Non Sweater - THE VETERINARY CLINICS Equine Practice

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°/c) 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 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 terrestrial 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 I 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 [I 0]. This heat is derived from the conver. SiOll of chemical energy into mechanical work. Only 25°/r, of the metabolic 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-to skin 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 thesecretory portion being coiled and _mbedded within the dermis. A straightand 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 ashaving two layers: an inner layer of cuboidal secretory epithelial cells, andan enveloping layer of myoepithelium. These myoepithelial cells are restingon 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 ofmonoamine oxidase in the nerve fibers suggesting adrenergic fiber innervation [17]. The secretory cells have cytoplasmic protusions that extend intothe lumen of the duct [16] suggesting an apocrine mode of secretion. Theapocrine mechanism of secretion is further supported by the observationthat the secretory cells do not contain glycogen [18].

Physiology of sweating in horses

Physiologic control of sweating ill horses is unique compared with other species. Horses have two mechanisms of control; humoral control via
Fig. I.

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. I). 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 P2-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 Pradrenoreceptors are stimulated [24]. Subsequent studies with equine sweat gland epithelial cell cultures have conclusively established that sweating in horses is regulated by P2-adrenoreceptors and mediated by cAMP and possibly intracellular free Ca that mediate the effects of _ragonists involve occupation of the receptor bythe agonist, resulting in a conformational change in the ex-subunit of thestimulatory G protein. This protein is involved in the activation of adenylatecyclase, which catalyzes the formation of cAMP. Protein kinase A is thenformed and produces the subsequent phosphorylation of cellular proteinand 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 anhidrosisAt present, the mechanisms of anhidrosis are unknown. Potential pathologic mechanisms can be classified as either a decreased stimulation of thesweat 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]. Heatstroke is a real possibility in thermally stressed animals; temps of above108°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]

Receptor exposure to agonist. 0 G protein uncoupling and activation 01 adenylc He cyclase CD Formation 01 cAMP and protein kinase A catalysed by i'lcfenylilW
cyclase and subsequent phosphorylation of cellular proteins.

However, despite the possibility of CNS dysfunction occuring when bodylemperat_res are severely elevated, it is unlikely that this is a factor in anhidrosis as the syndrome is reversible [2], and horses develop the conditionwithout 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 duringexercise via humoral stimulation [30]. Additionally, sweat gland innervation of anhidrotic horses has been reported to be normal. with no evidence ofaxonal degeneration [14]. These findings, coupled with the reversible natureof anhidrosis, make denervation an unlikely cause of anhidrosis. 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].

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. 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 _ragonists in both humoral and neural stimulation of sweating, and could potentially overstimulate _r 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 _2-adrenoreceptors, has been produced by incubating cultured equine sweat gland epithelial cells in a solution containing adrenaline [34]. This decreased sensitivity of _radrenoreceptors had an early and a late phase and resensitization of the Pr adrenoreceptors occurred slowly (t1/2 = 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 P2-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 P2-adrenoreceptors in equine sweat glands.In other species, overstimulation of _rreceptors 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 _rreceptor 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

Sweat gland perfusion

An adequate vascular supply is important for umoral stimulation ofsweating. 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 hothumid conditions has been reported to be abnormal [16]. Reported abnormalities included thickened basal lamina, evidence of poor myoepithelialcontraction, fibrocytes with dilated endoplasmic reticulum and vacuolation,and thickened connective tissues. The secretory cells had a marked reductionof vesicles with increased numbers of mitochondria and less rough endoplasmic reticulum. The luminal microvilli were often absent, and the cells hadbecome 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 [I 4J. Duct obstruction hasbeen speculated to be a response to prolonged stress and failure of secretion,, and may provide a mechanism of defense. against microbes invading the 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 _-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 _-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 _-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 maiply intracellular, total body potassium may be depleted, but undetected, 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 _- and a.-adrenergic receptor agonist properties, and therefore, may cause leukotrichia at the injection sites. Salbutamol sulfate, a specific _ragonist, 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 10-3 w\v to IO'-R 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 10-8 w\v dilution, and partially anhidrotic horses responded with dilutions between 10-4 w\v and 10-6 w\v. An unreported, semiquantitative test using terbutaline sulfate, another specific _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

Fig. 3. Response of normal horse toa semiquantitative test used to diagnose anhidrosis.

Fig. 4. A partial sweater. There is only a minimal response to the intradermal injections of a specific _radrenergic agonist.

Fig. 5. An anhidrotic horse: there is a complete lack of response to the specific _2-adrenergic agoni_t. 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 KCI 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, MP Co., Phoenix, AZ). Tyrosine is potentially involved in the resensitization of sequestered _rreceptors [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 _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 10-15 g per day for 4 to 8 days has been reported to be beneficial in the literature [40]. Practitioners havereported success supplementing with levo-thyroxine (THYRO-L, Vetamix, ShenandQah, IA) at a dose of 0.5-3.0 mg per 100 Ib 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.

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 _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.

Clenbuterol

There have been anecdotal reports that clenbuterol is effective in causing sweating in some anhidrotic horses. Clenbuterol is a _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 mlllOOO 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 _ragonist 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.

Future therapies

In humans, it has been shown that glucocorticoids increase the _rreceptor 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 down. regulation of _2-receptors as well [50,51].

References

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.

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