scholarly journals Influence of Prolonged Serotonin and Ergovaline Pre-Exposure on Vasoconstriction Ex Vivo

Toxins ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 9
Author(s):  
Eriton E. L. Valente ◽  
David L. Harmon ◽  
James L. Klotz
Keyword(s):  
Blood Vessels ◽  
Ergot Alkaloid ◽  
Inhibitory Concentration ◽  
Contractile Response ◽  
Ex Vivo ◽  
Ergot Alkaloids ◽  
Exposure Period ◽  
Inhibitory Response ◽  
Previous Exposure ◽  
Ic50 Concentration

Ergot alkaloid mycotoxins interfere in many functions associated with serotonergic neurotransmitters. Therefore, the objective was to evaluate whether the association of serotonin (5-hydroxytryptamine, 5-HT) and ergot alkaloids during a 24 h pre-incubation could affect the vascular contractile response to ergot alkaloids. To evaluate the effects of 24 h exposure to 5-HT and ergot alkaloids (ergovaline, ERV), two assays were conducted. The first assay determined the half-maximal inhibitory concentration (IC50) following the 24 h pre-exposure period, while the second assay evaluated the effect of IC50 concentrations of 5-HT and ERV either individually or in combination. There was an interaction between previous exposure to 5-HT and ERV. Previous exposure to 5-HT at the IC50 concentration of 7.57 × 10−7 M reduced the contractile response by more than 50% of control, while the exposure to ERV at IC50 dose of 1.57 × 10−10 M tended to decrease (p = 0.081) vessel contractility with a response higher than 50% of control. The 24 h previous exposure to both 5-HT and ERV did not potentiate the inhibitory response of blood vessels in comparison with incubation with each compound alone. These results suggest receptor competition between 5-HT and ERV. More studies are necessary to determine the potential of 5-HT to treat toxicosis caused by ergot alkaloids.

scholarly journals PSII-24 Assessment of the contractility of bovine lateral saphenous and digital veins in response to ergot alkaloids

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 375-375
Author(s):  
James L Klotz ◽  
Hannah Stokley ◽  
Huihua Ji ◽  
Nabanita Chattopadhyay ◽  
David L Harmon
Keyword(s):  
Blood Vessels ◽  
Cross Sections ◽  
Saphenous Vein ◽  
Contractile Response ◽  
Ergot Alkaloids ◽  
Peripheral Vasculature ◽  
Response Data ◽  
Randomized Design ◽  
Representative Model ◽  
The Impact

Abstract Decreased blood flow caused by vasoconstriction is a hallmark of ergot alkaloid exposure. Previous research has utilized the cranial branch of the lateral saphenous vein as a model to characterize the impact of ergot alkaloids on bovine peripheral vasculature. The digital vein is more distal and closer to the hoof where damage caused by vasoconstriction occurs and may be more sensitive to ergot alkaloids. Thus, the objective was to compare contractility of the bovine lateral saphenous vein and the digital vein to increasing concentrations of ergot alkaloids. Blood vessels were collected from Holstein steers at slaughter (n = 12; 551 ±29 kg), cleaned, cut into 2-mm cross-sections, and mounted in a multi-myograph. In the myograph blood vessels were submersed in continuously gassed (95% O2/5% CO2) Krebs-Henseleit buffer. Following a 1.5-hr tension equilibration, blood vessels were exposed to a reference dose of 1x10-4 M norepinephrine. Digital and lateral saphenous veins from each steer were then exposed to increasing concentrations of a-ergocryptine (ERP), ergotamine (ERT), ergocristine (ERS), ergocornine (ERO), ergonovine (ERN), tall fescue seed extract (EXT; dilutions based on measured ergovaline concentration), lysergic acid (LSA), and lysergol (LYS) were diluted to final concentrations for use in the tissue bath of 5x10-10 to 1x10-4 M. All resultant contractile response data were normalized as a percentage of the 1x10-4 M norepinephrine response and analyzed as randomized design for effects of vein and alkaloid concentration. The maximal contractile response induced by EXT, ERT, ERO, ERS, and ERP did not differ by vein type and EXT was the most vasoactive alkaloid. The response to ERN was greater for the saphenous than the digital vein (P = 0.03) and LYS and LSA did not differ (P >0.05). These data confirm that the cranial branch of lateral saphenous vein is a representative model of peripheral vasculature of the bovine hindlimb.

