- Toxicokinetics of the Ergot Alkaloids
- Future Research Directions
Thermal Response, Heat Tolerance, and Stress
Hyperthermia is a primary characteristic of fescue toxicosis that often is used to define the magnitude of this condition. Environmental stress is a key determinant of the change in thermal status associated with fescue toxicosis (Hemken et al., 1984) and may result in increases or decreases in core body temperature from normal. In addition, there is a temporal determinant of the thermal stress-toxin response, with a distinct separation of short-term (acute) and long-term (chronic) responses that may encompass the adaptive response.
Initial studies in this area concentrated on the short-term response to an injected dose of readily available ergot alkaloids, such as ergotamine tartrate, known to reduce feed intake in domestic animals (Greatorex and Mantle, 1973, 1974; Osborn et al., 1992). Carr and Jacobson (1969) injected ergotamine tartrate (intramuscular, 35-92 mg/kg BW) into Holsteins at an 18.5°C Tair and noted an 8°C decrease in tail skin temperature, an indication of reduced blood flow. Administration (oral or intraperitoneal) of an 80% ethanol extract of E+ fescue under the same environmental condition also reduced skin temperature and increased rectal temperature. They suggested that reduced skin blood flow might diminish heat loss and result in hyperthermia during heat stress, with similar shifts in flow at cold air temperature to reduce skin temperature. Likewise, the reduced blood flow to appendages during cold stress could limit nutrient flow and result in tissue necrosis. Browning et al. (1998) also noted reduced skin temperature in Angus heifers injected at Tair = 35.2°C with either ergotamine tartrate or ergonovine maleate at rates of 5 to 7 mg/animal in both cases. Both treatments increased respiration rate (60-90 bpm); however, there was no significant effect on rectal temperature, suggesting that any increased heat was dissipated by increased heat loss. In contrast, intraperitoneal injection of heat-stressed cattle (Tair = 31°C) with ergovaline (5.2 mg/kg BW/d) for 3 d increased both core body temperature and respiration rate (Al-Haidary et al., 1995). Skin temperatures in the hip and back also were lowered, suggesting reduced blood flow and heat loss. These contrasting results indicated that ergovaline may be more potent than other ergopeptine alkaloids in producing signs associated with fescue toxicosis. McCollough et al. (1994) injected calves intravenously with ergotamine, ergine, and ergovaline and found that ergovaline was more effective than the other compounds in rate and magnitude of reduction in tail skin temperature, again supporting ergovaline as the more potent ergopeptine alkaloid.
The effect of ergopeptine alkaloids on thermoregulatory ability is highly dependent on Tair. This was demonstrated initially using classical biomedical animal models. In an early study, Roberts et al. (1949) injected rats intraperitoneally with ergotoxine (4.5 mg/kg BW) at Tair = 28 to 30°C. The rats were tested at ages 12 d (juvenile) and 37 d (adult) and exhibited hypothermic and hyperthermic responses, respectively. This differing response with age occurred as a result of the fact that this Tair was a cold stress for juveniles but a mild heat stress for the adults. It also demonstrated the dependency of the ergopeptine alkaloid response on Tair. Neal and Schmidt (1985) noted hypothermia in rats fed a diet with 50% E+ tall fescue for 15 d at Tair = 24 to 32°C and concluded that the rat is an inappropriate model for fescue toxicosis. However, they did not realize that the fescue toxicosis condition can shift core temperature above and below normal level at different Tair levels.
Few studies have been conducted under controlled environmental conditions to verify these shifts and determine mechanisms of action. Adult rats have been tested in environmental chambers at Tair values known to represent cold (7-9°C), thermoneutral (22°C), and hot (31-33°C) conditions following a single intraperitoneal injection of ergovaline (15mg/kg BW; Spiers et al., 1995; Zhang et al., 1994). Hyperthermia in the hot environment was preceded by a reduction in tail skin temperature with no shift in heat production, indicating that the cause was a reduction in cutaneous heat loss (Spiers et al., 1995). A decrease in core temperature occurred for the thermoneutral treatment; this is due to both an increase in peripheral heat loss, as indicated by an increase in tail skin temperature, and a reduction in heat production, as evidenced by reduced heat production (Zhang et al., 1994). Significant hypothermia also occurred in the cold after injection of ergovaline (Spiers et al., 1995), as a result of a reduction in heat production. It is apparent that ergovaline can affect either heat production or heat loss mechanisms, with the determining factor being which action is most in use at any given Tair (i.e., heat production in the cold and heat loss in the heat).
