Vet Clin Equine 18 (2002) Equine anhidrosis

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1 Vet Clin Equine 18 (2002) Equine anhidrosis Jeremy D. Hubert, BVSc, MRCVS, MS a, *, Ralph E. Beadle, DVM, PhD a, Gary Norwood, DVM b a School of Veterinary Medicine, Department of Veterinary Clinical Sciences, Equine Health Studies Program, Louisiana State University, Baton Rouge, LA 70803, USA b Backstretch Equine Surgery and Medicine, 539 Bonnabel Boulevard, Metairie, LA 70005, USA Equine anhidrosis, dry coat, and nonsweating are all terms used to describe the disease in horses characterized by the inability to sweat effectively in response to appropriate stimuli. Although the epidemiology and clinical signs of the disease have largely been elucidated, anhidrosis is still widely prevalent, and methods of prevention and treatment are being sought. Initial reports date back to the 1920s, when Thoroughbreds from Australia developed this condition after being transported to Malaysia [1]. Later it was reported that such horses improved once they were removed from the tropical environment and maintained 10 to 30 days in a cooler and drier climate. [2]. This article reviews the epidemiology, proposed pathophysiologic mechanisms, clinical features, diagnosis, and treatment. Epidemiology of anhidrosis The disease commonly occurs in countries with hot, humid climates including the American Gulf Coast states. The precise prevalence of the disease is unknown; however, it has been estimated that up to 20% of horses in the Miami area of Florida may be affected [3,4]. Anhidrosis was originally assumed to be associated with an acclimatization stress [2], but a survey conducted in Florida in 1982 showed that more native horses were affected than imported horses [4]. Horses involved in strenuous activities were originally reported to be the most prone to develop anhidrosis [2], but this does This article, with modifications, was previously published in Compendium on Continuing Education for the Practicing Veterinarian 1998;20(7):846 53, with permission. * Corresponding author. address: jhubert@mail.vetmed.lsu.edu (J.D. Hubert) /02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII:S (02)

2 356 J.D. Hubert et al / Vet Clin Equine 18 (2002) not correlate with a study where only 7 out of 24 affected horses were performance horses [4]. Another study found that the frequency is higher in horses in training and lower in adolescent horses [3]. There is no coat color, age, sex, or breed predilection. A link between anhidrosis and high protein diets has been reported [5], but this finding was not corroborated in another study [4]. Nonpregnant mares were reported in one study to have a statistically significant higher incidence of anhidrosis [3]. Clinical signs of anhidrosis Horses with normal thermoregulatory abilities will be able to reduce their body temperature to within normal limits in approximately 30 minutes after exercise, and the inability to cool out to normal temperatures within this time is indicative that a horse may be suffering from anhidrosis. The predominant sign of impending anhidrosis is usually tachypnea [3]. Affected horses will have increased respiratory rates at rest, while body temperature and pulse rate are variably increased when compared with those of control horses under identical conditions [2 5]. Horses showing evidence of respiratory distress will have respiratory rates between 60 and 120 breaths per minute [3]. Partially anhidrotic horses will breath rapidly for extended periods of time after being thermally challenged [3]. Horses with acute onset anhidrosis may demonstrate a partial or complete absence of sweating when exposed to appropriate stimuli. A decrease in the rate of sweating also indicates the possibility of anhidrosis. The sweating rate will, however, depend on the intensity of exercise, duration of exercise, and ambient temperature [6]. Horses with long-standing anhidrosis may reveal dry, flaky skin, alopecia, lethargy, anorexia, and a decreased water intake. Areas on the body that may retain the ability to sweat include those under the mane, in the saddle and halter areas, and in the axillary, inguinal, and perineal regions [2 5]. Thermoregulation in horses Thermoregulation is attained by two main mechanisms in terrestial mammals; namely panting and sweating [7]. Heat dispersed via the respiratory tract in exercising horses may account for 15% to 25% of total heat loss, whereas evaporation of sweat accounts for up to 65% of their heat loss [6]. In this regard, it has been calculated that evaporation of 1 liter of sweat can dissipate the amount of heat generated in 1 to 2 minutes of high-intensity exercise by horses [8]. During exercise there is an initial rise in temperature, which may be advantageous for performance because it increases the rate of aerobic energy production, thereby minimizing the necessity for anaerobic energy production [9]. As work effort increases, heat production in skeletal muscle can increase more than 50 times [10]. This heat is derived from the conversion of chemical energy into mechanical work. Only 25% of the metabolic

