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J Appl Physiol 84: 207-214, 1998;
8750-7587/98 $5.00
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A role for gastrointestinal endotoxins in enhancement of heat tolerance by physical fitness

Sotaro Sakurada and J. Robert S. Hales

School of Physiology and Pharmacology, University of New South Wales, Sydney 2052, Australia

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

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 (Tre) 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 Tre in fit animals. In sedentary animals, however, Tre 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 Tre 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.

microspheres; regional blood flow; gastrointestinal tract; brain; indomethacin; sheep; treadmill; fever

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

A GREATER TOLERANCE of hot environments by physically fit than by unfit people is well known (2, 19), and there is no doubt that physically fit animals are less prone to heatstroke (14). Physical fitness results in improved cardiovascular capacity (32, 33), and this provides advantages to compensate against heat stress, including the maintenance of blood flow through heat-loss effector organs such as skin (37). The normal circulatory responses to heat stress include reductions in blood flow to the gastrointestinal tract (24). However, the normal barrier to movement of endotoxins from the gut lumen into plasma is critically dependent on the local blood supply (11, 15, 35, 43), and there is increasing evidence that these endotoxins can reduce heat tolerance (23, 24). If the greater cardiovascular capacity of fit people allows them to maintain a better gastrointestinal blood flow than unfit people, this would constitute a mechanism for detrimental effects of increased plasma levels of endotoxins to be reduced in fit compared with unfit people. It might be necessary for sedentary people to reduce gastrointestinal blood flow to such an extent that relatively high endotoxin levels and low heat tolerance result.

The intestines normally contain large quantities of highly toxic lipopolysaccharides (LPS, or endotoxin) sloughed from the walls of gram-negative bacteria. However, intestinal bacteria and LPS cause no harm when they are confined to the intestinal lumen, and they do not cross the intestinal wall at a rate greater than the ability of the liver to remove them from the circulation. Several investigations have indicated that the critical requirement for maintenance of an impermeable barrier in the intestinal wall is an adequate blood supply (11, 15, 35, 43). A number of natural conditions can lead to substantial reductions in intestinal blood flow: exercise and/or heat stress (37), elevated catecholamine levels (8), hypovolemia or hypotension (17), or hypoxemia (16). The fact that LPS leaks out of the gut under so many different conditions, especially during heat stress, suggests that, even in a healthy person, small amounts of toxic LPS may enter the circulation more often than is usually recognized. This leads to an ordered rise in serum concentrations of cytokines (20, 34, 41), which will elevate the hypothalamic set point for body temperature regulation (28, 36), thereby causing thermoregulatory mechanisms to operate to reduce heat loss (such as by reducing skin blood flow) and/or to increase heat production, as occurs in the normal development of fever. Endotoxins also reduce cardiac contractility (1), which would reduce heat tolerance by limiting cardiac capacity. Hales and Nagai (25) have shown that indomethacin (Indo) can improve heat tolerance of normal rabbits presumably by blocking prostaglandin synthesis involved in the pathways of endotoxin action. Furthermore, intravenous (iv) endotoxin reduced heat tolerance. These results strongly suggest that endotoxins leak out of the gut, get into the circulation, and enhance hyperthermia even in moderate levels of hyperthermia.

To examine the possibility that endotoxins are a determinant of the lower heat tolerance in sedentary compared with fit people, two series of experiments were performed. In the first series, the effect of Indo on heat tolerance of sedentary and fit sheep was determined. In the second series, blood-flow distribution (including in gastrointestinal organs) was measured in the two groups at normothermia and during progressive hyperthermia.

    METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Animals. Nine 2- to 3-yr-old Merino wethers were used. They were housed indoors in pens (1.5 × 1.8 m) with ambient temperatures of 9-26°C and lights on from 0600 to 1800. They were fed a maintenance ration of 600 g/day of pelleted alfalfa hay and wheat chaff, with water available ad libitum. They were habituated to the experimental conditions, i.e., to stand, held by a yoke, in a mobile cage or to run on a treadmill in a climate-controlled room.

