Sakurada, Sotaro, and J. Robert S. Hales. A role for gastrointestinal endotoxins in enhancement of heat tolerance by physical fitness. J. Appl. Physiol. 84(1): 207-214, 1998.To further elucidate mechanisms underlying the higher heat tolerance of physically fit compared with sedentary people, we have investigated the possibility that endotoxins (of gastrointestinal origin) act, as in the normal development of fever, to raise body temperature and therefore reduce heat tolerance. In an initial series of experiments, five physically fit and four sedentary sheep were exposed twice at rest to an environment of 42/35°C (dry/wet bulb temperature). When animals were given normal saline iv, rectal temperature (T_re) rose at a significantly higher rate in sedentary than in fit animals; this confirms that heat tolerance is improved by physical fitness. Treatment with iv indomethacin did not affect the rate of rise of T_re in fit animals. In sedentary animals, however, T_re was lowered to approximate that of fit animals. Because indomethacin blocks prostaglandin pathways involved in endotoxin-induced fever, the indomethacin-induced improvement of heat tolerance of sedentary but not fit animals supports the contention that endotoxins play a role in determining that difference in heat tolerance. In a second series of experiments, quantitative cardiovascular measurements were made by using radioactive microspheres. Under normothermic conditions, blood flows in the brain, ileum, and diaphragm were higher in fit than in sedentary animals. During hyperthermia up to T_re of 42°C (in a 42/39°C environment), fit compared with sedentary animals exhibited 1) a greater increase in cardiac output, 2) an increase in blood flow through arteriovenous anastomoses to higher and better maintained levels, 3) less reduction in blood flow to the ileum, and 4) greater increase in blood flows to the myocardium, turbinates, nasal mucosa, and respiratory muscles. Endotoxins are likely to come from the gut lumen, because reduction of gut blood flow forms part of the normal response to heat stress. We suggest that improvement of heat tolerance by physical fitness is caused by a greater cardiovascular capacity that permits not only greater perfusion of heat-loss tissues but the maintenance of a better gastrointestinal tract blood supply, thereby better maintaining the normal barrier to movement of endotoxins from gut lumen to plasma. Sedentary people, with their lower cardiovascular capacity, redistribute more blood flow away from the gut during environmentally induced hyperthermia, thus allowing endotoxin-induced fever to aggravate hyperthermia.