3 J.D. Hubert et al / Vet Clin Equine 18 (2002) energy is converted to mechanical work, with the remainder generating body heat, which must be dissipated during or after exercise [11]. A number of factors can influence the rate at which horses lose heat by the evaporation of sweat. First, the rate at which heat can be dissipated by evaporation depends upon the rate of air movement across the skin and the water vapor pressure difference between the skin and the environment [8]. Thus, when the ambient humidity is high, there is a reduction in the rate at which sweat is evaporated. Second, horses have a large body volume-toskin surface ratio, which results in a relatively small surface area from which evaporation can occur [6]. Finally, it has been shown in humans that there is competition for cardiac output between the skin and muscle during exercise whereby maintenance of cardiovascular function takes precedence over thermoregulatory function [12]. This results in less blood flow to the skin, and ultimately a slower rate of heat loss than would occur if skin blood flow were maintained during exercise [9]. It has recently been shown that nonspecific inhibition of nitric oxide synthase reduces the sweating response and increases the body temperature of exercising horses [13]. These findings suggest that nitric oxide may modulate the sweating response to exercise in horses. It was not determined whether this modulation was acting centrally or peripherally. Histology of equine sweat glands Histological evaluation of the horse sweat gland has been performed [14]. They are classified as apocrine, and in normal horses are tubular, with the secretory portion being coiled and embedded within the dermis. A straight and unbranched duct opens into a hair follicle adjacent to the skin surface (Fig. 1). Evans et al [14] described the secretory tubules of equine sweat glands as having two layers: an inner layer of cuboidal secretory epithelial cells, and an enveloping layer of myoepithelium. These myoepithelial cells are resting on a basal lamina [15] and surrounded by a layer of connective tissue and an outer sheath of fibrocytes [16]. Within this fibrocytic sheath are small blood vessels and nerve fibers [17]. Histochemical staining reveals the presence of monoamine oxidase in the nerve fibers suggesting adrenergic fiber innervation [17]. The secretory cells have cytoplasmic protusions that extend into the lumen of the duct [16] suggesting an apocrine mode of secretion. The apocrine mechanism of secretion is further supported by the observation that the secretory cells do not contain glycogen [18]. Physiology of sweating in horses Physiologic control of sweating in horses is unique compared with other species. Horses have two mechanisms of control; humoral control via

4 358 J.D. Hubert et al / Vet Clin Equine 18 (2002) Fig. 1. Dual physiologic control of sweating in horses. adrenergic agonists secreted from the adrenal medulla into the circulation, and nervous control via autonomic adrenergic nerves [6]. Work in donkeys indicated that the main component of equid sweat control is neural, with the humoral component becoming active during exercise. [19] (Fig. 1). Initial studies suggested both cholinergic and adrenergic agonists induced sweating in horses [20], but later studies have concluded that equine sweat glands are insensitive to carbamylcholine and controlled only by adrenergic neurotransmitters [21]. It has been demonstrated that stimulation of equine sweat glands occurs through b 2 -adrenergic receptor stimulation [22,23]. Investigations with individual equine sweat glands in vitro demonstrated that cyclic adenosine monophosphate (camp) acts as a principal secondmessenger when b 2 -adrenoreceptors are stimulated [24]. Subsequent studies with equine sweat gland epithelial cell cultures have conclusively established that sweating in horses is regulated by b 2 -adrenoreceptors and mediated by campand possibly intracellular free Ca ++ [25]. Intracellular mechanisms

