Equine gastrointestinal motility — ileus and pharmacological modification

Abstract

Colic is a common problem encountered in equine practice. Alteration of gastrointestinal motility is often the underlying cause for abdominal pain. Gastrointestinal motility can be measured as myoelectric activity, mechanical activity, and transit of intraluminal contents. Regulation of motility is based on a complex interaction between central innervation, autonomic innervation, and the enteric nervous system. Various humoral and neurochemical substances are required to interact flawlessly to allow propulsive motility. Ileus is defined as the absence of propulsive aboral movement of gastrointestinal contents, irrespective of its pathophysiology. Potential etiologies for ileus are described in this review. The prokinetic drugs available for clinical use are discussed. Choosing the appropriate prokinetic drug requires knowledge about the complex nature of gastrointestinal motility and its abnormalities.

Introduction

Gastrointestinal propulsive motility depends on a complex interaction between neural, hormonal, vascular, and neuromuscular pathways. Disruption of this intricate interaction leads to stasis of aboral movement of food material, also called ileus. Unfortunately, this is a common and often fatal problem in the horse. A variety of prokinetic agents have been used in the horse with variable success. Choosing the appropriate prokinetic drug requires knowledge about the physiology and pathology of equine gastrointestinal motility. Also, one needs to know the mechanism of action and potential efficacy of the drug chosen to treat a particular form of ileus. The purpose of this paper is to review the current literature and summarize up-to-date information on the physiology, pathology, and treatment of ileus.

Materials and methods

Literature searches were carried out using the advanced search options of the new PubMed system of the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM), USA (1966–2004/06). Further literature searches were conducted in the Veterinary Science Database (CAB International, Ovid Technologies, Boston, Massachusetts, USA) by using search and retrieval software (WinSPIRS, version 2.0; SilverPlatter International, N.V. [1973–2004/05], Ovid Technologies, Boston, Massachusetts, USA). Keywords originally used were combinations of “equine” or “horse” with “ileus,” “gastrointestinal motility,” “prokinetic,” or “intestine.” Upon evaluation of articles published relevant to equine motility and related topics, the literature search was extended to include the gastrointestinal physiology, pathophysiology, and pharmacology of other species. Also, textbooks were used to retrieve information that would help readers to better understand or elucidate the subject.

Physiology

1. Normal gastrointestinal motility patterns

The net movement of intraluminal contents is defined by gastrointestinal motility. Assessing gastrointestinal motility accurately in vivo can be quite challenging. Three basic parameters of gastrointestinal motility can be measured: myoelectric activity, mechanical activity, and transit of intraluminal contents. Myoelectric and mechanical activities are indirect measures of gastrointestinal motility, but they do not always accurately correlate with the transit of intraluminal contents (1).

Two types of myoelectric activity have been described — slow waves and spiking activities. Slow waves (basic electrical rhythm, electrical control activity, pacesetter potential) are subthreshold electrical potentials that do not cause smooth-muscle contractions (2). These slow waves maintain the contractile excitability of smooth muscle. Spiking activities (intermittent electrical response activity) are action potentials superimposed on the slow waves and result in intestinal contractions (2,3). These spikes assume various patterns, depending on the species and the area of the gastrointestinal tract.

In most species, the migrating myoelectric complex (MMC) is a myoelectric pattern found in the stomach and small intestine many hours after a meal (interdigestive state) or during fasting. In horses, the MMC is always present (3,4). In most species, there is a differentiation in motility pattern between fasted and fed states. That, however, does not apply in horses (4). Some authors believe that the relatively small equine stomach (compared with that of most monogastric animals) and the greater frequency of food intake are responsible for this lack of differentiation (4).