scholarly journals PSVII-33 Determination of serotonergic receptor profiles in equine palmar artery and vein and uterine artery

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 312-313
Author(s):  
James Klotz ◽  
Karen McDowell
Keyword(s):  
Blood Vessels ◽  
Cross Sections ◽  
Uterine Artery ◽  
Serotonin Receptor ◽  
Contractile Response ◽  
Ergot Alkaloids ◽  
Fungal Endophyte ◽  
Fescue Toxicosis ◽  
Receptor Subtypes ◽  
Randomized Design

Abstract Ergot alkaloids are secondary metabolites produced by the fungal endophyte (Epichloë coenophiala) found in tall fescue (Lolium arundinaceum). Previous research has demonstrated that ergot alkaloids are vasoactive in equine palmar artery and vein but less in uterine artery. Work in cattle has shown that ergot alkaloids interact with serotonin receptors causing prolonged vasoconstriction associated with fescue toxicosis. The objective of this study was to pharmacologically assess vasoactivity of equine palmar artery and vein and uterine artery using selective agonists for serotonin receptor subtypes 5HT1B, 1D, 2A, 2B, and 7. Following euthanasia, palmar arteries, veins and uterine arteries were collected from 6 mixed breed mares. Blood vessels were separated, cleaned of external connective and adipose tissue, divided into 2–3 mm cross-sections and suspended in multi-myograph chambers containing continuously oxygenated Krebs-Henseleit buffer (95%O2/5%CO2; pH=7.4; 37°C). Following a 90-min equilibration of vascular tension and recovery from a reference addition of 1x10-4 M norepinephrine, increasing concentrations of agonists CP 93129 dihydrochloride (5HT1B), PNU 142633 (5HT1D), and TCB-2 (5HT2A) were added in 15-min intervals to assess to role of these receptors in vasoconstriction. Agonists BW 723C86 (5HT2B) and LP 44 (5HT7) were added to blood vessels precontracted with 1x10-4 M ergonovine to assess these receptors and vasorelaxation. Data were normalized as percent contractile response induced by the reference additions and analyzed as a completely randomized design using SAS. The agonists for 5HT1B and 1D did not induce a contractile response in any blood vessels tested (P > 0.05). The agonist for 5HT2A induced contractile response in all vessels tested (P < 0.05). The agonists for 5HT2B and 7 did not induce vasorelaxation different from ergonovine control (only vehicle additions) (P > 0.05). These results indicate that future work with ergot alkaloid induced vasoconstriction in equine vasculature should target the 5HT2A receptor.

scholarly journals Vasoactive Effects of Acute Ergot Exposure in Sheep

Toxins ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 291
Author(s):  
Rossalin Yonpiam ◽  
Jair Gobbet ◽  
Ashok Jadhav ◽  
Kaushik Desai ◽  
Barry Blakley ◽  
...  
Keyword(s):  
Single Dose ◽  
Chronic Exposure ◽  
Contractile Response ◽  
Ergot Alkaloids ◽  
Acute Exposure ◽  
Control Group ◽  
Vascular Effects ◽  
Adrenergic Antagonist ◽  
Vascular Sensitivity ◽  
Dose Dependent

