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Biomedical subjects

W D Dettbarn

Publications and source records attributed to W D Dettbarn.

At least 55 records · Page 3Linked to original sources
PubMed1986

Evidence of necrosis in human intercostal muscle following inhalation of an organophosphate insecticide.

Intercostal muscle samples obtained from autopsy of a 51-year-old male exposed to an organophosphate insecticide were analyzed for cholinesterase activity and muscle fiber integrity. Muscle cholinesterase activity, 5 days after exposure, was reduced to 53% of control values. Histological analysis indicated the presence of muscle fibers with subsarcolemmal grouped granular basophilic inclusions and scattered necrotic fibers. Results indicate that acute organophosphate exposure through inhalation can lead to skeletal muscle fiber damage in humans, similar to results obtained by ingestion. Furthermore, the pathology is comparable to the histological alterations observed in rats following acute injection of organophosphates.

Aerosols↗
PubMed1986

Differential effect of denervation on free-radical scavenging enzymes in slow and fast muscle of rat.

To determine the effect of denervation on the free-radical scavenging systems in relation to the mitochondrial oxidative metabolism in the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles, the sciatic nerve of the rat was crushed in the midthigh region and the muscle tissue levels of five enzymes were studied 2 and 5 weeks following crush. Recently developed radioimmunoassays were utilized for the selective measurement of cuprozinc (cytosolic) and mangano (mitochondrial) superoxide dismutases. Total tissue content of cuprozinc superoxide dismutase showed a mild decrease after denervation in slow but not in fast muscle. Manganosuperoxide dismutase and fumarase decreased markedly at 2 weeks and returned toward control levels by 5 weeks, the changes appearing to be greater in slow than in fast muscle. At 2 weeks, cytochrome c oxidase decreased significantly in slow, but not in fast muscle. GSH-peroxidase at baseline was 10-fold higher in slow than in fast muscle, markedly decreased at 2 weeks in slow muscle, and returned toward control levels at 5 weeks, whereas the total enzyme activity in fast muscle did not change through 5 weeks. These data represent the first systematic report of free radical scavenging systems in slow and fast muscles in response to denervation. Selective modification of cuprozinc and manganosuperoxide dismutases and differential regulation of GSH-peroxidase was demonstrated in slow and fast muscle.

Animals↗
PubMed1985

The aminoglycoside antibiotic, gentamicin, fails to block increases in miniature endplate potential frequency induced by the sulfhydryl reagent, N-ethylmaleimide, in low calcium solutions.

N-ethylmaleimide (NEM) increases the frequency of miniature endplate potentials (MEPPs) at the adult rat hemidiaphragm. This sulfhydryl-alkylating agent produces comparable effects in the absence of added calcium (2 mM EGTA), suggesting that the drug releases calcium from internal stores, or promotes calcium-independent release by depolarizing the nerve terminal or interacting more directly with the release mechanism. These increases in frequency are not blocked by the aminoglycoside antibiotic, gentamicin; although the latter agent reduces quantal content and the elevations in MEPP frequency induced by high potassium solutions. The results suggest that gentamicin and NEM act at different sites at the presynaptic terminal, and that the aminoglycosides block voltage-dependent presynaptic calcium influx.

Action Potentials↗
PubMed1985

Changes in the cholinergic system of rat sciatic nerve and skeletal muscle following suspension-induced disuse.

Muscle disuse-induced changes in the cholinergic system of sciatic nerve, slow-twitch soleus (SOL), and fast-twitch extensor digitorum longus (EDL) muscles were studied in rats. Rats with hind limbs suspended for 2 to 3 weeks showed marked elevation in the activity of choline acetyltransferase in sciatic nerve (38%), in the SOL (108%), and in the EDL (67%). Acetylcholinesterase (AChE) activity in the SOL increased 163% without changing the molecular forms pattern of 4S, 10S, 12S, and 16S. No significant (P greater than 0.05) changes in the activity and molecular forms pattern of AChE were seen in the EDL or in AChE activity of sciatic nerve. Nicotinic receptor binding of [3H]acetylcholine was increased in both muscles. When measured after 3 weeks of hind limb suspension the normal distribution of type I fibers in the SOL (87%) was reduced (to 58%) and a corresponding increase in types IIa and IIb fibers occurred. In the EDL no significant change in fiber proportion was observed. Muscle activity, such as loadbearing, appeared to have a greater controlling influence on the characteristics of the slow-twitch SOL muscle than on the fast-twitch EDL muscle.