All experiments were approved by the Animal Care and Ethics Committee of the University of New South Wales.

Exercise training. Five sheep (fit group) weighing 37-54 kg, with a mean fleece depth of 44.9 ± 4.8 mm, had two training sessions at ambient temperature of 16°C daily for at least 3 mo. Each session consisted of walking on a treadmill at 10° gradient for 5 min at 2.5 km/h followed by 20 min at 4.5 km/h. In the first session, heart rate (HR) was measured by using electrocardiography (ECG) just before starting exercise, 5-15 s, and ~5 min postexercise. Four sheep (sedentary group) weighing 42-55 kg, with a mean fleece depth of 41.3 ± 11.1 mm, stood still on the treadmill for 30 min daily.

Effect of Indo. All experiments were performed in conscious animals. After the 3-mo training period, each sheep was exposed twice (with ~1 wk between exposures) at rest to an environment of 42°C dry bulb and 35°C wet bulb (50% relative humidity). At least 3 h before the experiment, a polyethylene catheter (1.0-mm ID, 1.5-mm OD; Dural Plastics and Engineering, Sydney, Australia) prefilled with heparinized (250 IU/ml) sterile saline was inserted by percutaneous puncture into an external jugular vein of the conscious animal. The animal was then transferred into the anteroom (22.4 ± 1.2°C) of the climate room and stood quietly in its cage. A rectal temperature (Tre) probe, ECG leads, and a pneumography belt were attached. In the second exposure, when the monitored parameters were stable, Indo trihydrate (5 mg/kg dissolved with ~2.5 ml of saline; Merck Sharp & Dohme, Sydney) was slowly injected via the iv catheter. The animal was wheeled into the climate room 30 min after the first injection. Additional Indo (0.25 mg/kg) was injected every 30 min during heat exposure. In the first exposure, the same volume of saline was injected at corresponding times. These treatments were not randomized, because preliminary experiments revealed that a variable period of time, sometimes more than a week, was needed to fully recover from the Indo.

Tre were monitored by using a potentiometric recorder (Speedmax; Leeds & Northrup, Eight Mile Plains, Australia) and a 38-swg copper-constantan thermocouple mounted in the tip of a plastic rod (0.5-mm OD) inserted 10 cm into the rectum. HR was measured by using the ECG, and respiratory frequency was monitored by using a pneumograph connected to a strain-gauge transducer, both recording on a model 7 polygraph (Grass Instruments, Quincy, MA). After the experiment, the animal was returned to its pen. The training sessions were restarted several days after the heat exposure.

Cardiovascular measurements. After the sheep was fully recovered and after retraining, the second series of experiments was performed. Approximately 7 days before the experiment, we prepared the sheep surgically with the use of general anesthesia (<1 h) induced by thiopentone sodium iv and maintained with halothane (2-4%) in O2. Polyethylene catheters (1.0-mm ID, 1.5-mm OD; Dural Plastics and Engineering) were placed in both femoral arteries via the saphenous branches and, under fluoroscopic guidance, in the left cardiac ventricle via a common carotid artery. Additionally, two polyvinyl catheters (1.0-mm ID, 2.0-mm OD; Dural Plastics and Engineering) were passed under fluoroscopic guidance via the external jugular vein into the right atrium and pulmonary artery. Catheters were filled with 150 mg chloramphenicol (chloramphenicol 150; Delta Laboratories, Kuring-Gai, Sydney, Australia) and 1,000 IU heparin per ml of normal saline (Multiparin; Fisons, Sydney, Australia). Catheters were flushed with heparinized saline and refilled daily with the chloramphenicol + heparin + saline mixture. Broad spectrum antibiotics [penicillin and streptomycin (Penstrep), 2 ml im; Troy Laboratories, Smithfield, NSW, Australia] were administered routinely at surgery and for the following 2 days.