Ergotism is a common and increasing problem in Saskatchewan’s livestock. Chronic exposure to low concentrations of ergot alkaloids is known to cause severe arterial vasoconstriction and gangrene through the activation of adrenergic and serotonergic receptors on vascular smooth muscles. The acute vascular effects of a single oral dose with high-level exposure to ergot alkaloids remain unknown and are examined in this study. This study had two main objectives; the first was to evaluate the role of α1-adrenergic receptors in mediating the acute vasocontractile response after single-dose exposure in sheep. The second was to examine whether terazosin (TE) could abolish the vascular contractile effects of ergot alkaloids. Twelve adult female sheep were randomly placed into control and exposure groups (n = 6/group). Ergot sclerotia were collected and finely ground. The concentrations of six ergot alkaloids (ergocornine, ergocristine, ergocryptine, ergometrine, ergosine, and ergotamine) were determined using HPLC/MS at Prairie Diagnostic Services Inc., (Saskatoon, SK, Canada). Each ewe within the treatment group received a single oral treatment of ground ergot sclerotia at a dose of 600 µg/kg BW (total ergot) while each ewe in the control group received water. Animals were euthanized 12 h after the treatment, and the pedal artery (dorsal metatarsal III artery) from the left hind limb from each animal was carefully dissected and mounted in an isolated tissue bath. The vascular contractile response to phenylephrine (PE) (α1-adrenergic agonist) was compared between the two groups before and after TE (α1-adrenergic antagonist) treatment. Acute exposure to ergot alkaloids resulted in a 38% increase in vascular sensitivity to PE compared to control (Ctl EC50 = 1.74 × 10−6 M; Exp EC50 = 1.079 × 10−6 M, p = 0.046). TE treatment resulted in a significant dose-dependent increase in EC50 in both exposure and control groups (p < 0.05 for all treatments). Surprisingly, TE effect was significantly more pronounced in the ergot exposed group compared to the control group at two of the three concentrations of TE (TE 30 nM, p = 0.36; TE 100 nM, p < 0.001; TE 300 nM, p < 0.001). Similar to chronic exposure, acute exposure to ergot alkaloids results in increased vascular sensitivity to PE. TE is a more potent dose-dependent antagonist for the PE contractile response in sheep exposed to ergot compared to the control group. This study may indicate that the dry gangrene seen in sheep, and likely other species, might be related to the activation of α1-adrenergic receptor. This effect may be reversed using TE, especially at early stages of the disease before cell death occurs. This study may also indicate that acute-single dose exposure scenario may be useful in the study of vascular effects of ergot alkaloids.

scholarly journals Assessment of ergot (Claviceps purpurea) exposure in pregnant and postpartum beef cows

2018 ◽  
Vol 98 (4) ◽  
pp. 688-700 ◽  
Author(s):  
T. Grusie ◽  
V. Cowan ◽  
J. Singh ◽  
J. McKinnon ◽  
B. Blakley
Keyword(s):  
Ergot Alkaloid ◽  
Post Partum ◽  
Ergot Alkaloids ◽  
Maximum Size ◽  
Beef Cows ◽  
Plasma Prolactin ◽  
Claviceps Purpurea ◽  
Ambient Temperatures ◽  
Beef Cow ◽  
The Impact

Cows were fed ration for 9 wk containing 5, 48, 201, and 822 μg kg−1 ergot alkaloids. The objective was to evaluate the impact of ergot consumption in beef cow–calf operations. Ergot alkaloids up to 822 μg kg−1 did not alter the weight of peripartum and postpartum beef cows (P = 0.93) or nursing calves (P = 0.08), rectal temperature (P = 0.16), or plasma prolactin concentrations (P = 0.30) at moderate ambient temperatures. Ergot did not influence the time (>1 ng mL−1; P = 0.79) or the progesterone concentration (P = 0.38) at the time of first postpartum rise or the size of the first (14 ± 0.6 mm; P = 0.40) and second (13 ± 0.5 mm; P = 0.41) follicles to ovulate. The maximum size of the first postpartum corpus luteum (CL) was 4 mm larger in the 822 μg kg−1 ergot group compared with the control (P = 0.03) for the first ovulation post partum, but not for the second (P = 0.11). There was no effect of ergot exposure on the number of days until the appearance of the first (43 ± 4 d; P = 0.95) or second (52 ± 4 d; P = 0.98) CL post partum. Ergot alkaloid concentrations up to 822 μg kg−1 did not affect pregnancy rates (X2 = 0.36). In conclusion, ergot alkaloid exposure for 9 wk to concentrations as high as 822 μg kg−1 did not alter performance in pregnant and postpartum beef cattle at moderate ambient temperatures.

