Tall fescue (Lolium arundinaceum) occupies nearly 35 million acres (12 million hectares) in the United States and is the most abundant and economically important forage grass of the transition zone east of the Mississippi River. It is a hardy and persistent forage with excellent nutritive value. These characteristics led to early and rapid adoption of tall fescue as a primary forage crop for cattle, sheep, and horses during the 1940s. Although nutritional analyses predicted that tall fescue would support good body weight gains in grazing livestock, it failed to produce gains on par with similar forages (for example, orchardgrass). In fact, tall fescue induced a form of ergotism (intoxication), now known as fescue toxicosis, in these animals. Fescue toxicosis is actually made up of three metabolic syndromes: “fescue foot,” “summer slump,” and “fat necrosis.”
During the late 1970s, the presence of an endophytic (grows inside a plant as a symbiont) fungus (Neotyphodium coenophialum) in tall fescue was linked to poor body weight gains. Subsequently, it was determined that the endophyte produced ergot alkaloids (for example, ergovaline and lysergic acid), which constitute a class of chemicals that contain ergotamine and the hallucinogenic drug of abuse, LSD (lysergic acid diethylamide). Likewise, these alkaloids (see illustration) are of the same class as those responsible for severe outbreaks of ergotism (for example, St. Anthony's Fire) in humans during the Middle Ages. However, in human cases of ergotism, the fungus responsible for production of the ergot alkaloids (for example, ergotamine) was the ergot (Claviceps purpurea) of rye (Secale cereale).
Vasculature
The circulatory system, through its network of blood vessels, provides tissue level removal of metabolic waste products and delivery of necessary nutrients, oxygen, hormones, growth factors, and immune components needed to maintain health and productivity. Blood vessels (arteries, veins, and capillaries) are composed of tissues arranged in three concentric layers (tunicae) of tissue. Beginning at the lumen (blood side of the vessel), the intima (first layer) is composed of endothelial cells (lining the lumen), subendothelial connective tissue, and an internal elastic lamina. The internal elastic lamina forms the separation of the intima from the media (middle layer). The media consists of smooth muscle cells, elastic fibers, and the external elastic lamina. The external elastic lamina separates the media from the adventitia (outer layer). The adventitia is a poorly defined layer of connective tissue containing nerves and small blood vessels needed to support the media of larger blood vessels. Generally, these layers are best defined in larger arteries and less defined in smaller vessels and veins. Capillaries, the smallest blood vessels, lack the smooth muscle cells found in the media of other blood vessels, but have a small number of pericytes that constrict similar to smooth muscle cells to reduce the diameter of the vessel.
Compromise of the circulatory system with fescue toxicosis is well documented and explains many of the symptoms and outcomes (see table). For example, dry gangrene of extremities occurs as a result of the additive effects of alkaloid-induced vasoconstriction with constriction due to cold weather (a heat conservation mechanism), leading to cessation of blood flow to extremities and subsequent death of the tissue. Likewise, alkaloid-induced vasoconstriction can impede heat transfer from internal organs to the skin for dissipation and thus induces increased rectal temperatures (representative of increased internal body temperature). As a consequence of the temperature increase, behavioral adaptations (for example, reduced grazing, and standing in the shade and water) are induced. An additional complication occurs because of alkaloid-induced cell proliferation and death, resulting in altered vascular morphology.
Syndromes |
Symptoms |
|---|---|
Fescue foot |
• Lameness |
• Fetlock/hoof swelling | |
• Dry gangrene of extremities | |
• Loss of tail tips, hooves, and ear tips | |
Summer slump |
• Reduced grazing |
• Extended time in shade and water (mud holes, ponds, and streams) | |
• Reduced weight gains | |
• Rough hair | |
• Elevated rectal temperature | |
• Increased respiration rate and salivation | |
• Reduced serum prolactin and milk production | |
• Dystocia (difficult birth) in pregnant mare | |
• Death of foal and mare | |
Fat necrosis |
• Hard fat deposits around internal organs |
• Reduced weight gains | |
• Poor health and appearance |
Ergot alkaloids and vascular morphology
During the 1960s and 1970s, prior to the linkage of endophyte-infected tall fescue to fescue toxicosis, researchers described gross changes in vascular morphology in cattle consuming tall fescue or alcohol extracts of the plant. Some of the reported morphological changes included blood vessel congestion, perivascular hemorrhage, blood vessel distension, thickened walls, and small luminal diameters in peripheral blood vessels (for example, in the foot). The noted changes may occur as a result of hypertrophy and/or hyperplasia of smooth muscle cells and/or death of endothelial cells.
Hypertrophy (an increase in size of the smooth muscle cells) would reduce luminal size and blood flow. This is analogous to a smaller internal diameter pipe not being able to carry as much water as a larger one. However, this mode has yet to be empirically proven. Hyperplasia (an increase in the number of smooth muscle cells) would have an effect similar to hypertrophy, that is, thickening of the media while reducing luminal size and blood flow. Evidence for hyperplasia was demonstrated in the mid-1990s, when it was reported that ergovaline was able to stimulate quiescent smooth muscle cell growth in a petri dish. These first two modes can provide explanation of how ergot alkaloids contribute to blood vessel congestion, thickened walls, and small luminal diameters. However, compromise of the endothelial cell layer would be required for hemorrhage or leaking. Endothelial cell death has been shown by treating bovine (cattle) pedal vein endothelial cells grown in a petri dish with ergovaline and monitoring cell viability. Ergovaline induced endothelial cell death in this in vitro system and thus provided evidence for how ergot alkaloids may induce perivascular hemorrhage, as these cells normally prevent blood components from escaping into perivascular tissues.