Blood-flow rates were quantitatively measured with radioactive microspheres as detailed previously (22). Six different labels were used in random order: 141Ce, 51Cr, 113Sn, 85Sr, 95Nb, and 46Sc (New England Nuclear, Boston, MA, via Du Pont Chemicals, Sydney, Australia). Cardiac output (CO) and tissue blood flows were measured six times in each animal by injecting a dose of ~0.5 × 106 microspheres/kg body weight into the left ventricle and withdrawing the reference or artificial organ blood sample from a femoral artery at a precisely measured rate of ~20 ml/min. To measure the total proportion of CO passing through arteriovenous anastomoses (AVA), a blood sample was concurrently withdrawn from the pulmonary artery at a precisely measured rate of ~11 ml/min. After the experimental protocol was completed, the sheep was killed by an overdose of pentobarbital sodium, and tissues of interest were removed. Sufficiently small organs were placed directly into tubes for gamma assay (model 5320 gamma spectrometer; Packard, Canberra, Australia), whereas large organs were weighed, homogenized, and subsampled.

Pulsatile arterial blood pressure (BP) was recorded on a model 7 polygraph (Grass Instruments) via a femoral catheter and strain-gauge transducer (DTX disposable pressure transducer kits; Viggo-Spectramed, Oxnard, CA) mounted at heart level: HR and mean arterial blood pressure (MAP) were calculated from this. Pulsatile central venous pressure was recorded on the polygraph via the right atrial catheter and a strain-gauge transducer (4-327-I; Bell & Howell). On the day of the experiment, the animal stood quietly in its cage in the anteroom. All catheters were flushed and prepared for the measurements. The positions of the left ventricle, right atrium, and pulmonary artery catheters were confirmed from their characteristic pressure patterns. When Tre, HR, MAP, and respiratory frequency indicated that the animal was in a steady state (after 1-3 h), control measurements were taken over an ~5-min period. Paired arterial and mixed venous blood samples were drawn at the beginning of this period. Microspheres were then injected into the left ventricle, and from just before to 30 s after the injection, the reference blood sample was withdrawn from a femoral artery catheter to measure CO and tissue blood flows. From just before to 2 min after the injections, the pulmonary artery blood sample was withdrawn to calculate AVA blood flow. After the measurements, 20 ml of 6% Dextran 70 in 0.9% NaCl (Macrodex; Pharmacia, Sydney, Australia) was injected iv to restore blood volume. The animal then entered the climate room wherein dry and wet bulb temperatures were set at 42°C and 39°C, respectively (85% relative humidity). In the hot condition, Tre of the animal increased continuously, and when Tre reached 40.0, 40.5, 41.0, 41.5, and 42.0°C, sets of the measurements were repeated. After the measurements at a Tre of 42°C, the animal was killed and dissected.

O2 consumption (VO2). VO2 was calculated by employing the Fick equation and measurements of CO and arteriovenous difference in blood O2 content. The latter was determined from oxyhemoglobin saturation and hemoglobin concentration by using an automated analysis system (model 288; Corning). Blood gases and pH were simultaneously measured and corrected to the Tre of the animals.

Statistics. A two-way or three-way analysis of variance with repeated measures was used to assess significance of the effects of fitness, Indo treatment, and heat stress. Linear regression analysis was performed for change in Tre during heat exposure. The slopes of Tre/time in each group of each treatment were compared by using analysis of covariance after a multiple-comparison test. P < 0.05 was considered the level of significance.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Effect of exercise training. Figure 1 shows that, after the 3-mo training program, HR of the fit group decreased significantly at rest, after 5-10 s of exercise, and 5 min after the exercise session.


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  		Fig. 1.   Heart rate of 5 sheep at rest and at 5-15 s and 5 min postexercise, before starting exercise training (open bars) and after completing 3 mo training (solid bars). * Significantly different values before and after exercise training; P < 0.05.