Isolation of ergovaline, ergoptine, and ergonine, new alkaloids of the peptide type, from ergot sclerotia

1979 ◽  
Vol 57 (13) ◽  
pp. 1638-1641 ◽  
Author(s):  
Rudolf Brunner ◽  
Peter Leopold Stütz ◽  
Hans Tscherter ◽  
Paul Albert Stadler
Keyword(s):  
Total Synthesis ◽  
Ergot Alkaloid ◽  
Ergot Alkaloids ◽  
Extraction Processes

The isolation of three new ergot alkaloids of the peptide type from sclerotia of Clavicepspurpurea and from mother liquors of rye ergot alkaloid extraction processes is described. The constitution of the new alkaloids ergovaline, ergoptine, and ergonine has been established by comparison with compounds previously obtained by total synthesis.

scholarly journals 2',3'-Dideoxyadenosine is selectively toxic for TdT-positive cells

Blood ◽  
1988 ◽  
Vol 71 (6) ◽  
pp. 1601-1608
Author(s):  
Z Spigelman ◽  
R Duff ◽  
GP Beardsley ◽  
S Broder ◽  
D Cooney ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Ex Vivo ◽  
Exposure Period ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Parental Line ◽  
Continuous Exposure ◽  
Hiv Replication

The 2′,3′-dideoxynucleosides (ddNs) are currently undergoing clinical evaluation as antiretroviral agents in HIV-infected individuals. When phosphorylated, the ddNs (ddNTPs) function as chain-terminating substrate analogues with reverse transcriptase, thereby inhibiting HIV replication. These nucleoside analogues can also inhibit, by chain- terminating additions, the primitive lymphoid DNA polymerase, terminal deoxynucleotidyl transferase (TdT). To determine the effect of possible intracellular chain-terminating additions of ddNMPs by TdT, we exposed a series of TdT-positive and TdT-negative cell lines to 2′,3′- dideoxyadenosine (ddA), a representative ddN. At ddA concentrations 25- fold higher than required for inhibition of HIV replication, progressive dose-related cytotoxicity was observed in the TdT-positive cell lines. This was accentuated by the adenosine deaminase inhibitor Coformycin (CF), presumably by enhancing the intracellular generation of ddATP from ddA. A central role of TdT in mediating the ddA/CF cytotoxicity was suggested by studies in a pre-B-cell line rendered TdT positive by infection with a TdT cDNA-containing retroviral vector. After a 48-hour continuous exposure period to 250 mumol/L ddA and 30 mumol/L CF, 30% cell death was observed in the TdT-negative parental line, whereas 90% cell death was observed in the TdT-positive daughter line. Exposure of fresh TdT-positive leukemic cells to ddA/CF for 72 hours ex vivo resulted in cytotoxicity (six cases of acute lymphocytic leukemia [ALL]) while not affecting TdT-negative acute leukemic cells (six cases). We conclude that ddA/CF selectively damages TdT-positive cells, presumably by chain-terminating additions of ddAMP, and that this may have therapeutic relevance in TdT-positive malignant disease.

scholarly journals Effect of Fluoxetine and Paroxetine on Intestinal Motility in Presence of Ondansetron in ex-vivo Model