The MMC is cyclic with 3 phases: phase 1 is a period of no spiking activity; in phase 2, there is intermittent spiking activity; and in phase 3 regular spiking activity occurs (5). Some authors have described a phase 4 activity that consists of a bridging irregular phase separating phase 3 from phase 1 (6,7). Smooth muscle contractions are correlated with phase 2 and 3 (5,8). In fasted ponies, the stomach contracted 2 to 3 times per minute during periods of phase 3 (8). When the stomach was inactive (phase 1), the duodenum and jejunum were in phase 3 (8,9). As the ileum entered phase 3, its contractions became longer in duration (mean, 45 min) than those in the jejunum (mean, 8 min). This is unique in horses and proposedly aids in maintaining homeostasis and in transferring ingesta as quickly as possible to the cecum and colon (4). The intense phase 3 spiking activity in the ileum, sometimes referred to as the “migrating action-potential complex” (MAPC), immediately precedes cecal myoelectric activity 72% of the time. This myoelectric coupling of the ileum and cecum is suspected to facilitate rapid transit of ingesta (10).

In the cecum, as measured with an intraluminal pressure system, frequent low-amplitude peaks were seen in the cecal base and body, consistent with a haustra-to-haustra mixing pattern. Once every 22 min, coordinated pressure peaks originated in the cecal body and progressed to the cecal base, or vice versa. During this event, the right ventral colon remained quiet. Once every 3 min, concurrent with a loud “rush” on auscultation, aborally-propagating progressive pressure peaks occurred in the cecal base, cecocolic orifice, and adjacent right ventral colon. This pattern, which appeared to originate from a pacemaker in the cecal body, resulted in movement of ingesta from the cecum into the colon at approximately 4 cm/s (4,11). Retropulsive pressure peaks, originating from a hypothetical pacemaker in the pelvic flexure and ending at the cecocolic orifice, were also reported (11). Another group used endoscopy through a cecal cannula, as well as cinefluoroscopy, to evaluate motility of the cecum and right ventral colon. They described movement of cecal contents from the body to the cupola, followed by simultaneous contraction of the cupola and elevation and opening of the cecocolic orifice, which allowed outflow of ingesta into the right ventral colon (12,13). The motility pattern described for the cecum (cecal myoelectric complex) and colon was later confirmed in another study in which electrodes surgically implanted on the ileum, base of the cecum, and pelvic flexure were used (7,14).

Other groups investigated equine colonic myoelectric activity by using electrodes surgically fixed to the serosa in the pelvic-flexure region (15) and the ileum, cecum, and right ventral colon (14). They reported aborally migrating long-spike-burst (LSB) complexes that occurred sporadically for up to 8 min, aborally migrating LSB and short-spike-burst (SSB) complexes that lasted up to 5 min (slowly migrating cluster of short and long SSB’s [SMC]), series of propagated spike bursts (termed colonic migrating myoelectric complex CMMC), and single sporadic LSBs that traveled both orally and aborally from the pelvic flexure (15). The presence of a pacemaker in the pelvic flexure was later confirmed: Investigators reported an increased neuronal density and a 10-fold increase in neurons reactive to vasoactive intestinal peptide (VIP) at the pelvic flexure (16). However, the pelvic flexure may not be the only pacemaker site in the large intestine: Throughout the colon, LSBs were observed traveling orally and aborally (15). Myenteric-plexus and neuron density was increased not only in the pelvic flexure but also in the left dorsal and transverse colon, when compared with the colon as a whole (17). Coupling of ileal, cecal, and proximal colonic myoelectric activity has been suggested, since ileal MAPC’s were frequently followed by the so-called cecal myoelectric complex, which propagated rapidly over the cecal base and continued into the right ventral colon as CMMC (11,14). The small colon has also exhibited motility and myoelectric patterns similar to those described for the pelvic-flexure region of the large colon (8). Myoelectric and mechanical activities are closely related; however, transit of intraluminal contents does not always correlate with them (3).

2. Regulation of gastrointestinal motility

Visceral smooth muscle is unitary or syncytial smooth muscle (18). When an action potential is elicited anywhere within the muscle mass, it travels in all directions. The normal slow-wave or resting potential of visceral smooth muscle is between -50 and -60 millivolts (mV). Smooth-muscle contraction occurs when the cell-membrane potential rises to threshold at about -40 mV (18). Contraction results from an increased concentration of calcium in the cytoplasm (19). Calcium entry into the muscle fibers is regulated by the protein calmodulin (18). Two mechanisms are known to cause an increase of cytoplasmic calcium. Electromechanical coupling occurs when depolarization of the cell membrane results in calcium influx in response to acetylcholine (ACh), and pharmacomechanical coupling occurs secondary to receptor interaction and is independent of the membrane potential (19).