Effects of Indo. Tre in the anteroom was, for fit and sedentary animals, respectively, 39.3 ± 0.2 and 39.4 ± 0.05°C with saline, 39.3 ± 0.1 and 39.4 ± 0.1°C with Indo, and 39.5 ± 0.1 and 39.8 ± 0.2°C premicrosphere experiment. There were no significant differences between groups. Effects of exposure to the moderately hot environment (42/35°C) are shown in Fig. 2. With saline, Tre rose at a significantly higher rate in sedentary than in fit animals, and Indo treatment abolished this difference by causing Tre in the sedentary group to rise at a significantly lower rate than with saline; however, the slopes of data for the fit group did not differ between treatments. Statistically, only the slope of the data for sedentary animals with saline is significantly steeper than the other three slopes of data. With saline, HR before heat exposure was lower in the fit than in the sedentary animals (53.4 ± 9.0 vs. 73.0 ± 5.2 beats/min; P < 0.05), and during the heat exposure (Fig. 3), HR increased in the fit group by only 10 beats/min, whereas the HR in the sedentary group increased continuously up to 108.3 ± 14.9 beats/min. After injection of 5 mg/kg of Indo, HR dropped significantly, and HR remained at the low level in both groups until the heat exposure started. With heat exposure (and continuing Indo injections), HR of the sedentary group increased, but significantly less than in those receiving saline. HR responses of the fit group were unaltered. Respiratory frequency increased from ~50 breaths/min for both groups and both treatments in the anteroom to peaks of 320 ± 18 breaths/min in sedentary animals and 280 ± 10 breaths/min in fit animals. The saline-treated sedentary animals showed a tendency toward the biphasic pattern of panting usually seen only with high levels of heat stress. That is, the initial normal, rapid, shallow panting gives way to slower, deeper, second-phase panting as the heat load increases.


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  		Fig. 2.   Changes in rectal temperature (Tre; means ± SE) during exposure of 5 fit and 4 sedentary sheep to moderately hot environment (42/35°C dry/wet bulb temperature). * Slope of Tre vs. time for sedentary sheep treated with saline (bullet ) is significantly steeper than when treated with indomethacin (Indo; open circle ) or for fit sheep treated with either saline (black-triangle) or Indo (triangle ), P < 0.05.


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  		Fig. 3.   Heart rate and respiratory frequency (means ± SE) of 5 fit and 4 sedentary sheep in anteroom (negative time) and during exposure to moderately hot environment. Heart rate increased significantly during exposure and was significantly different between fit and sedentary and between saline and Indo. Heart rate dropped significantly after injection of 5 mg/kg of Indo. Respiratory frequency increased significantly during exposure; P < 0.05.

Cardiovascular experiments in a severely hot environment. The animals were exposed to the 42/39°C environment until Tre reached 42°C; this took 105 ± 4.7 min in fit and 86 ± 4.2 min in sedentary animals [not significant (NS)]. CO (Fig. 4) normally did not differ between the two groups. However, with heat exposure, the CO of fit animals almost doubled, whereas the CO of sedentary animals increased by only 25% (change NS). MAP (Fig. 4) normally and during heat exposure tended to be lower in fit than in sedentary animals (NS), and both groups increased slightly (NS) during heat exposure. Central venous pressure of fit and sedentary animals did not differ significantly, either normally or during heat stress; it decreased at an approximately uniform rate from 6.7 ± 1.2 to 2.7 ± 1.1 mmHg in the fit group and from 5.5 ± 0.6 to 3.4 ± 1.7 mmHg in the sedentary group.


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  		Fig. 4.   Mean arterial blood pressure and cardiac output (means ± SE) of 5 fit and 4 sedentary sheep when normothermic (NT) and then as Tre increased during exposure to a severely hot environment. Cardiac output increased significantly during heat exposure and was significantly different between groups (P < 0.05). Neither blood pressure differences between groups nor changes during heat stress were significant.

