated from Arunlakshana-Schild plots to be (log M) 9.48 ± 0.07, 6.74 ± 0.22, 6.30 ± 0.20 and 9.3 ± 0.22 respectively. The potency of acetylcholine in inducing endothelium-dependent relaxation was 7.82 ± 0.09 (IC50). Atropine, pirenzepine and 4-DAMP displayed competitive antagonism towards the endothelium-dependent relaxation to acetylcholine but methoctramine had no effect. The pA2 values for atropine and 4-DAMP for the relaxation to acetylcholine were estimated from Arunlakshana-Schild plots to be (log M) 9.15 ± 0.23 and 9.63 ± 0.28, respectively. These results suggest that the muscarinic M3 receptor subtype mediates both endothelium-dependent relaxation and contraction to acetylcholine in SHR aorta.link_to_subscribed_fulltex