In general, regulation of motility occurs as a complex interaction of central innervation, autonomic innervation, and the enteric nervous system. However, control of intestinal contractions by the enteric nervous system is independent of the central nervous system (18). The enteric nervous system is a collection of neurons in the gastrointestinal tract that control motility, exocrine and endocrine secretions, and microcirculation (20). It consists of the myenteric (Auerbach’s) plexus and the submucosal (Meissner’s) plexus. The myenteric plexus lies between the longitudinal and circular layers of smooth muscle and extends the entire length of the gut. It primarily provides motor innervation to the 2 muscle layers and secretomotor innervation to the mucosa (17,20). There are also a substantial number of connections from the myenteric plexus to submucosal ganglia and sympathetic ganglia (20). The submucosal plexus, located between the circular muscle layer and the muscularis mucosa, is best developed in the small intestine and mainly controls secretion (18).

The enteric nervous system influences the gastrointestinal tract either directly through neurotransmitters or indirectly through intermediate cells, such as the interstitial cells of Cajal, cells of the immune system, or endocrine cells (20). In humans, the interstitial cells of Cajal are electrically coupled with smooth-muscle cells and are believed to be responsible for the rhythmicity of slow-wave activity (5). Similarly, in horses, baseline myogenic activity appears to be initiated through the cells of Cajal, independent of sympathetic and parasympathetic input, since baseline myogenic response in the equine jejunum was minimally affected by adrenergic and cholinergic blockade (21). In the horse, the location of the interstitial cells of Cajal varies between segments of intestine: in the small intestine, they are located predominantly at the level of the myenteric plexus, whereas in the large intestine, they are found mainly in the circular muscle layer. Also, the highest densities of interstitial cells of Cajal are found in the ileum, pelvic flexure and cecum (22). When the equine interstitial cells of Cajal had been damaged, for example, due to grass sickness, a reduced slow wave frequency of the small intestine was observed in vitro (23).

The parasympathetic and sympathetic nerves connect the enteric nervous system to the central nervous system. In humans, the intensity and frequency of intestinal contractions is influenced by the parasympathetic (via vagus and pelvic nerves) and sympathetic (via cranial and caudal myenteric plexus) nervous systems and by hormones (18). Acetylcholine (ACh) is the main excitatory neurotransmitter in the gut of all species. It promotes contraction through muscarinic type-2 receptors on the smooth-muscle cell (24). Interestingly, ACh can also relax circular smooth muscle, when the smooth-muscle tone is very high. This inhibitory response may be caused by ACh stimulating the release of nitric oxide from enteric neurons (25). Sympathetic stimulation inhibits ACh release from the cholinergic fibers, via activation of alpha-2 adrenergic receptors located pre-synaptically on cholinergic neurons in the enteric ganglia (26). However, alpha-2 agonists have also been reported to induce contraction in longitudinal smooth-muscle strips from the equine jejunum (21). Tetrodotoxin, a neural sodium-channel blocker, prevented this alpha-2 agonist-mediated contraction. Since alpha-2 receptors are located presynaptically, they are able to regulate not only the release of ACh, but also the release of other neurotransmitters. Therefore, apparently a different neurotransmitter was being released by the presynaptic alpha-2 agonists. Also alpha-1, beta-1, and beta-2 receptor stimulation was shown, in an equine in vitro model, to decrease jejunal myogenic activity (21). Norepinephrine was shown, in an in vitro study, to be another important neurotransmitter in the enteric nervous system of horses, causing relaxation of jejunal smooth muscle strips. However, it was also shown that high tone circular or high-intensity stimulated longitudinal muscle strips from the equine jejunum are able to contract in response to norepinephrine (21).

