13 results on '"Finch SC"'
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2. Identification and Structure Elucidation of Janthitrems A and D from Penicillium janthinellum and Determination of the Tremorgenic and Anti-Insect Activity of Janthitrems A and B.
- Author
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Babu JV, Popay AJ, Miles CO, Wilkins AL, di Menna ME, and Finch SC
- Subjects
- Animals, Insecticides pharmacology, Mice, Molecular Structure, Moths drug effects, Moths physiology, Sheep, Tremor physiopathology, Insecticides chemistry, Mycotoxins chemistry, Mycotoxins pharmacology, Penicillium chemistry, Sheep Diseases drug therapy, Tremor drug therapy
- Abstract
New compounds, 11,12-epoxyjanthitrem B (1) and 11,12-epoxyjanthitrem C (4), were isolated from Penicillium janthinellum and given the trivial names janthitrem A and janthitrem D, respectively. The known compounds janthitrem B (2) and janthitrem C (3) were also isolated, and NMR assignments were made for all four compounds. This showed that the previously published NMR assignments for 3 needed considerable revision. 1 and 2 were used as model compounds for the more complex, and highly unstable, epoxyjanthitrems that have been isolated from perennial ryegrass infected with the AR37 endophyte and which contain an epoxide group analogous to that of 1. Both 1 and 2 induced tremors in mice and reduced weight gain and food consumption of porina ( Wiseana cervinata) larvae, although 1 showed greater potency. This shows the importance of the epoxy group and suggests that epoxyjanthitrems are likely to be involved in the observed effects of the AR37 endophyte on livestock and insects.
- Published
- 2018
- Full Text
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3. Ergovaline does not alter the severity of ryegrass staggers induced by lolitrem B.
- Author
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Finch SC, Vlaming JB, Sutherland BL, van Koten C, Mace WJ, and Fletcher LR
- Subjects
- Animal Feed adverse effects, Animal Feed analysis, Animal Feed microbiology, Animals, Endophytes, Incidence, New Zealand epidemiology, Proportional Hazards Models, Severity of Illness Index, Sheep, Tremor chemically induced, Tremor epidemiology, Ergotamines analysis, Indole Alkaloids analysis, Lolium microbiology, Mycotoxins analysis, Sheep Diseases chemically induced, Sheep Diseases epidemiology, Tremor veterinary
- Abstract
Aim: To investigate a possible interaction between lolitrem B and ergovaline by comparing the incidence and severity of ryegrass staggers in sheep grazing ryegrass (Lolium perenne) containing lolitrem B or ryegrass containing both lolitrem B and ergovaline., Methods: Ninety lambs, aged approximately 6 months, were grazed on plots of perennial ryegrass infected with either AR98 endophyte (containing lolitrem B), standard endophyte (containing lolitrem B and ergovaline) or no endophyte, for up to 42 days from 2 February 2010. Ten lambs were grazed on three replicate plots per cultivar. Herbage samples were collected for alkaloid analysis and lambs were scored for ryegrass staggers (scores from 0-5) weekly during the study. Any animal which was scored ≥4 was removed from the study., Results: Concentrations of lolitrem B did not differ between AR98 and standard endophyte-infected pastures during the study period (p=0.26), and ergovaline was present only in standard endophyte pastures. Ryegrass staggers was observed in sheep grazing both the AR98 and standard endophyte plots, with median scores increasing in the third week of the study. Prior to the end of the 42-day grazing period, 22 and 17 animals were removed from the standard endophyte and AR98 plots, respectively, because their staggers scores were ≥4. The cumulative probability of lambs having scores ≥4 did not differ between animals grazing the two pasture types (p=0.41)., Conclusions and Clinical Relevance: There was no evidence for ergovaline increasing the severity of ryegrass staggers induced by lolitrem B. In situations where the severity of ryegrass staggers appears to be greater than that predicted on the basis of concentrations of lolitrem B, the presence of other tremorgenic alkaloids should be investigated.
- Published
- 2018
- Full Text
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4. Pathological changes seen in horses in New Zealand grazing Mediterranean tall fescue (Lolium arundinaceum) infected with selected endophytes (Epichloë coenophiala) causing equine fescue oedema.
