Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro

Cherewyk, Jensen E; Parker, Sarah; Blakley, Barry; Al-Dissi, Ahmad

doi:10.1093/jas/skaa203

Cited by 15 publications

(13 citation statements)

References 29 publications

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“…Arteries were collected, as described previously ( Cherewyk et al, 2020 ). Twelve healthy steers (15–30 mo old) of mixed breed were euthanized at a local abattoir with a single animal being killed during each visit.…”

Section: Methodsmentioning

confidence: 99%

“…The S -epimers of ergot alkaloids have been denoted as non or less bioactive compared to their corresponding R -epimers ( Smith and Shappell, 2002 ; Klotz, 2015 ). Recently, the S -epimers demonstrated biological activity, causing vascular contractility in isolated bovine vascular rings ( Cherewyk et al, 2020 ). Investigating the potential sustained contractile response of S -epimers could further evaluate their biological activity ( Mulac et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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Sustained vascular contractile response induced by an R- and S-epimer of the ergot alkaloid ergocristine and attenuation by a noncompetitive antagonist

Cherewyk

Parker

Blakley

et al. 2022

Journal of Animal Science

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Vasoconstriction is a known effect associated with ergot alkaloid consumption. The vascular contractile responses are often sustained for an extended period after exposure. Ergot alkaloids exist in two molecular configurations, the C-8-(R)-isomer (R-epimer) and the C-8-(S)-isomer (S-epimer). The sustained vascular contractile response to the R-epimers have been studied previously, unlike the S-epimers which are thought to be biologically inactive. Additionally, antagonists have been utilized to attenuate the vascular contraction associated with the R-epimers of ergot alkaloids utilizing ex vivo techniques. This study utilized an arterial tissue bath to examine and compare the sustained vascular contractile response attributed to ergocristine (R) and ergocristinine (S) using dissected bovine metatarsal arteries. The contractile blocking effect of a non-competitive alpha-adrenergic antagonist, phenoxybenzamine (POB), was also investigated in precontracted arteries. Arteries (n=6/epimer) were exposed to a single dose of ergocristine or ergocristinine (1 × 10 -6 M in buffer). Each of the epimer doses were followed by a POB (1 × 10 -3 M) or methanol (control) treatment at 90 minutes and the response was observed for another 90 min. Both epimers produced a sustained contractile response over the 180 min incubation period in the control groups. The R-epimer caused a greater sustained contractile response from 60-180 min post epimer exposure, compared to the S-epimer (P < 0.05, Generalized Estimating Equations, Independent t-test). Phenoxybenzamine caused a decrease in the contractile response induced by ergocristine and ergocristinine from 105 – 180 min, compared to the control (P < 0.05, Generalized estimating equations, Paired t-test). Overall, these results demonstrate the presence of a sustained vascular contractile response attributed to the R and S-epimer of an ergot alkaloid with differences in contractile response between the epimers, suggesting differences in receptor binding mechanisms. Furthermore, this study demonstrated that a non-competitive antagonist could attenuate the sustained arterial contractile effects of both ergot configurations ex vivo. Additional investigation into S-epimers of ergot alkaloids is needed. This research contributes to the understanding of the ergot epimer-vascular receptor binding mechanisms, which may support the investigation of different approaches of minimizing ergot toxicity in livestock.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sustained vascular contractile response induced by an R- and S-epimer of the ergot alkaloid ergocristine and attenuation by a noncompetitive antagonist

Cherewyk

Parker

Blakley

et al. 2022

Journal of Animal Science

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“…We recently showed that the S-epimers of ergot alkaloids are vasoactive causing vasoconstriction of bovine dorsal metatarsal arteries in vitro [37]. It is, therefore, possible that the effects seen in this study are related to the combined activity of the R and S epimers and not just the R-epimers.…”

Section: Discussionmentioning

confidence: 58%

Vasoactive Effects of Acute Ergot Exposure in Sheep

Yonpiam

Gobbet

Jadhav

et al. 2021

Toxins

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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.

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“…The dose-dependent decrease in contractility after pre-incubation with ERV and the occurrence of this effect at a very low dose (1 × 10 −10 M) was evidence that the effect of ergot alkaloids on blood vessels is mediated by both the dose and the time that the receptors are exposed. Without previous exposure, the ergopeptine ergot alkaloids normally reduce the contractility of vessels at concentrations higher than 1 × 10 −7 to 1 × 10 −6 M [4,22,23], which are considerably higher than the ergovaline levels expected in plasma of ruminants consuming ergot alkaloids [24]. The difference in the concentration of ergot alkaloids and the observed responses in the literature indicates that the duration of exposure can influence the ergot alkaloid effect.…”

Section: Discussionmentioning

confidence: 91%

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

Valente

Harmon

Klotz

2021

Toxins

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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.

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Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro

Cited by 15 publications

References 29 publications

Sustained vascular contractile response induced by an R- and S-epimer of the ergot alkaloid ergocristine and attenuation by a noncompetitive antagonist

Sustained vascular contractile response induced by an R- and S-epimer of the ergot alkaloid ergocristine and attenuation by a noncompetitive antagonist

Vasoactive Effects of Acute Ergot Exposure in Sheep

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

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