Acetylcholinesterase↗
PubMed1985

Is fast fiber innervation responsible for increased acetylcholinesterase activity in reinnervating soleus muscles?

During reinnervation of the completely denervated rat hind limb we observed previously a temporary overproduction of acetylcholinesterases in the soleus but not in the extensor digitorum longus muscle. In the present study, we investigated whether the predominantly slow soleus, which is low in AChE activity, is initially reinnervated by axons that originally innervated fast muscle fibers with high AChE activity, such as those of the extensor digitorum longus. Local denervation of the rat soleus was carried out to eliminate reinnervation by axons destined for other muscles. This produced an overshoot in AChE activity that was qualitatively similar to that observed with high sciatic crush. Local denervation of the soleus in the guinea pig was done because this muscle is composed solely of slow (type I) fibers, thereby virtually eliminating the possibility of homologous muscle fast fiber innervation. The overshoot in this preparation was qualitatively similar to that seen with distal denervation in the guinea pig and local and distal denervation in the rat. Thus, initial fast fiber innervation is not responsible for the patterns of change in AChE activity seen with reinnervation in the soleus. We concluded that the neural control of AChE is different in these two muscles and may reflect specific differences in the characteristics of AChE regulation in fast and slow muscle. How these neural influences are translated into muscle synthesis and degradation remains unknown.

Acetylcholinesterase↗
PubMed1985

Mechanisms involved in the development of tolerance to DFP toxicity.

Rats treated daily with diisopropylfluorophosphate (DFP) (0.5 mg/kg, sc), an inhibitor of acetylcholinesterase (AChE) activity, exhibited the symptoms of cholinergic hyperactivity between Days 3 and 5 similar to those observed 15 min after a single acute dosage (1.5 mg/kg, sc). A significant (p less than 0.05) decrease in the activities of both AChE and cholinesterase (BuChE) (greater than 80%) occurred in muscles and in brain regions and of aliesterases in liver (greater than 92%) at this time. Further administration of DFP (0.5 mg/kg, for 7-14 days) led to behavioral tolerance, where symptoms of toxicity disappeared such as muscle fasciculations, tremors, and muscle necrosis. The activity of aliesterases in liver and AChE in muscles significantly (p less than 0.01) recovered, while no such recovery was seen in brain AChE. DFP toxicity was potentiated in rats that were pretreated with BuChE inhibitors, such as iso-OMPA (3 mg/kg, sc) or mipafox (0.05 mg/kg, sc), 30 min prior to DFP (0.5 mg/kg, sc). The severity of cholinergic hyperactivity and inhibition of aliesterase in liver, AChE and BuChE activity in brain and muscles was greater when compared to the effects of DFP alone. Both iso-OMPA and mipafox completely abolished the tolerance development to DFP, since no animal survived more than 5 days of combined treatment. The observed adaptation to DFP toxicity appears to be due to recovery of aliesterase, BuChE, and AChE activity as well as decreased nicotinic binding sites at the neuromuscular junction, as previously reported.

Acetylcholinesterase↗
PubMed1984

Pesticide induced muscle necrosis: mechanisms and prevention.

The nerve agent soman, as well as other organophosphates such as paraoxon and phospholine in concentrations that caused cholinergic symptoms induced a progressive dose-related necrosis in rat skeletal muscle fibers. The severity of the myopathy depended on a critical decrease in activity and duration of acetylcholinesterase (AChE) inhibition. The number of muscle fibers affected was greatest with soman, followed by tertiary phospholine, paraxon , and quaternary phospholine. The necrotic nerve fibers were repaired within 1 week. Atropine and gentamycin in concentrations that do not block neuromuscular transmission, attenuate the necrotic action of the organophosphates by interacting with the presynaptic Ca2+ uptake mechanism. The half-time recovery rate of AChE after exposure to soman varied between 12 hr for sciatic nerve, 5-9 days for muscle, and 14 days for brain. AChE activity of peripheral nerve was minimally inhibited by soman and had recovered to control activity within 24 hr. The reason for this apparent insensitivity of the nerve AChE to soman may be due to the high activity of an enzyme that hydrolyzes soman. AChE at the neuromuscular junction in part has a protective and regulatory function through its control of free acetylcholine (ACh). By limiting the accumulation of ACh and the extent of its interaction with pre- and postsynaptic membranes, the morphological integrity of nerve terminals and muscle is preserved.