- Author
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Munday JS, Finch SC, Vlaming JB, Sutherland BL, and Fletcher LR
- Subjects
- Animals, Horse Diseases pathology, Horses, Animal Feed microbiology, Food Microbiology, Horse Diseases chemically induced, Lolium microbiology, Mycotoxins toxicity, Neotyphodium metabolism
- Abstract
Aim: To investigate whether Mediterranean tall fescue (Lolium arundinaceum (Schreb.) Darbysh. (syn Festuca arundinacea)) infected with selected fungal endophytes (Epichloë coenophiala (formerly Neotyphodium coenophialum)) caused equine fescue oedema when grown in New Zealand, and to examine the pathological changes associated with this intoxication., Methods: Horses were grazed on Mediterranean tall fescue that was infected with the endophytes AR542 (n=2), or AR584 (n=3), or Mediterranean tall fescue that was endophyte-free (n=2). Blood samples were taken up to 7 days after the start of feeding to detect changes in concentrations of total protein in serum and packed cell volume. Any horse showing clinical evidence of disease was subject to euthanasia and necropsy., Results: Within 6 days, both horses grazing fescue infected with AR542 became depressed and lethargic. One horse grazing fescue infected with endophyte AR584 became depressed within a 5-day feeding period while another horse in this group died shortly after being removed from the AR584 pasture. The third horse in this group did not develop clinical signs within the 5-day feeding period. However, haemoconcentration and hypoproteinaemia was detected in all horses grazing Mediterranean tall fescue that was infected by AR542 or AR584 endophyte. No abnormalities were observed in horses grazing fescue that was endophyte-free. Necropsy examination was performed on two horses grazing fescue infected with AR542 and one horse grazing fescue infected with AR584. All three horses had marked oedema of the gastrointestinal tract. Histologically, the oedema was accompanied by large numbers of eosinophils, but no necrosis., Conclusions: Horses grazing Mediterranean tall fescue that was infected by AR542 or AR584 developed hypoproteinaemia and haemoconcentration, most likely due to leakage of plasma proteins into the gastrointestinal tract. This suggests that these selected endophytes produce a compound that is toxic to horses, although the toxic principle is currently unknown., Clinical Relevance: Mediterranean tall fescue that is infected by AR542 or AR584 should not be fed to horses in New Zealand. This intoxication should be considered in horses in which a rapid onset of hypoproteinaemia and haemoconcentration is detected. This intoxication should also be considered if marked gastrointestinal oedema is observed.
- Published
- 2017
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5. Combined effects of fungal alkaloids on intestinal motility in an in vitro rat model.
- Author
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Dalziel JE, Dunstan KE, and Finch SC
- Subjects
- Animals, Drug Synergism, Ergotamine administration & dosage, Indole Alkaloids administration & dosage, Male, Muscle Contraction drug effects, Muscle, Smooth drug effects, Mycotoxins administration & dosage, Rats, Rats, Sprague-Dawley, Colon drug effects, Ergotamine toxicity, Indole Alkaloids toxicity, Mycotoxins toxicity
- Abstract
Diarrhea is caused by factors that alter absorption and secretion of water and ions across the intestinal epithelium and disrupt motility. Parasitic infection, stress, poor nutrition, and exposure to plant or fungal toxins predispose livestock to noninfectious diarrhea. This is more prevalent in sheep that graze pastures infected with wild-type endophytic fungus, suggesting the involvement of fungal alkaloids. These increase smooth muscle contraction: ergovaline/ergotamine (ergot alkaloid) activates serotonin (5-HT) receptors, and lolitrem B (indole diterpene) inhibits large-conductance Ca2+-activated K+ (BK) channels. Because of their separate mechanisms of action the objective of this study was to investigate whether they act synergistically to increase smooth muscle contraction. Effects of ergotamine (1 µM) and lolitrem B (0.1 µM) on the tension and frequency of spontaneous contractions were investigated in a longitudinal preparation of isolated distal colon. The compounds were dissolved in 0.1% dimethyl sulfoxide (DMSO) and applied separately or together for 1 h. Ergotamine increased contractile tension compared to the pretreatment control (P<0.01) and produced a short-lived increase in frequency (P<0.001). Lolitrem B increased contractile tension (P<0.05) but had no effect on frequency. When applied together, the contractile tension was greater than the sum of the compounds applied separately (P<0.05). The frequency of contractions was increased (P<0.05) but was not significantly different from that for ergotamine alone. The increased contractile tension when both compounds were applied together indicates that ergotamine and lolitrem B acted synergistically to increase smooth muscle contraction, suggesting that they would alter motility in vivo.