2020 ◽  
Vol 1 (3) ◽  
pp. 5
Author(s):  
Ayesha Afzal ◽  
Ammara Khan ◽  
Khalida Ajmal ◽  
Abeera Sikandar ◽  
Saima Rafiqu ◽  
...  
Keyword(s):  
Intestinal Motility ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Contractile Response ◽  
Ex Vivo ◽  
Ex Vivo Model ◽  
Rabbit Ileum ◽  
Medical College ◽  
Fixed Concentration ◽  
Antidepressant Effects

Objective: To understand the effects of fluoxetine and paroxetine with ondansetron on the intestinal motility of rabbit ileum. Study Design: Observational study. Place and Duration of Study: The study was conducted from March to April 2018 in a multidisciplinary lab of Army Medical College, Rawalpindi.Materials and Methods: The contractile effect of intestinal motility was recorded in the power lab. Subjects were twenty four healthy rabbits (Oryctolagus Cuniculus). Semi log dose-response curve was constructed for increasing concentrations of serotonin, ondansetron, fluoxetine, and paroxetine (10-9 to 10-6 M) alone and then in the presence of a fixed concentration of ondansetron (10-6 M) to observe the modulatory role of ondansetron. The serotonin mediated contractions were taken as control.Results: Ondansetron and serotonin caused an increase in the contractile response of rabbits ileum. A depressive response was observed when the contractions were recorded with increased concentration of fluoxetine and paroxetine in the presence of ondansetron. Conclusion: Ondansetron when used concomitantly with selective serotonin reuptake inhibitors(SSRIs), abolishes their antidepressant effects by causing a decrease in the intestinal motility of rabbit ileum.

scholarly journals Enhancement of Methacholine-Evoked Tracheal Contraction Induced by Bacterial Lipopolysaccharides Depends on Epithelium and Tumor Necrosis Factor

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
T. Secher ◽  
F. Rodrigues Coelho ◽  
N. Noulin ◽  
A. Lino dos Santos Franco ◽  
V. Quesniaux ◽  
...  
Keyword(s):  
Contractile Response ◽  
Ex Vivo ◽  
Adaptor Protein ◽  
Respiratory Pattern ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Bacterial Lipopolysaccharides ◽  
Necrosis Factor

Inhaled bacterial lipopolysaccharides (LPSs) induce an acute tumour necrosis factor-alpha (TNF-α-) dependent inflammatory response in the murine airways mediated by Toll-like receptor 4 (TLR4) via the myeloid differentiation MyD88 adaptor protein pathway. However, the contractile response of the bronchial smooth muscle and the role of endogenous TNFα in this process have been elusive. We determined the in vivo respiratory pattern of C57BL/6 mice after intranasal LPS administration with or without the presence of increasing doses of methacholine (MCh). We found that LPS administration altered the basal and MCh-evoked respiratory pattern that peaked at 90 min and decreased thereafter in the next 48 h, reaching basal levels 7 days later. We investigated in controlled ex vivo condition the isometric contraction of isolated tracheal rings in response to MCh cholinergic stimulation. We observed that preincubation of the tracheal rings with LPS for 90 min enhanced the subsequent MCh-induced contractile response (hyperreactivity), which was prevented by prior neutralization of TNFα with a specific antibody. Furthermore, hyperreactivity induced by LPS depended on an intact epithelium, whereas hyperreactivity induced by TNFα was well maintained in the absence of epithelium. Finally, the enhanced contractile response to MCh induced by LPS when compared with control mice was not observed in tracheal rings from TLR4- or TNF- or TNF-receptor-deficient mice. We conclude that bacterial endotoxin-mediated hyperreactivity of isolated tracheal rings to MCh depends upon TLR4 integrity that signals the activation of epithelium, which release endogenous TNFα.

scholarly journals Kisspeptin-10 Inhibits Angiogenesis in Human Placental Vessels ex Vivo and Endothelial Cells in Vitro