VO2 of fit and sedentary animals did not differ significantly either normally or during heat stress. It increased as Tre rose to 40.5°C and then essentially plateaued, i.e., from 103 ± 27 to 191 ± 42 ml/min in the fit group and from 125 ± 20 to 190 ± 31 ml/min in the sedentary group.

Blood gases and pH did not differ significantly between sedentary and fit animals, both showing the well-established effects of panting: PO2 increased significantly in arterial blood but did not change in mixed venous blood. PCO2 decreased significantly in both arterial and mixed venous blood. pH increased significantly in both arterial and mixed venous blood.

Detailed tissue blood-flow data are given in Table 1. Normal blood flows in the brain, ileum, and diaphragm muscle were significantly higher in fit than in sedentary animals. With heat exposure, there were significant decreases in blood flow in the brain, pineal and parotid glands, and the gastrointestinal tract of both fit and sedentary groups. Figure 5 illustrates the ileal blood flow responses.

                              
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  		Table 1.   Blood flow rate of conscious sheep at rest when normothermic and in hot environment when rectal temperature reached 40.0, 40.5, 41.0, 41.5, and 42°C

Blood flow significantly increased during heat exposure, in the myocardium, thyroid, and sublingual salivary glands, nasal mucosa, and turbinates, respiratory muscles, and fat.

The total blood flow through AVA (Fig. 6) increased significantly with heat exposure of both fit and sedentary animals. However, whereas the fit group showed essentially a continuous increase, reaching ~5 times normothermic levels, the sedentary group only approximately doubled their AVA blood flow and showed no further increase above 40.5°C Tre.

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

With exercise training of the sheep, metabolic rate was not measured; however, the very significant drop in HR (resting and postexercise) over the 3-mo period leaves no doubt that their fitness had greatly increased. HR is a primary indicator of fitness, being lower in fit than in sedentary subjects during a fixed intensity of exercise (32). Also, daily exercise training at a given intensity yields reductions in HR closely correlated with increases in maximal VO2 (9).


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  		Fig. 5.   Blood flow (means ± SE) of ileum of 5 fit (black-triangle) and 4 sedentary (open circle ) sheep when NT and then during exposure to a severely hot environment. Blood flow of ileum and stomach decreased significantly during heat exposure; P < 0.05.


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  		Fig. 6.   Total blood flow (means ± SE) through arteriovenous anastomoses (AVA) when NT and as Tre increased during exposure to severely hot environment. Heat-induced increases were significant (P < 0.01) in both sedentary (open circle ) and fit (black-triangle) groups, and the latter attained significantly higher levels; P < 0.05.

Indo did not affect Tre in normal animals. However, during heat exposure, the rate of rise in Tre with saline was steeper than that with Indo in the sedentary group. Hales and Nagai (25) have shown that the Tre in normal rabbits rose at a lower rate with Indo compared with in the same animals when untreated. It has been reported that Indo alone has no effect on body temperature in thermoneutral conditions (29), but because of its blockade of prostaglandin production (12) Indo prevents the rise of core temperature after administration of endotoxin. Thus the present results and those of Hales and Nagai (25) indicate that an endotoxin-prostaglandin pathway can play a role in the rise of core temperature during heat exposure even in the normal subject. Is this attributable to blockade by Indo of the elevation in set point temperature normally caused by endotoxin, or could some other mechanism be involved? In the present study, HR was significantly depressed by Indo treatment, a response that would be elicited if arterial BP increased. In fact, it has been reported that Indo causes systemic vasoconstriction and elevation of BP (3, 42). Therefore we checked this in one of our animals. Immediately after the injection of Indo (5 mg/kg), we observed a rise of MAP by 30 mmHg that lasted 15 min. These effects of Indo on cardiovascular function might change body core temperature via changes in metabolic rate or blood flow distributions to heat-loss organs. However, resting body core temperature did not change, even though the HR decreased markedly and presumably MAP increased; only the rise of body core temperature during heat exposure was suppressed. Therefore, the differences in rate of rise in the body core temperature in the moderately hot environment could not be explained solely by the effects of Indo on BP and HR. It appears most probable that in our heat-stressed sedentary animals, Indo led to enhanced heat loss by blocking effects of endotoxins. Endotoxins normally cause fever by raising hypothalamic set-point temperature, which leads to suppression of heat-loss mechanisms, such as reducing skin blood flow, and consequently elevating body temperature (30).