- Published
- 2013
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6. The evaluation of fungal endophyte toxin residues in milk.
- Author
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Finch SC, Thom ER, Babu JV, Hawkes AD, and Waugh CD
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- Animal Feed analysis, Animals, Chromatography, High Pressure Liquid, Female, Food Contamination, Mycotoxins metabolism, Cattle physiology, Endophytes metabolism, Fungi metabolism, Lolium microbiology, Milk chemistry, Mycotoxins chemistry
- Abstract
Aim: To determine the concentrations of fungal endophyte toxins in the milk of cows fed perennial ryegrass containing wild-type or AR37 endophyte., Methods: Groups of 10 multiparous Holstein-Friesian cows were fed wild-type (containing lolitrem B) or AR37 (containing epoxy-janthitrems) endophyte-infected perennial ryegrass (Lolium perenneL.). Animals were kept indoors and fed for 12 days. Over this period, animals were regularly assessed for ryegrass staggers and herbage intake measured. At the conclusion of the 12-day indoor-feeding period, cows were grazed on AR1 (toxin-free) pastures for a further 8 days. Daily individual milk samples and milk yields were collected over the complete 20-day period. Milk samples were analysed for endophyte toxins using HPLC methods developed during this study. Daily herbage samples were also taken and concentrations of endophyte toxins measured., Results: Methods were successfully developed for the analysis of lolitrem B and epoxy-janthitrems in milk which allowed the concentrations of these compounds in milk to be compared with the concentrations in feed consumed by the animals. Both toxin types could be detected in milk after only 1 day of exposure to respective treatment pastures. The maximum concentration of endophyte toxins in milk was 5 ng/mL lolitrem B and 109 ng/mL epoxy-janthitrems from cows fed wild-type and AR37 endophyte-infected ryegrass pastures, respectively. Concentrations of epoxy-janthitrems present in herbage were much higher than for lolitrem B (Day 1-12 average of 14.6 and 1.8 ppm, respectively). Despite the high concentrations of epoxy-janthitrems consumed by cows fed AR37 endophyte-infected pastures no signs of ryegrass staggers were observed over the experimental period, whereas those cows fed wild-type endophyte-infected pastures all showed signs of ryegrass staggers. This is consistent with the view that epoxy-janthitrems are low potency tremorgens. At the conclusion of the toxin feeding period, endophyte toxin concentrations in milk quickly dropped to almost zero after 8 days. A comparison of the quantities of lolitrem B and epoxy-janthitrems consumed by each cow with the quantities secreted in milk showed that only very low proportions of the total amount ingested are secreted in milk (0.23% lolitrem B and 0.49% epoxy-janthitrems)., Conclusion: Lolitrem B and epoxy-janthitrems can be detected in the milk of cows consuming wild-type and AR37 endophyte-infected perennial ryegrass, respectively. Concentrations detected were low and changed quickly in association with the amounts being consumed by the cows. Available evidence gives no indication that these compounds may pose a threat to human health.
- Published
- 2013
- Full Text
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7. The evaluation of endophyte toxin residues in sheep fat.