5 J.D. Hubert et al / Vet Clin Equine 18 (2002) that mediate the effects of b 2 -agonists involve occupation of the receptor by the agonist, resulting in a conformational change in the a-subunit of the stimulatory G protein. This protein is involved in the activation of adenylate cyclase, which catalyzes the formation of camp. Protein kinase A is then formed and produces the subsequent phosphorylation of cellular protein and altered cellular response [26] (Fig. 2). The autocrine role played by pyrimidine and purine nucleotide receptor stimulation in the control of sweating in horses remains to be determined [27]. Potential mechanisms of anhidrosis At present, the mechanisms of anhidrosis are unknown. Potential pathologic mechanisms can be classified as either a decreased stimulation of the sweat gland or a lack of response of the gland to stimulation. Central nervous system and nervous control The Central nervous system (CNS), via the hypothalamus, provides control over both the humoral and neural mechanisms of anhidrosis [28]. Heat stroke is a real possibility in thermally stressed animals; temps of above 108 F have been shown to cause CNS dysfunction in dogs [29]. Muscle temperatures of up to 111 F have been recorded after intense exercise in horses, thereby illustrating the potential risk for CNS damage in these animals [7]. Fig. 2. b Adrenergic receptor complex.

6 360 J.D. Hubert et al / Vet Clin Equine 18 (2002) However, despite the possibility of CNS dysfunction occuring when body temperatures are severely elevated, it is unlikely that this is a factor in anhidrosis as the syndrome is reversible [2], and horses develop the condition without having developed such high temperatures. Although it has been shown that equine sweat glands are innervated [14,16], denervated horse skin retains the ability to produce sweat during exercise via humoral stimulation [30]. Additionally, sweat gland innervation of anhidrotic horses has been reported to be normal, with no evidence of axonal degeneration [14]. These findings, coupled with the reversible nature of anhidrosis, make denervation an unlikely cause of anhidrosis. Adrenal function It has been hypothesized that decreased production of epinephrine by the adrenal medulla may be a cause of anhidrosis [20]. However, it has been reported that anhidrotic horses have higher circulating concentrations of epinephrine when compared with healthy horses [31]. Also, adrenomedullary denervated donkeys retain the ability to sweat in response to thermal stimulation [19]. Therefore, decreased production of epinephrine by the adrenal glands is an unlikely cause of anhidrosis. Sweat gland perfusion An adequate vascular supply is important for humoral stimulation of sweating. Electron microscopic examinations of blood vessels from anhidrotic horses demonstrated these structures to be normal [16]. Therefore, a structural vascular impairment does not appear to be a contributing factor. However, a dynamic impaired dermal perfusion can occur during intense exercise when fluid loss and maintenance of cardiovascular function results in less blood flow to the skin [12]. Sweat gland histopathology The ultrastructure of sweat glands from anhidrotic horses housed in hot humid conditions has been reported to be abnormal [16]. Reported abnormalities included thickened basal lamina, evidence of poor myoepithelial contraction, fibrocytes with dilated endoplasmic reticulum and vacuolation, and thickened connective tissues. The secretory cells had a marked reduction of vesicles with increased numbers of mitochondria and less rough endoplasmic reticulum. The luminal microvilli were often absent, and the cells had become flattened; in some cases, secretory granules were replaced by myoepithelium. Cellular debris was often present within the lumen of the duct, and in some cases the lumen was fully obstructed [14]. Duct obstruction has been speculated to be a response to prolonged stress and failure of secretion, and may provide a mechanism of defense against microbes invading the