We have not directly measured the plasma endotoxin levels. However, they have been reported to increase in the anesthetized hyperthermic monkey (18), in heatstroke patients (6), and in the strenuously exercising horse (5). The source of such endotoxin is likely to be the gastrointestinal tract because 1) the increase in circulating endotoxin levels can be prevented by prior treatment with nonabsorbable oral antibiotics (7) and 2) hepatic portal blood endotoxin levels increase significantly sooner than arterial levels (18). The intestines normally contain large quantities of endotoxin sloughed from the walls of gram-negative bacteria. However, intestinal bacteria and endotoxins cause no harm when they are confined to the intestinal lumen and do not cross the intestinal wall at a rate greater than the ability of the liver to remove them from circulation. Several investigations have suggested that the critical requirement for maintenance of an effective barrier in the intestinal wall is an adequate blood supply (16, 35, 43). Fink et al. (11) have reported that, in swine, 50% reduction of the mesenteric blood flow from the resting value is enough to break the intestinal barrier to the endotoxin. During heat exposure, the normal redistribution of CO includes decreased gastrointestinal blood flow (21).

In the present study, we have confirmed that intestinal and stomach blood flow decrease during heat exposure. We also found that after sheep acquire physical fitness, normal ileal blood flow is elevated to such an extent that, even after a decline to 65% of its normal level, it is still equal to normal values for ileal blood flow in comparable sedentary sheep (Table 1, Fig. 5). Furthermore, in the sedentary animals, ileal blood flow declined to the remarkably low level of 24.7 ± 2.8 ml · 100 g-1 · min-1, which was only 45% of normal levels in the fit animals. Such low perfusion would also aggravate the usual lactacidosis that develops from heat-induced splanchnic vasoconstriction (44), and acidosis also increases ileal permeability (39). Tissue hypoxia (15), which is likely to be greater in our sedentary than fit animals, and hyperthermia per se (18) also reduce effectiveness of the gastrointestinal barrier to movement of endotoxins. The above discussion points clearly to the likelihood that higher plasma levels of endotoxins in sedentary compared with fit animals are responsible for the enhanced heat tolerance seen in the latter. Additionally or alternatively, fit animals might have their heat tolerance enhanced via an increased tolerance of endotoxins acquired during exercise training. This proposal (23) is based on reports that not only does endotoxin exposure enhance heat tolerance (10) but heat exposure enhances endotoxin tolerance (38).

In the present study, maintenance of much higher levels of ileal blood flow in the fit compared with the sedentary animals would be achievable via the greater cardiovascular capacity and larger blood volume that is known to develop with increasing fitness (32, 33). These adaptations not only enable maintenance of elevated blood flow to heat-loss effector organs (including AVA; see Fig. 6), but the present study indicates that this is achieved while maintaining the gastrointestinal barrier to endotoxins.

Although the detailed mechanism by which variations in the intestinal barrier to endotoxins occur is not the subject of this study, possible involvement of reactive oxygen species (ROS) is noteworthy. That is, both low blood flow (31) and hyperthermia per se (40) can induce production of ROS, which can increase permeability of the intestinal wall. To compensate for the action of ROS, nitric oxide (NO) may be released (26), which can lead to systemic vasodilatation and hypotensive circulatory collapse. The latter is often seen in heatstroke patients (24), and "inappropriate" vasodilatation of intestinal vasculature has been reported in some hyperthermic experimental animals (23, 24). In the present study, vasodilatation showed signs of appearing at Tre of 41.5 and 42°C in the sedentary sheep (Fig. 5). Perhaps the higher levels of AVA perfusion in the sedentary sheep at Tre of 41°C and above (Fig. 6) are also associated with changes in ROS or NO status.