- Author
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Finch SC, Fletcher LR, and Babu JV
- Subjects
- Adipose Tissue metabolism, Animal Feed, Animals, Lolium microbiology, Molecular Structure, Mycotoxins metabolism, Time Factors, Adipose Tissue chemistry, Endophytes chemistry, Mycotoxins chemistry, Neotyphodium metabolism, Sheep metabolism
- Abstract
Aim: To monitor changes in concentrations of lolitrem B and epoxy-janthitrems in the fat of sheep grazing perennial ryegrass infected with wild-type- and AR37-endophyte, respectively, during the time of year when ryegrass staggers would be expected to be observed., Methods: Ten 5-month-old lambs with no previous exposure to endophytes were grazed on either wild-type (containing lolitrem B, n = 5) or AR37 (containing epoxy-janthitrems, n = 5) endophyte-infected perennial ryegrass (Lolium perenne L.) pastures between October 2008 and June 2009. Animals were regularly assessed for ryegrass staggers using the Keogh scale (0 = no signs, 5 = severe tremors). When a score of > 3.5 was observed animals were removed from the treatment pastures for 1 month. Fat biopsy samples were taken from each animal at approximately monthly intervals and analysed for endophyte metabolites using high performance liquid chromatography (HPLC) methods developed during this study. Regular herbage samples were also taken and concentrations of endophyte metabolites measured., Results: Efficient and reproducible methods to analyse both lolitrem B and epoxy-janthitrems in fat were developed. Concentrations of lolitrem B and epoxy-janthitrems in herbage and in sheep fat increased from late November to peak in mid-February. Ryegrass staggers was observed in both groups of sheep at this time. Following 1 month of grazing non-infected pasture mean concentrations in fat of lolitrem B decreased by 43% from 61.8 to 35.3 ppb, and of epoxy-janthitrems by 38% from 1032.0 to 639.5 ppb. Maximum concentrations in herbage of epoxy-janthitrems (35.7 ppm) were higher than of lolitrem B (3.4 ppm), but signs of staggers were less severe in sheep grazing pasture containing the former compared with the latter (median Keogh scores in late February were 2 and 3, respectively), consistent with epoxy-janthitrems being low potency toxins., Conclusion: This study demonstrated that concentrations of epoxy-janthitrems and lolitrem B in sheep fat increased quickly during the initial phase of the study when concentrations in pasture increased, and decreased when animals were removed from pastures containing these compounds. These data will be used in the risk assessment of the endophyte metabolites.
- Published
- 2012
- Full Text
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8. Mechanism of action of lolitrem B, a fungal endophyte derived toxin that inhibits BK large conductance Ca²+-activated K+ channels.
- Author
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Imlach WL, Finch SC, Zhang Y, Dunlop J, and Dalziel JE
- Subjects
- Cell Line, Dose-Response Relationship, Drug, Electrophysiology, Humans, Indole Alkaloids, Inhibitory Concentration 50, Mycotoxins metabolism, Protein Binding, Calcium metabolism, Indoles pharmacology, Large-Conductance Calcium-Activated Potassium Channels antagonists & inhibitors, Mycotoxins pharmacology
- Abstract
The aim of this study was to compare the mode of action of the commonly used BK inhibitor paxilline with that of the more recently discovered lolitrem B. Similarities and differences in characteristics of inhibition between the two compounds were investigated. We have previously shown that lolitrem B does not affect the BK channel G-V, in contrast to the rightward shift produced by paxilline. These different effects on the voltage-dependence of activation suggest different modes of action for these two compounds. In this study we show that inhibition by both paxilline and lolitrem B is characterized by an open state preference for BK (hSlo) channels. Both compounds had a 3-fold higher apparent affinity under conditions likely to favour the open state, suggesting they have a similar BK conformational preference for binding. Furthermore, both compounds had a calcium concentration-dependence to their inhibitory effects. The G-V shift induced by paxilline was calcium concentration-dependent., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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9. Structural determinants of lolitrems for inhibition of BK large conductance Ca2+-activated K+ channels.