Ergot alkaloids, biogenic amine receptors, and vasoconstriction
Although ergot alkaloids may induce morphological changes in the vasculature, the primary mechanism by which these alkaloids induce circulatory compromise is via vasoconstriction (contraction of smooth muscle cells resulting in decreased luminal diameter and blood flow). Both in vivo (in the animal) and in vitro (tissue culture) research studies have clearly demonstrated the contractile potential of a number of ergot alkaloids (for example, lysergic acid and ergovaline). Recent studies, using Doppler ultrasound, have conclusively demonstrated that ergovaline causes constriction of luminal diameter and reduces blood flow through the caudal (tail) vein and artery in cattle consuming endophyte-infected tall fescue. Doppler ultrasound has improved our ability to study the circulatory compromise of fescue toxicosis in real time and should provide a good picture of an animal's recovery following removal of alkaloid exposure during future studies. The tail vessel findings are representative of what happens to blood flow in a number of other cattle and sheep tissues, including leg skin, adrenal glands, rib skin, cerebellum, duodenum (small intestine), and colon, upon consumption of ergot alkaloids by these animals. Blood flow through these latter tissues was determined by tracking radioactive beads through the blood vessels, which is a more difficult and costly method compared to Doppler ultrasound.
In vitro contractility studies have been used extensively to investigate the vascular activity of drugs and toxicants. In these studies, a ring of blood vessels is suspended between a fixed point and a transducer that converts the mechanical contraction exerted by the vessels in response to the addition of ergot alkaloids to an electrical signal that is recorded by a computer as a contractile force. Studies conducted in this manner have conclusively demonstrated that the ergopeptines (for example, ergotamine and ergovaline) are more effective as vasoconstrictors (that is, they are more toxic) than lysergic acid. Additionally, bioaccumulation in vascular tissue has been shown for ergovaline, but not for lysergic acid, using these types of studies. Furthermore, these studies have provided researchers with potential cell surface targets for treating fescue toxicosis. From these in vitro studies, it has been demonstrated using receptor antagonists that ergot alkaloid-induced vasoconstriction is mediated through activation of biogenic amine receptors (serotonin and α-adrenergic receptors). These receptors act as on/off switches for muscle contraction in the blood vessels. When turned on, these switches cause reduced blood flow as a consequence of the reduced luminal diameter occurring via constriction.
The findings of relative potency and bioaccumulation have clearly demonstrated that lysergic acid, although a potential hallucinogen, is not a major player in circulatory compromise of peripheral tissues, whereas the ergopeptines are of great concern. The latter indicates a need to focus research efforts on reducing exposure to ergopeptines, decreasing sensitivity of the animal's tissues to ergopeptines, and/or enhancing clearance of the ergopeptines in order to reduce or eliminate fescue toxicosis.
Potential solutions to fescue toxicosis
During the last two decades, significant progress has been made in developing novel endophyte-infected tall fescue cultivars that retain hardiness and persistence while eliminating the ergot alkaloids and thus fescue toxicosis. However, these new cultivars have not yet significantly replaced the toxic endophyte-infected tall fescue varieties in the field. Locations with rough and steep topographies are not conducive to renovation (replacement) with the new tall fescue varieties. Additionally, problems with the old variety recovering from stray plants and existing seed banks continue to decrease the effectiveness of replacement with novel endophytes. Efforts to dilute the amounts of ergot alkaloids that are consumed or absorbed by livestock have also been tried through a variety of methods: interseeding pastures with clover, using supplemental feeds while animals are on pasture, and using binding agents to inhibit ergot alkaloid absorption. However, none of these have been entirely successful.
Problems with replacing toxic cultivars of tall fescue and/or decreasing ergot alkaloid intake and absorption have led to treatments designed to block alkaloid interactions at the vascular biogenic amine receptors. This approach has been partially successful in reducing the severity of fescue toxicosis when drugs (receptor antagonists) such as metoclopramide, sulpiride, and domperidone are used. In fact, the effectiveness of domperidone in treating fescue toxicosis in pregnant mares has led many veterinarians in the Bluegrass region of Kentucky to use the drug to avoid costly reproductive problems (see table). However, no drug has been successful in completely reversing fescue toxicosis.
Expansion of livestock production to meet world protein demand without expanding land use will require that fescue toxicosis be overcome using new and innovative approaches. Future efforts to address fescue toxicosis should continue to exploit efforts currently showing promise and should explore modifying animal metabolism of the alkaloids. This latter approach may be accomplished through genetic selection of animals naturally resistant to the alkaloids, modification of rumen microbes, or modification of the metabolism of animals through the use of nutrients and nutraceuticals.
See also: Alkaloid; Blood vessels; Endophytic fungi; Ergot and ergotism; Fescue; Forage crops; Fungal biotechnology; Fungal ecology; Fungal infections; Fungi; Grass crops; Mycology; Mycotoxin
