Mechanism of Action of Domperidone for Treating Equine Fescue Toxicosis

The action of domperidone as a D2 dopamine receptor blocker prevents the ergot alkaloids from mimicking dopamine actions. The most apparent action of dopamine and the ergot alkaloids in the fescue-endophyte symbiont is their prolactin-lowering effect. With administration of domperidone to mares consuming E+ tall fescue, prolactin returned to normal levels and even increased above normal levels in most instances (Redmond et al., 1994). Although prolactin is a major factor in equine fescue toxicosis, it is only one of many hormones that are influenced. Prolactin, progestogens, and estrogen are major factors in the milk production maladies observed in E+ mares, and administration of domperidone returns these hormones to near normal levels and functions. In addition, the effect of domperidone on peripheral circulation as an a-1 receptor antagonist provides for its remediation of the negative microcirculatory effects of the alkaloids.

Since the hypothalamic-pituitary-adrenal axis (HPA) of the fetus in mares consuming E+ tall fescue appears to be compromised, resulting in prolonged gestation lengths and the associated problems, domperidone may have some effect on the HPA system. This hypothesis is borne out by the fact that mares that receive domperidone while grazing E+ tall fescue foal at or near their expected foaling date with normal, healthy foals. Adrenocorticotrophic hormone (ACTH) levels in foals from mares consuming E+ fescue are low. Since ACTH is the stimulus for adrenal cortisol release and since normal fetal adrenal cortisol levels appear to be necessary to trigger parturition, one can speculate that domperidone may be affecting this system. Zerbe et al. (1993) administered domperidone to dogs and observed an enhanced ACTH response to corticotrophic releasing hormone (CRH) injections. Thus, domperidone could be reversing the effects of E+ tall fescue on gestation length by causing an increase in adrenal cortisol through CRH stimulated release of ACTH.

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