- Author
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Imlach WL, Finch SC, Dunlop J, and Dalziel JE
- Subjects
- Cell Line, Dose-Response Relationship, Drug, Humans, Indole Alkaloids, Inhibitory Concentration 50, Mycotoxins administration & dosage, Mycotoxins chemistry, Neurotoxins administration & dosage, Neurotoxins chemistry, Potassium Channel Blockers administration & dosage, Potassium Channel Blockers chemistry, Potassium Channel Blockers pharmacology, Structure-Activity Relationship, Large-Conductance Calcium-Activated Potassium Channels antagonists & inhibitors, Mycotoxins pharmacology, Neurotoxins pharmacology
- Abstract
Lolitrem B is an indole-diterpenoid neurotoxin which is the main causative agent of ryegrass staggers, an animal disease associated with tremors and incoordination. It is also a potent inhibitor of large conductance calcium-activated potassium (BK) channel activity (IC(50)=4 nM). Furthermore, we have recently shown that the motor function deficits induced by lolitrem B are specifically mediated by BK channels, making the toxin a valuable tool for investigating the molecular function and physiological roles of these channels. To determine what structural features of BK channel agents are required for high potency, the effect of lolitrem B and seven structurally-related lolitrems on BK channel activity has been measured. Concentration-responses and conductance-voltage (G-V) relationships were determined for each compound and related to the different structure types. This study has identified seven new BK channel inhibitors and has allowed the identification of two key structural features required for high potency BK channel activity by lolitrems.
- Published
- 2009
- Full Text
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10. The molecular mechanism of "ryegrass staggers," a neurological disorder of K+ channels.
- Author
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Imlach WL, Finch SC, Dunlop J, Meredith AL, Aldrich RW, and Dalziel JE
- Subjects
- Animals, Cattle, Indole Alkaloids, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, Lolium microbiology, Mice, Mice, Knockout, Nervous System Diseases veterinary, Patch-Clamp Techniques, Cattle Diseases etiology, Indoles toxicity, Large-Conductance Calcium-Activated Potassium Channel beta Subunits antagonists & inhibitors, Mycotoxins toxicity, Nervous System Diseases etiology
- Abstract
"Ryegrass staggers" is a neurological condition of unknown mechanism that impairs motor function in livestock. It is caused by infection of perennial ryegrass pastures by an endophytic fungus that produces neurotoxins, predominantly the indole-diterpenoid compound lolitrem B. Animals grazing on such pastures develop uncontrollable tremors and become uncoordinated in their movement. Lolitrem B and the structurally related tremor inducer paxilline both act as potent large conductance calcium-activated potassium (BK) channel inhibitors. Using patch clamping, we show that their different apparent affinities correlate with their toxicity in vivo. To investigate whether the motor function deficits produced by lolitrem B and paxilline are due to inhibition of BK ion channels, their ability to induce tremor and ataxia in mice deficient in this ion channel (Kcnma1(-/-)) was examined. Our results show that mice lacking Kcnma1 are unaffected by these neurotoxins. Furthermore, doses of these substances known to be lethal to wild-type mice had no effect on Kcnma1(-/-) mice. These studies reveal the BK channel as the molecular target for the major components of the motor impairments induced by ryegrass neurotoxins. Unexpectedly, when the response to lolitrem B was examined in mice lacking the beta4 BK channel accessory subunit (Kcnmb4(-/-)), only low-level ataxia was observed. Our study therefore reveals a new role for the accessory BK beta4 subunit in motor control. The beta4 subunit could be considered as a potential target for treatment of ataxic conditions in animals and in humans.
- Published
- 2008
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11. Presumptive tremorgenic mycotoxicosis in a dog in New Zealand, after eating mouldy walnuts.
- Author
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Munday JS, Thompson D, Finch SC, Babu JV, Wilkins AL, di Menna ME, and Miles CO
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- Animals, Diagnosis, Differential, Dog Diseases pathology, Dogs, Food Microbiology, Male, Mycotoxicosis complications, Mycotoxicosis diagnosis, New Zealand, Nuts microbiology, Tremor etiology, Tremor veterinary, Dog Diseases diagnosis, Mycotoxicosis veterinary, Mycotoxins poisoning
- Abstract
Case History: A 1-year-old, intact male Labrador-cross dog vomited after eating walnuts that had been on the ground for 5 months. The dog then developed tremors, ataxia, increased salivation, and hyperaesthesia., Clinical Findings: The dog had marked generalised tremors, ataxia and a temperature of 39.9 degrees C. Both pupils were of normal size and normally responsive to light. Vomiting was induced, and walnut shell was visible in the vomitus., Diagnosis: Due to the sudden onset of tremors, lack of exposure to other convulsive toxins, and the evidence of ingestion of walnuts, the provisional diagnosis was tremorgenic mycotoxicosis. The dog was treated symptomatically, and made a full recovery over 18 hours. Tremorgenic mycotoxins were detected within walnuts collected from the dog's environment., Clinical Relevance: Fungi that produce tremorgenic mycotoxins are present in New Zealand. Intoxication should be suspected in dogs that suddenly develop muscle tremors, especially if there is a history of ingestion of mouldy food 2-3 hours prior to the development of tremors.