Acetylcholine↗
PubMed1984

The influence of 2-chloroprocaine on the subsequent analgesic potency of bupivacaine.

Isolated rat sciatic nerves were used to study the interaction between 2-chloroprocaine (2-CP) and bupivacaine (BP). Five nerves studied as controls were treated with 5 X 10(-4) M BP and the amplitude of the compound action potential (CAP) evoked by suprathreshold stimulation was measured. This concentration of BP completely blocked nerve conduction; but, following washout with normal Krebs-Ringer solution, the CAP amplitude recovered to 50% of initial values in 50 (+/- 4) min with a rate of recovery of 1.7 (+/- 0.6) %/min. In another series of experiments, five nerves were blocked first with 5 X 10(-4) M 2-CP, allowed to fully recover, and then were blocked with BP under the same conditions as the controls. Under these conditions, the half time for the recovery of CAP amplitude following BP was shortened to 25 (+/- 5) min, with a rate of recovery of 2.8 (+/- 0.3) %/min. When five nerves were exposed to a 5 X 10(-4) M solution of a 2-CP metabolite, 4-amino-2-chlorobenzoic acid, no nerve blockade was produced. When these nerves subsequently were blocked with BP, recovery to 50% of initial values occurred in 22 (+/- 5) min, with a rate of recovery of 2.0 (+/- 0.2) %/min. Although pretreatment with either 2-CP or 4-amino-2-chlorobenzoic acid significantly shortened the duration of BP-induced nerve blockade, neither drug had a significant effect on the rate of recovery once the CAP amplitude returned to measurable values.

Action Potentials↗
PubMed1983

A comparison of the effects of acute and chronic cholinesterase inactivation on spontaneous transmitter release.

The irreversible inhibitor of acetylcholinesterase (AChE), paraoxon, when given in vivo to rats in a single injection (0.23 mg/kg s.c.) raised the miniature endplate potential (MEPP) frequency to values greater than 3 times control levels in 34% of the fibers in the rat phrenic nerve-hemidiaphragm preparation. The elevated MEPP frequencies were observed in areas of extensive muscle twitching and were associated with high frequencies of giant MEPPs. Following 3 daily injections of paraoxon; the overall MEPP frequency was reduced below control levels, the frequency of giant MEPPs returned to normal, and a greater percentage of fibers showed no spontaneous activity. This depressant effect of chronic AChE inhibition on the overall MEPP frequency diminished during 1-2 weeks of daily paraoxon treatment (0.12 mg/kg s.c. paraoxon/day). After one week of recovery from 14 daily paraoxon injections (0.12 mg/kg, 1 injection/day), the original response to a single injection (0.23 mg/kg) was restored. In an attempt to determine whether paraoxon exerts its effects on spontaneous release by depolarizing the presynaptic terminal, the effect of increases in the potassium concentration on the MEPP and giant potential frequency were examined in control (saline injection) preparations, and preparations treated with 1 or 3 daily injections of paraoxon. The results suggest that paraoxon does not act by reducing the presynaptic membrane potential, but may interact more directly with the mechanism(s) responsible for regulating the release of MEPPs and giant MEPPs.

Animals↗
PubMed1983

Characterization of acetylcholinesterase molecular forms in slow and fast muscle of rat.