7 J.D. Hubert et al / Vet Clin Equine 18 (2002) gland [32]. As such, duct obstruction is not considered to be a likely cause of anhidrosis [14,32]. The sweat glands of anhidrotic horses have been examined histologically after having undergone a period of thermal stress, and then again after 6 weeks in a controlled, cool environment [32]. Glandular profiles after thermal stress were characterized by the degree of thinning or flattening and damage to the secretory cells. This may provide a means to predict the severity of anhidrosis and the prognosis for recovery, and to provide criteria for future management [32]. It can be concluded that cellular degeneration is a result, and not a cause, of anhidrosis [14,32]. Desensitization or downregulation of receptors Heat stress may result in higher than normal concentrations of circulating epinephrine. Plasma taken from horses at rest showed significantly higher levels of epinephrine in anhidrotic horses compared with unaffected horses [31]. Catecholamines participate as b 2 -agonists in both humoral and neural stimulation of sweating, and could potentially overstimulate b 2 - receptors. Langley and Bennett described a decreased sensitivity to adrenaline that occurred when they injected horses with adrenaline and then exercised them several hours later [33]. A corroborative study by Evans et al indicated that as a result of intravenous epinephrine administration, partially anhidrotic horses ceased sweating for 2 weeks [2]. A similar phenomenon, described as persistent desensitization of b 2 -adrenoreceptors, has been produced by incubating cultured equine sweat gland epithelial cells in a solution containing adrenaline [34]. This decreased sensitivity of b 2 -adrenoreceptors had an early and a late phase and resensitization of the b 2 - adrenoreceptors occurred slowly (t 1/2 ¼ 6.3 hours). The cause of this decreased sensitivity to adrenaline was not fully determined. However, it was shown that increased phosphodiesterase activity may have been contributing to the late phase desensitivity. Both the in vivo and in vitro phenomena described above document the fact that b 2 -adrenoreceptors in horse sweat glands are subject to decreased sensitivity following intense stimulation. Further studies will be needed to determine the molecular basis for this persistent desensitization of b 2 -adrenoreceptors in equine sweat glands. In other species, overstimulation of b 2 -receptors can cause a diminished function of the receptors [35]. This can result in a marked reduction in the response of the receptors to further stimulation with a variable period of unresponsiveness. Historically, this phenomenon was described as desensitization or downregulation, but recent studies have shown that desensitization is a separate entity from downregulation [36]. Desensitization is a phosphorylation-dependant rapid uncoupling of the b 2 -receptor from the G protein. For resensitization to occur, sequestration of the receptor away from the normal site on the cell surface to another site within the cell must take place. Resensitization of the receptor is a slower

8 362 J.D. Hubert et al / Vet Clin Equine 18 (2002) process than the uncoupling mechanism of desensitization [36], and may be part of the normal mechanism of receptor turnover within cells. Downregulation is an actual decrease in the total number of receptors in the cellular pool of receptors or a lower receptor density [36]. This is a slow process, and is a long-term mechanism that may involve altered receptor protein synthesis or altered receptor protein degradation. Downregulation has been shown to be accompanied by a decrease in b-adrenergic receptor messenger RNA concentrations [36]. Thyroid hormones Thyroid hormones are known to have modulating effects on adrenergic receptors [35]. Tissues are more responsive to b-adrenergic catecholamines when thyroid hormone concentrations are elevated, and conversely, when hypothyroidism occurs, they are less responsive [37]. In himans, symptoms of hyperthyroidism suggest increased sympathetic drive or increased plasma concentrations of catecholamines [35]. It has also been shown that there is a decreased density of b-adrenergic receptors in hypothyroid animals, decreased receptor coupling to the adenylate cyclase system, and ultimately receptor function is minimized [38]. The role played by thyroid hormones in the pathophysiology of anhidrosis is equivocal. In horses, some of the secondary clinical signs of decreased thyroid function are similar to those of anhidrosis [5]; however, it has been reported that thyroidectomized horses appear to sweat normally [39]. It has also been reported that there is no statistical difference in T 3 and T 4 plasma concentrations between normal and anhidrotic horses [3]. However, therapy with iodinated casein, a thyroid hormone precursor, has some reports of success [40]. This latter finding allows postulation that there may be a role played by thyroid hormones. Electrolyte abnormalities The effect of electrolyte losses incurred during exercise and long-term exposure to a hot humid climate is often thought to be involved in anhidrosis: one common therapeutic approach is oral electrolyte supplementation [3]. Even though significant quantities of electrolytes, including potassium and calcium, are lost in sweat [41], statistically significant electrolyte abnormalities have not been reported for horse with anhidrosis. Experimental depletion of extracellular and presumably intracellular Ca ++ in vitro decreased the sweat response, indicating that sweat secretion may be dependent upon concentrations of intracellular calcium [24]. However, hypocalcemia has not been reported as a cause of anhidrosis. Low potassium intake in ponies resulted in a more rapid onset of fatigue during treadmill exercise and decreased sweat production [42]. Although these ponies were hypokalemic, studies have shown that anhidrotic horses have normal serum potassium concentrations [3]. However, as potassium is mainly intracellular, total body potassium may be depleted, but undetected,