Most studies of the effect of fescue toxicosis on thermoregulation have been only a few hours or days, with few controlled long-term studies that would represent a more realistic scenario. Such studies are more complex than short-term ones because they must consider the time element and the possibility of adaptations to the test Tair and/or the toxins in question. Likewise, issues such as circadian rhythms and the indirect effect of reduced feed intake become critical. In general, there is a long-term reduction in feed intake of cattle grazing E+ tall fescue at Tair above 31°C (Hemken et al., 1981) and decreased ADG (Hoveland et al., 1983; Schmidt et al., 1982). The accompanying hyperthermia is due to a reduction in heat loss as a result of increased peripheral vasoconstriction (Osborn et al., 1992; Rhodes et al., 1991).
Both short- and long-term shifts in thermal status have been reported in animals administered E+ tall fescue under controlled environmental conditions. Al-Haidary et al. (2001) fed cattle a diet with E+ tall fescue seed (5 mg ergovaline/kg BW/d) for several days at 31°C. The primary effect on thermoregulatory ability (i.e., hyperthermia, increased respiration rate) was during the night, when there was a steady accumulation of metabolic heat following digestion of the daily meals, without the typical increase in the thermal gradient for heat dissipation (i.e., Tair was constant). As noted for rats, there was no change in metabolic rate or skin and respiratory vaporization rates. Skin temperature did not increase with core temperature, suggesting that there was little increase in peripheral heat loss under these conditions (Osborn et al., 1992; Rhodes et al., 1991; Solomons et al., 1989). Rhodes et al. (1991), using radiolabeled microspheres to measure vascular flow rates, found that flow rate to the skin covering the ribs was reduced in steers fed a diet containing E+ fescue seed (0.52 mg/kg ergovaline). Gadberry et al. (2003) noted that lambs fed a 10% E+ fescue seed diet (640 mg/kg) for 14 d during heat stress had reduced feed intake and ADG as well as evidence of reduced peripheral heat loss. No increase in the level of hyperthermia was noted to support a vasomotor response preceding the body temperature response. Aldrich et al. (1993a,b) fed steers an E+ tall fescue diet (285 mg/kg ergovaline) for 20 d at Tair = 32°C and noted hyperthermia with no effect on metabolic heat production or respiratory vaporization. However, skin vaporization was reduced by 50%; this observation was used to explain the hyperthermia. A rodent model for fescue toxicosis has been used to determine the long-term response of rats to fescue toxicosis (Spiers et al., 2005). Adult male rats, implanted intraperitoneally with temperature transmitters to monitor core temperature and general activity, were fed an E+ or an E- seed diet. Hypothermia was noted at thermoneutrality, with hyperthermia during heat stress, supporting observations in long-term studies in cattle. Activity level was lower in rats fed the E+ diet than in control rats during all periods. This response has not been measured in cattle or other species because similar transmitting sensors are unavailable for large animals.
Circadian shift in internal body temperature often has been overlooked in determining the change in thermal status associated with fescue toxicosis. The recent advent of thermal sensors now allows for this evaluation. In one study, beef calves were exposed to 31°C for 3 d and then fed a diet containing E+ tall fescue seed (5 mg ergovaline/kg BW/d) for 5 d while remaining at this Tair (Al-Haidary, 1995; Al-Haidary et al., 1995). The effects of this treatment were seen near midnight, with an increase in core temperature above control level. Likewise, there was an increase in respiration rate at this time. None of the other variables (i.e., skin temperature, skin or respiratory vaporization, metabolic rate) was affected. This would suggest that differences in heat production and water vaporization, at least during the daily peak in thermal status, are not responsible for noted shifts in body heat content associated with intake of E+ tall fescue. A more likely explanation would be the inability to increase peripheral blood flow to augment heat loss and dissipate the accumulated daily heat during the night.
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