- Published
- 2008
- Full Text
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12. The fungal neurotoxin lolitrem B inhibits the function of human large conductance calcium-activated potassium channels.
- Author
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Dalziel JE, Finch SC, and Dunlop J
- Subjects
- Cells, Cultured, Humans, Indole Alkaloids, Inhibitory Concentration 50, Large-Conductance Calcium-Activated Potassium Channels, Membrane Potentials drug effects, Patch-Clamp Techniques, Potassium Channels, Calcium-Activated physiology, Transfection, Mycotoxins pharmacology, Neurotoxins pharmacology, Potassium Channels, Calcium-Activated antagonists & inhibitors, Potassium Channels, Calcium-Activated drug effects
- Abstract
The effects of the mycotoxin lolitrem B on the function of hSlo large conductance calcium-activated potassium channels expressed in HEK293 cells have been investigated using inside-out membrane patches. Lolitrem B potently inhibited hSlo potassium currents activated by depolarising voltage pulses in the presence of 10 microM free calcium. At a concentration of 100 nM, lolitrem B rapidly and completely inhibited outward potassium currents. The concentration that produced half-maximal inhibition was 3.7 nM, indicating a high apparent affinity for hSlo channels. This is the first time that a molecular site of action has been identified for a compound of the lolitrem structural class of indole diterpene and identifies a novel BK channel blocker.
- Published
- 2005
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13. Tremorgenic mycotoxins paxilline, penitrem and lolitrem B, the non-tremorgenic 31-epilolitrem B and electromyographic activity of the reticulum and rumen of sheep.
- Author
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McLeay LM, Smith BL, and Munday-Finch SC
- Subjects
- Animals, Atropine pharmacology, Electromyography, Indole Alkaloids, Male, Muscle Contraction drug effects, Muscle Contraction physiology, Muscle, Smooth drug effects, Muscle, Smooth innervation, Orchiectomy, Reticulum drug effects, Reticulum innervation, Rumen drug effects, Rumen innervation, Sheep, Vagus Nerve physiology, Indoles toxicity, Muscle, Smooth physiology, Mycotoxins toxicity, Reticulum physiology, Rumen physiology
- Abstract
The mycotoxic tremorgens penitrem, paxilline and lolitrem B had profound effects on electromyographic (EMG) activity of smooth muscle of the reticulorumen in conscious sheep, with a similar time course of action to their respective characteristic effects on the induction (1 to 2, 15 to 20 and 20 to 30 minutes) and the duration (1 to 2, 1 to 2 and 8 to 12 hours) of tremoring. Responses to penitrem revealed a greater sensitivity of smooth muscle than skeletal muscle. Effects included an inhibition of the vagally-dependent cyclical A and B sequences of contraction of the reticulorumen, an increase in their amplitude and an excitation of local intrinsic activity contributing to elevated baselines and the occurrence of chaotic activity of the reticulum. The excitatory local effects were partially blocked by atropine, indicating that stimulation of muscarinic cholinoceptors was involved. Increased local activity may mediate a reflex inhibition of cyclical contractions. A non-tremorgenic isomer of lolitrem B (31-epilolitrem B) had no effect on the reticulorumen. The intensity and duration of the effects of lolitrem B, up to 12 hours, indicate that severe disruption of digestion may occur in animals grazing endophyte-infected pasture., (Copyright 1999 W.B. Saunders Company Ltd.)
- Published
- 1999
- Full Text
- View/download PDF
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