Development of physical fitness altered the normal (i.e., resting at approximately thermoneutrality) blood flows in some tissues. The brain is noteworthy, with fit vs. sedentary blood flows of 76.5 ± 6.7 vs. 52.3 ± 4.5 ml · 100 g-1 · min-1, respectively. In view of the constancy of total brain perfusion in the face of widely varying conditions, we must ask by what mechanism such an elevated flow could develop in the physically fit animals, assuming that for sheep, a sedentary state, and therefore blood flow of 52.3 ± 4.5 ml · 100 g-1 · min-1, is normal. Neither blood pressure, nor blood gases, nor pH differed between the two groups. The blood-brain barrier is commonly regarded as eliminating or minimizing effects of circulating hormones. However, we are unaware of information on effects of endorphins produced within the brain. Plasma endorphin levels increase with hypohydration (13) and are elevated in heatstroke patients (4). Some of the most marked changes in blood flow are those positively correlated with metabolic requirements of the brain. However, these changes usually occur in the particular region(s) involved in changes in bodily activities (such as localized exercise) and are offset by decreased blood flow in other regions, so that total brain blood flow remains unaltered (27). However, estimation of vascular resistances (from blood flow and arterial pressure, assuming cerebral venous pressure is constant and low) yields 1.35 vs. 2.15 units for fit vs. sedentary sheep, respectively. That is, a significantly lower resistance in fit animals must be caused by either dilatation of vessels already perfused or by recruitment of additional vessels. Either way, blood volume in the brain is increased, and because volume of the cranial cavity cannot change, if we presume that intracranial pressure was not greatly elevated in our fit and apparently healthy animals, cerebrospinal fluid or brain tissue volume must have decreased with development of physical fitness. Brain weight did not differ (110.9 ± 2.5 vs. 107.4 ± 4.3 g, fit vs. sedentary, respectively). Teleologically, as with the higher normal blood flow in the ileum of the fit animals, this provides a greater safety margin for decreases in brain blood flow that are likely to occur during exercise or heat stress (e.g., due to CO2 washout).

In conclusion, fit sheep showed better heat tolerance than did sedentary sheep. Indo improved the heat tolerance of sedentary but not fit animals. Gastrointestinal blood flow decreased during the heat exposure; however, the fit sheep could maintain the blood flow better than the sedentary sheep. It is suggested that endotoxins, probably from the gut lumen, reduce the heat tolerance of the normal subjects, and the greater heat tolerance of fit subjects could be caused by their greater cardiovascular capacity that permits the maintenance of a better gastrointestinal tract blood supply, thereby better maintaining the normal barrier to movement of endotoxins from the gut lumen into the plasma. The probable enhancement of endotoxin tolerance by exercise training would also be beneficial to fit subjects.

    ACKNOWLEDGEMENTS

The authors are grateful to G. Gazibarich, J. Rawlinson and Dr. R. Kaur for technical assistance and to Merck Sharp & Dohme for their generous provision of water-soluble indomethacin.

    FOOTNOTES

This study was partly supported by grants from the National Health and Medical Research Council of Australia and the Australian Research Council.

Present address of J. R. S. Hales: Faculty of Veterinary Science, Univ. of Sydney, Camden, NSW 2570, Australia.

Address for reprint requests: S. Sakurada, Dept. of Physiology, School of Medicine, 13-1 Takara-machi, Kanazawa 920, Japan (E-mail: sakurada{at}med.kanazawa-u.ac.jp).

Received 5 May 1997; accepted in final form 12 September 1997.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

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