Multiple molecular forms of acetylcholinesterase (AChE EC 3.1.1.7) from fast and slow muscle of rat were examined by velocity sedimentation. The fast extensor digitorum longus muscle (EDL) hydrolyzed acetylcholine at a rate of 110 mumol/g wet weight/hr and possessed three molecular forms with apparent sedimentation coefficients of 4S, 10S, and 16S which contribute about 50, 35, and 15% of the AChE activity. The slow soleus muscle hydrolyzed acetylcholine at a rate of 55 mumol/g wet weight/hr and has a 4S, 10S, 12S, and 16S form which contribute 22, 18, 34, and 26% of AChE activity, respectively. A single band of AChE activity was observed when a 1M NaCl extract with CsCl (0.38 g/ml) was centrifuged to equilibrium. Peak AChE activity from EDL and SOL extracts were found at 1.29 g/ml. Resedimentation of peak activity from CsCl gradients resulted in all molecular forms previously found in both muscles. Addition of a protease inhibitor phenylmethylsulfonyl chloride did not change the pattern of distribution. The 4S form of both muscles was extracted with low ionic strength buffer while the 10S, 12S, and 16S forms required high ionic strength and detergent for efficient solubilization. All molecular forms of both muscles have an apparent Km of 2 x 10(-4) M, showed substrate inhibition, and were inhibited by BW284C51, a specific inhibitor of AChE. The difference between these muscles in regards to their AChE activity, as well as in the proportional distribution of molecular forms, may be correlated with sites of localization and differences in the contractile activity of these muscles.

Acetylcholine↗
PubMed1983

Nerve crush induced changes in molecular forms of acetylcholinesterase in soleus and extensor digitorum muscles.

The molecular forms of acetylcholinesterase (AChE, EC 3.1.1.7) extracted from the fast twitch extensor digitorum longus (EDL) and slow twitch soleus (SOL) muscles, were separated by velocity sedimentation after sciatic nerve crush. Three molecular forms were routinely separated from EDL and four from SOL muscle. In the EDL, the 4S and 10S represented the greatest amounts of AChE, and in the SOL the 12S and 16S were the major constituent forms of the enzyme. Total AChE activity in EDL and SOL muscles rapidly decreased after nerve crush. During reinnervation (2 weeks postcrush), total AChE activity in the EDL gradually recovered, whereas the SOL exhibited a 2.5-fold transient increase above control. Immediately after denervation, decreases in the three AChE forms from the EDL (4, 10, and 16S) were evident, whereas the SOL exhibited both rapid increases (4 and 10S) and decreases (12S and 16S). In both muscles the 4S form reappeared before the 16S and 10S molecular forms, suggesting that the light form, 4S, may be a precursor of the heavier molecules. Transient increases during reinnervation occurred in the 16S AChE form in both muscles; however, they were approximately five times greater in the SOL than in the EDL. In the SOL all other molecular forms showed similar increases, whereas none was seen in the EDL. Possible mechanisms are differences in synthesis and catabolism, and in release of molecular forms from these muscles.

Acetylcholinesterase↗
PubMed1980

Presynaptic and postsynaptic neuromuscular effects of a specific inhibitor of acetylcholinesterase.

Previous studies have shown indirectly that the neuromuscular effects of nonselective cholinesterase inhibitors are mediated through the inhibition of acetylcholinesterase (AChE). To test this hypothesis more directly we studied the effects of the specific inhibitor of AChE, BW 284c51, at the neuromuscular junction of rat diaphragms. BW 284c51 inhibits AChE in a dose-dependent partially reversible manner at all concentrations tested (10(-9) to 10(-4) M). Maximum inhibition was never greater than 92%. The drug increased miniature end-plate potential (MEPP) amplitude and prolonged half-decay time at 10(-7) and 10(-6) M. However, BE 284c51 had no effect on the resting membrane potential at any concentration. BW 284c51 at 10(-7) M reversibly increased MEPP frequency by almost 4-fold. There was a 2-fold increase in the occurrence of giant MEPPs in the presence of BW 284c51. The quantum content (m) of the end-plate potential was increased in 10(-7) M BW 284c51 as were end-plate potential amplitude and quantum size (q). Animals injected subcutaneously with 10 mg/kg of BW 284c51 displayed typical signs of AChE inhibition including salivation, whole body tremor and prostration. Spontaneous muscle fasciculation was more noticeable after in vivo injection of BW 284c51 than after in vitro administration. Furthermore, MEPP frequencies were considerably faster when the drug was injected in vivo than when applied in vitro. The data are discussed with respect to the hypothesis that inhibition of AChE causes presynaptic as well as postsynaptic effects.

Aniline Compounds↗