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5927-5934 ◽  
Author(s):  
Thayalini Ramaesh ◽  
James J. Logie ◽  
Antonia K. Roseweir ◽  
Robert P. Millar ◽  
Brian R. Walker ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Ex Vivo ◽  
Umbilical Vein ◽  
Biologically Active ◽  
Trophoblast Invasion ◽  
In Vitro Assays ◽  
Dependent Manner ◽  
Inhibition Of Proliferation

Recent studies suggest that kisspeptin (a neuropeptide central to the regulation of gonadotrophin secretion) has diverse roles in human physiology, including a putative role in implantation and placental function. Kisspeptin and its receptor are present in human blood vessels, where they mediate vasoconstriction, and kisspeptin is known to inhibit tumor metastasis and trophoblast invasion, both processes involving angiogenesis. We hypothesized that kisspeptin contributes to the regulation of angiogenesis in the reproductive system. The presence of the kisspeptin receptor was confirmed in human placental blood vessels and human umbilical vein endothelial cells (HUVEC) using immunochemistry. The ability of kisspeptin-10 (KP-10) (a shorter biologically active processed peptide) to inhibit angiogenesis was tested in explanted human placental arteries and HUVEC using complementary ex vivo and in vitro assays. KP-10 inhibited new vessel sprouting from placental arteries embedded in Matrigel and tube-like structure formation by HUVEC, in a concentration-dependent manner. KP-10 had no effect on HUVEC viability or apoptosis but induced concentration-dependent inhibition of proliferation and migration. In conclusion, KP-10 has antiangiogenic effects and, given its high expression in the placenta, may contribute to the regulation of angiogenesis in this tissue.

scholarly journals Differentially expressed genes in cotyledon of ewes fed mycotoxins

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
J. L. Britt ◽  
R. E. Noorai ◽  
S. K. Duckett
Keyword(s):  
Wound Healing ◽  
Differentially Expressed Genes ◽  
Ergot Alkaloid ◽  
Ergot Alkaloids ◽  
Late Gestation ◽  
Fetal Weight ◽  
Differentially Expressed ◽  
Coagulation Cascade ◽  
Peroxisome Proliferator ◽  
Metabolism Regulation

Abstract Background Ergot alkaloids (E+) are mycotoxins produced by the endophytic fungus, Epichloë coenophiala, in tall fescue that are associated with ergotism in animals. Exposure to ergot alkaloids during gestation reduces fetal weight and placental mass in sheep. These reductions are related to vasoconstrictive effects of ergot alkaloids and potential alterations in nutrient transport to the fetus. Cotyledon samples were obtained from eight ewes that were fed E+ (n = 4; E+/E+) or E- (endophyte-free without ergot alkaloids; n = 4; E−/E-) seed during both mid (d 35 to 85) and late (d 85–133) gestation to assess differentially expressed genes associated with ergot alkaloid induced reductions in placental mass and fetal weight, and discover potential adaptive mechanisms to alter nutrient supply to fetus. Results Ewes fed E+/E+ fescue seed during both mid and late gestation had 20% reduction in fetal body weight and 33% reduction in cotyledon mass compared to controls (E−/E-). Over 13,000 genes were identified with 110 upregulated and 33 downregulated. Four genes had a |log2FC| > 5 for ewes consuming E+/E+ treatment compared to controls: LECT2, SLC22A9, APOC3, and MBL2. REViGO revealed clusters of upregulated genes associated glucose, carbohydrates, lipid, protein, macromolecular and cellular metabolism, regulation of wound healing and response to starvation. For downregulated genes, no clusters were present, but all enriched GO terms were associated with anion and monocarboxylic acid transport. The complement and coagulation cascade and the peroxisome proliferator-activated receptor signaling pathway were found to be enriched for ewes consuming E+/E+ treatment. Conclusions Consumption of ergot alkaloids during gestation altered the cotyledonary transcriptome specifically related to macronutrient metabolism, wound healing and starvation. These results show that ergot alkaloid exposure upregulates genes involved in nutrient metabolism to supply the fetus with additional substrates in attempts to rescue fetal growth.

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