9 J.D. Hubert et al / Vet Clin Equine 18 (2002) and this would help to explain anecdotal reports that some anhidrotic horses respond to oral potassium supplementation. Diagnosis of anhidrosis Diagnosis of anhidrosis can be tentatively made based on clinical signs and performance. It should be emphasized that, based on the development of increased respiratory effort and hyperthermia, anhidrotic horses are commonly presented to veterinary practitioners for diagnosis and treatment of respiratory disease. However, a semiquantitative test to evaluate sweating by induction of the sweat response, using dilute concentrations of epinephrine injected intradermally, has been developed, and will provide a more definitive diagnosis [43]. However, epinephrine is not completely suitable for such a diagnostic test because it has both b- and a-adrenergic receptor agonist properties, and therefore, may cause leukotrichia at the injection sites. Salbutamol sulfate, a specific b 2 -agonist, has been described for use in a semiquantitative test for anhidrosis in Thoroughbred horses [44]. A control of sterile water and six dilutions of salbutamol, from 10 ÿ3 w\v to 10 ÿ8 w\v, were injected intradermally. The results were read 20 minutes later. Horses with long-standing anhidrosis did not sweat at any of the dilutions. Normal horses sweated in response to the 10 ÿ8 w\v dilution, and partially anhidrotic horses responded with dilutions between 10 ÿ4 w\v and 10 ÿ6 w\v. An unreported, semiquantitative test using terbutaline sulfate, another specific b 2 -adrenergic receptor agonist, is also diagnostic (R.E. Beadle, personal communication, Louisiana State University, Baton Rouge, LA). The protocol and results are similar to that of the test using salbutamol, except a physiologic saline solution control is used (Figs. 3, 4 and 5). Treating anhidrosis Because there are no known proven treatments for anhidrosis, all of the therapies described for this condition are anecdotal. Treatment of anhidrosis can be categorized into management changes or medical therapy. A combination of both categories is usually necessary for any success in the management of this condition. Management changes The most reliable treatment for anhidrosis is environmental control. This involves management changes directed at removing anhidrotic horses from hot, humid climates and moving them to a cooler, drier environment. Ten to 30 days in such an environment for affected horses has been reported to relieve the signs [2]. In lieu of moving the affected animal, other management changes that are directed to providing a cooler environment may be of some benefit. These changes may include placing the animal in an air-conditioned stall. The use of misting fans and cooling the roof of the barn by running

10 364 J.D. Hubert et al / Vet Clin Equine 18 (2002) Fig. 3. Response of normal horse to a semiquantitative test used to diagnose anhidrosis. Fig. 4. A partial sweater. There is only a minimal response to the intradermal injections of a specific b 2 -adrenergic agonist. Fig. 5. An anhidrotic horse: there is a complete lack of response to the specific b 2 -adrenergic agonist.

