Vasoactive Effects of Acute Ergot Exposure in Sheep

Abstract

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.

Evolution of the Ergot Alkaloid Biosynthetic Gene Cluster Results in Divergent Mycotoxin Profiles in Claviceps purpurea Sclerotia

“…Therefore, the effects of ergot alkaloids on mammalian systems such as humans and livestock (i.e., cattle, sheep, horses and goats) are diverse, where, in the case of livestock, observed symptomatic responses to ergot alkaloid exposure can be highly variable and, therefore, historically difficult to diagnose [38]. Gangrenous ergotism occurs most frequently from acute ergot alkaloid exposure, caused by general blood vessel vasoconstriction and dysfunction resulting in tissue necrosis (dry gangrene) of the extremities such as the ear tips, tail, lower limbs and hooves [37][38][39]. In other instances, the consumption of subtle quantities of-and the prolonged exposure of livestock to-ergot alkaloids negatively impacts energy metabolism, feed efficiency and livestock productivity, as evidenced by decreases in food intake, live weight gain, circulating prolactin, reproductive performance, milk production and hyperthermia [37][38][39].…”

“…Gangrenous ergotism occurs most frequently from acute ergot alkaloid exposure, caused by general blood vessel vasoconstriction and dysfunction resulting in tissue necrosis (dry gangrene) of the extremities such as the ear tips, tail, lower limbs and hooves [37][38][39]. In other instances, the consumption of subtle quantities of-and the prolonged exposure of livestock to-ergot alkaloids negatively impacts energy metabolism, feed efficiency and livestock productivity, as evidenced by decreases in food intake, live weight gain, circulating prolactin, reproductive performance, milk production and hyperthermia [37][38][39]. Pregnant and lactating animals are most susceptible to ergot alkaloid exposure due to increased risk of abortion and agalactia syndrome (the absence or failure to secrete milk); there is a direct correlation of ergopeptide exposure with a decrease in prolactin, growth hormone and luteinizing hormone secretion, and the inhibition of milk production [37].…”

Global Impact of Ergot Alkaloids

“…A very specific pathology associated with ergot alkaloids and ergotism is a chronic vasoconstriction. Yonpaim et al [ 21 ] looked at the acute exposure of ergot alkaloids on vasoactivity in ovine vasculature, and Valente et al [ 22 ] evaluated prolonged ergot alkaloid exposure on the vasoactivity of bovine vasculature. Both studies [ 21 , 22 ] respectively evaluated aspects related to the ability of ergot alkaloids to interact with adrenergic and serotonergic receptors [ 23 ], and both papers concluded that receptor-mediated treatments for ergot alkaloid-induced vasoconstriction could be explored as potential therapies.…”

“…Yonpaim et al [ 21 ] looked at the acute exposure of ergot alkaloids on vasoactivity in ovine vasculature, and Valente et al [ 22 ] evaluated prolonged ergot alkaloid exposure on the vasoactivity of bovine vasculature. Both studies [ 21 , 22 ] respectively evaluated aspects related to the ability of ergot alkaloids to interact with adrenergic and serotonergic receptors [ 23 ], and both papers concluded that receptor-mediated treatments for ergot alkaloid-induced vasoconstriction could be explored as potential therapies. From a systemic evaluation of ergot alkaloids’ impact on the whole animal or microbiome, to the study of a specific symptom, there is much yet to be learned about how ergot alkaloids disrupt mammalian physiology.…”