- Toxicokinetics of the Ergot Alkaloids
- Future Research Directions
Blood, Immunity, and Inflammation
Most blood cellular parameters are not affected by E+ tall fescue intake; however, E+ tall fescue increased the number of erythrocytes and decreased their size (mean corpuscular volume) and hemoglobin values (Table 12-1, Oliver et al., 2000a). Reduced Cu levels probably contribute to the decreased mean corpuscular volume and have decreased mean corpuscular hemoglobin values owing to inhibitory effects on hemoglobin synthesis. Enzymatic activity in general, and hepatic enzyme activity in particular, were decreased by intake of E+ tall fescue (Thompson and Stuedemann, 1993; Stuedemann and Thompson, 1993; Schultze et al., 1999; Oliver et al., 2000a). Many factors lower enzymatic activity, but decreased feed intake may be the factor most responsible (Oliver et al., 2000a), resulting in reduced growth and tissue metabolism and mass. Serum cholesterol levels were consistently lowered, as well as serum globulin levels (Table 12-2; Oliver et al., 2000a). Specifically, a and g globulin levels were lowered (Table 12-3, Schultze et al., 1999).
Most mineral levels were unaffected by E+ tall fescue intake (Table 12-4, Oliver et al., 2000a). However, serum Cu levels were decreased (Saker et al., 1998; Oliver et al., 2000a). Dennis et al. (1998) documented lowered Cu levels in E+ tall fescue, which may account for the lowered serum Cu levels in cattle that graze E+ tall fescue. Vaccination response was similar in cattle that grazed E- or E+ tall fescue (Rice et al., 1997). However, in a later study, E+ tall fescue exposure lowered immune function in steers, which was associated with Cu deficiency (Saker et al., 1998). In addition, as noted earlier, g globulin levels are consistently suppressed by exposure to E+ tall fescue (Table 12-3, Schultze and Oliver, 1999). Thus, some compromise in immune status apparently occurs in animals that consume E+ tall fescue. The degree to which this results in morbidity or mortality has yet to be determined.
The vascular endothelium has been described as the cellular target for initial injury by the ergot alkaloids (Thompson et al., 1950). Direct evidence of endothelial damage by ergot alkaloids has been provided recently by exposing isolated bovine endothelial cells to ergovaline and ergine in vitro (Shappell, 2003). The ergine treatment at 10-5 M concentration had minimal effect, while ergovaline at this dose gave cytotoxic effects. At 10-4 M concentration, ergovaline caused marked cytotoxicity, while ergine caused only a slight toxic effect. Thus, the presence of ergot alkaloid-induced toxicity to endothelial cells in vivo (possibly as ergovaline effect alone or maybe as a synergistic response with other alkaloids present in E+ tall fescue) would result in elaboration of inflammatory mediators, as well as change in the clotting factor profile of the animal. Strickland et al. (1996) demonstrated a mitogenic effect of alkaloids (ergonovine, a-ergocryptine, ergovaline, N-acetyl loline) on isolated bovine vascular smooth muscle cells from the dorsal metatarsal artery, indicating that these alkaloids have an effect on blood vessel reactivity in cattle and that synergistic action of the alkaloids may be possible (Williams et al., 1975). Furthermore, damaged endothelial cells would allow access of various mediator agents to the underlying smooth muscle cell layer of blood vessels (Quinones-Baldrich, 1993), contributing to the thickened vessels seen at necropsy (Oliver and Schultze, 1997).
The pathological changes that occur from ergot alkaloid exposure in tall fescue toxicosis have inflammation as an important etiologic factor. Systemic inflammatory response syndrome, a condition whereby several bioactive compounds have been released from the cardiovascular tissues in response to a pathological insult, can be linked to many of the clinical signs of tall fescue toxicosis. These include: febrile response, hyperalgesia and lameness, stasis of blood in peripheral vessels, and coagulation defects. Biologically active substances produced by endothelial cells in the sera of cattle are impacted by exposure to ergot alkaloids and include increased angiotensin converting enzyme activity (unpublished data, J.W. Oliver, 1998) leading to increased angiotensin II levels. Angiotensin II is a potent vasoconstrictor substance that also impacts fluid and electrolyte balance through release of antidiuretic hormone and aldosterone (Drouet et al., 1988). In addition, activation of angiotensin II receptors on smooth muscle cells is known to induce mitogenesis (Quinones-Baldrich, 1993). There also is a trend for increased von Willibrand Factor (vWF) levels in cattle exposed to E+ tall fescue (unpublished data, J.W. Oliver, 1998). The vWF is a factor that functions as an adhesion molecule in the subendothelium for blood platelets during vascular injury (Ware and Heistad, 1993). Increased vWF levels are associated with increased risk for hypercoagulability and thrombosis, events prominent in severe tall fescue toxicosis. Additionally, thromboxane A2 (TXA2) levels are increased in cattle that graze E+ tall fescue (unpublished data, J.W. Oliver, 1998). Thromboxane A2 is a potent vasoconstrictor substance that is formed in blood platelets; increased blood levels of TXA2 indicate that thrombotic events are occurring. Thromboxane A2 also is known to have broncho-constrictive effects (Campbell, 1990). Nitric oxide, a potent vasorelaxant produced by vascular endothelium in the periphery (Chung and Fung, 1990; Gerstberger, 1999; Yamashita et al., 1998; Mills et al., 1997) also could be involved in alkaloid-induced perturbations of vascular function. In support of this supposition, Al-Tamimi et al. (2007) noted that rats fed a wild-type E+ tall fescue diet had lower blood nitric oxide level than controls and that the nighttime hyperthermia associated with fescue toxicosis was reduced by administration of molsidomine, a nitric oxide donor, suggesting the role of nitric oxide in generating this response. In addition, Oliver et al. (2000b) showed that arginine levels are decreased in cattle that graze E+ fescue, potentially resulting in nitric oxide deficiency. In fact, Oliver et al. (2001a,b) noted that nitric oxide synthesis was decreased in animals grazing E+ tall fescue (Oliver et al., 2001a,b), contributing to vasoconstriction and coagulopathy conditions.
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