11 J.D. Hubert et al / Vet Clin Equine 18 (2002) water on it will help maintain a cooler environment. Exercising the horse during the coolest part of the day is another adjustment that will help manage the disease. Medical therapies Electrolyte supplementation Horses with anhidrosis have reported serum electrolyte values within normal limits [3]. However, hypokalemia is often suspected in the etiology of anhidrosis [39]. Some practitioners report some success in supplementing with 60 g of KCl or lite salt in the feed. Intubation over several days with two packs of commercial electrolyte replacement product (Enterolyte H.E., Pfizer) has also been used with some success. Dietary supplements A nutritional feed supplement that contains L-tyrosine, ascorbic acid, niacin, and cobalt is commercially available (One AC, MPCo., Phoenix, AZ). Tyrosine is potentially involved in the resensitization of sequestered b 2 -receptors [45], and is a precusor for the formation of dopamine and thus catecholamines. However, plasma tyrosine levels are not decreased in anhidrotic horses [46]. Anecdotal reports among practitioners indicate a success rate of 30 80% using One AC, with the best results seen in moderately affected horses and by placing previously affected animals on the product prior to the beginning of the anhidrotic season. Best results are reported if strenuous training or work is reduced for approximately 3 weeks when started on the supplement. It should be noted that a lessening of the intensity of training or work alone has been reported to relieve the clinical signs of anhidrosis. Methyl dopa Using drugs to decrease sympathetic drive would seem to be logical in treating horses with anhidrosis. Methyl dopa has been used by some practitioners with reported success. An initial dosage of 3000 mg once daily was used increasing to 4000 mg once daily if no positive response in 3 4 days. In humans, methyl dopa decreases sympathetic outflow from the CNS and is associated with decreased tissue concentrations of norepinephrine and epinephrine [47]. When an anhidrotic horse is treated with this drug, the concentration of epinephrine at the b 2 -adrenergic receptor site would be expected to decrease, which may allow receptor resensitization. Despite anecdotal reports of success there are no controlled studies of the efficiency of this agent in anhidrotic horses. Thyroid supplementation Administering iodinated casein orally at g per day for 4 to 8 days has been reported to be beneficial in the literature [40]. Practitioners have

12 366 J.D. Hubert et al / Vet Clin Equine 18 (2002) reported success supplementing with levo-thyroxine (THYRO-L, Vetamix, Shenandoah, IA) at a dose of mg per 100 lb once a day. Hypothyroidism may exhibit similar clinical signs as anhidrosis, but there has been no documentation of changes in T 3 or T 4 levels in horses living in tropical or semitropical environments or with anhidrosis. Care should be taken when treating a horse with levo-thyroxine supplementation, as the resultant increased metabolic rate could be harmful with the completely anhidrotic horse overheating when exercised in extremely hot and humid weather. Clenbuterol There have been anecdotal reports that clenbuterol is effective in causing sweating in some anhidrotic horses. Clenbuterol is a b 2 -adrenergic agonist, and mild sweating is a recognized side effect of clenbuterol administration for respiratory signs especially at the higher dosage. Its effect is probably mutifaceted; both direct stimulation of the receptors on the sweat glands and increased peripheral blood flow. This increased blood flow could help cool the horse. The reported dosages ranged from 5 10 ml/1000 lbs of a 72.5 mcg/ml solution orally twice a day. The authors do not recommend the use of clenbuterol, as a prior report [43] indicates that stimulation of the sweat glands of anhidrotic horses with an exogenous b 2 -agonist results in enhanced prolonged desensitization. Alternative therapies There have been anecdotal reports of return to sweating following acupuncture. This response has been reported to last from a few days to several weeks. There have also been reports of success using homeopathic substances, that is, sulphur and lycopodium in combination. Other therapies One practitioner has reported response of anhidrotic horses to rubeolla virus immunomodulation while treating muscle problems (R.V.I., Eudaemonic Corporation, Omaha, NE). Lay persons have reported success by feeding dark beer daily. Future therapies In humans, it has been shown that glucocorticoids increase the b 2 -receptor gene in several cell types, and that glucocorticoids may prevent desensitization and restore downregulated receptors [48,49]. Other drugs such as nedocromil sodium and ketotifen have been reported to reduce the downregulation of b 2 -receptors as well [50,51].

13 J.D. Hubert et al / Vet Clin Equine 18 (2002) Summary The molecular basis of the pathophysiology of anhidrosis is still not well understood. Therefore, treatments are more often based on clinical impressions than on scientific fact. Treatment options for this condition will improve only when more is known about the molecular events that cause anhidrosis, especially as they relate to b 2 -receptor dysfunction and stimulussecretion coupling in the sweat glands of affected horses. Although this additional information is being attained, sound environmental management will continue to be a very important aspect of the treatment of horses affected with anhidrosis. References [1] Wright TWW, Tull TC. A preliminary report of an investigation of a condition known as dry coat in horses. Vet J 1925;81:235. [2] Evans CL, Smith DFG, Ross KA, et al. Physiological factors in the condition of dry coat in horses. Vet Rec 1957;69:1. [3] Mayhew IG, Ferguson HO. Clinical, clinicopathologic, and epidemiologic features of anhidrosis in central Florida Thoroughbred horses. J Vet Intern Med 1987;1:136. [4] Warner AE, Mayhew IG. Equine anhidrosis: a survey of affected horses in Florida. J Am Vet Med Assoc 1982;180:627. [5] Currie AK, Seager SWJ. Anhidrosis. In: Proceedings AAEP Annual Meeting; Dallas, TX. Nov 28 Dec 1, 1976, p [6] Hodgson DR, McCutcheon LJ, Byrd SK, et al. Dissipation of metabolic heat in the horse during exercise. J Appl Physiol 1993;74:1161. [7] Robertshaw D. The evolution of thermoregulatory sweating in man and animals. Int J Biometeorol 1971;15:263. [8] Geor RJ, McCutcheon LJ. Thermoregulation and clinical disorders associated with exercise and heat stress. Compend Contin Educ Pract Vet 1996;18:436. [9] Ingjer F, Stromme SB. Effects of active, passive or no warm up on the physiological response to heavy exercise. Eur J Appl Physiol 1979;40:273. [10] Nadel ER. Temperature regulation and prolonged exercise. Perspectives in exercise science and sports medicine. Carmel (IN): Benchmark Press; p [11] Carlson GP. Thermoregulation and fluid balance in the exercising horse. In: Snow DH, Persson SGB, Rose RJ, editors. Equine exercise physiology. Cambridge, UK: Granta Publications; p [12] Nadel ER, Cafarelli E, Roberts MF, et al. Circulatory regulation during exercise in different ambient temperatures. J Appl Physiol 1979;46:430. [13] Mills PC, Marlin DJ, Scott CM, et al. Nitric oxide and thermoregulation during exercise in the horse. J Appl Physiol 1997;82:1035. [14] Evans CL, Nisbet AM, Ross KA. A histological study of the sweat glands of normal and dry coated horses. J Comp Pathol 1957;67:397. [15] Bal SH. The skin. In: Swenson MJ, Reece WO, editors. Dukes physiology of domestic animals. Ithaca (NY): Cornell University Press; p [16] Jenkinson DM, Montgomery I, Elder HY, et al. Ultrastructural variations in the sweat glands of anhidrotic horses. Equine Vet J 1985;17:287. [17] Jenkinson DM, Blackburn PS. The distribution of nerves, monoamine oxidase and cholinesterase in the skin of the horse. Res Vet Sci 1968;9:165. [18] Sorensen VW, Prasad G. On the fine structure of horse sweat glands. Z Anat Entwickl. Gesch 1973;139:173.

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