The presence of nonadrenergic-noncholinergic neurotransmitters in the enteric nervous system was confirmed by subjecting circular and longitudinal smooth-muscle strips from the equine jejunum to electric-field stimulation when the adrenergic- and cholinergic-receptors were blocked (25). Inhibitory nonadrenergic-noncholinergic neurotransmitters in the gastrointestinal system of horses, namely adenosine triphosphate (ATP), vasoactive intestinal peptide (VIP), and nitric oxide, have been shown to be responsible for relaxation of circular and longitudinal smooth muscle strips in vitro (24). In circular smooth-muscle strips from the equine ventral colon that were subjected to electric-field stimulation, nitric oxide and an apamin-sensitive neurotransmitter inhibited contraction (27). Substance P, another nonadrenergic-noncholinergic neurotransmitter, was recently shown in horses to cause relaxation or contraction of jejunal smooth muscle, depending on the amount of stimulation and orientation of the smooth muscle (28). Possibly, substance P is also involved in contraction of the large colon (24).

Ileus

1. Pathophysiology of ileus

Gastrointestinal ileus has been defined as the functional inhibition of propulsive intestine activity, irrespective of its pathophysiology (24). The terminology used to describe the different clinical manifestations of motility disorders in the horse is confusing, with the terms ileus, postoperative ileus, endotoxemic ileus, idiopathic ileus, and adynamic ileus being used inconsistently in the literature (29). In humans, when using the duration of clinical signs for classification, ileus can be characterized as either adynamic (30), resulting from short-term alterations of gastrointestinal motility, or paralytic, when motility is lost for longer than 72 h (31). Ileus can develop from diseases directly involving the digestive system, or it can be a consequence of diseases in other body systems, such as trauma to retroperitoneal structures or irritation of the peritoneum (32). Shock; electrolyte imbalances; hypoalbuminemia; peritonitis; endotoxemia; and distension, ischemia, or inflammation of the intestinal tract have all been implicated as contributing to the pathophysiology of ileus in the horse (8,33–35).

Postoperative ileus (POI) has been well documented as occurring after laparotomy in humans (30) and horses (36). In one study, 21% (31/148) of horses that underwent surgical treatment of colic developed POI, which was fatal in 13% (4/31) of these cases. These horses were either euthanized due to severe colic or died because of a ruptured stomach. Horses with evidence of shock (high pulse rate, hemoconcentration, and high glucose concentration) and small-intestinal obstruction, with or without intestinal ischemia, were predisposed to the development of POI (34). In another study, 18% (69/376) of horses undergoing colic surgery developed POI. Sixteen percent of the POI cases (11/69) died, compared with 6% (18/307) fatality in horses without POI. Among horses undergoing colic surgery, those in which a small-intestinal resection and anastomosis were performed had an even greater risk of POI (42% of horses with anastomosis developed POI) (33). In an experimental model of POI in ponies, using jejunal trauma to create ileus, electrical activity was decreased and the normal synchrony of gastric and duodenal MMCs was disrupted. Corresponding with the decrease in myoelectric activity, gastrointestinal transit time also increased (36).

Many potential etiologic agents have been investigated to determine a cause for the development of POI. An imbalance between sympathetic and parasympathetic nervous-system input to the intestine has been postulated as an underlying cause. Sympathetic (adrenergic) hyperactivity results in reduction of propulsive motility, and an increase in sphincter tone. Parasympathetic (cholinergic) hypoactivity results in a decrease in gastrointestinal motility (21,32,36). Following intestinal surgery in humans, increased circulating levels of epinephrine and norepinephrine have been observed. In such patients, dopamine infusions have also been noted to suppress intestinal activity (32). In a model of POI in rats, where mechanical trauma to the small intestine and cecum was used, reserpine (depletes catecholamine stores) and L-nitroarginine (nitric-oxide synthase inhibitor) completely reversed the inhibition of ingesta transit. This finding supported the involvement of adrenergic and nitrergic neurons in the pathogenesis of POI (37). A model of POI in horses was used to assess the effects of specific adrenergic blockade (propanolol, yohimbine), parasympathetic stimulation (bethanechol), and dopaminergic antagonism (metoclopramide) (36). However, only a small number of horses were used and the protocol throughout the study was altered, so the results of this study might have been different with a larger number of animals. Propanolol did not improve motility. Yohimbine alone and in combination with bethanechol improved intestine activity moderately, confirming some adrenergic hyperactivity in the development of POI (38). The best results were achieved with metoclopramide, revealing dopaminergic involvement as well. It is likely that abnormalities of the enteric nervous system and damage to muscle cells generating slow waves also contribute to the development of ileus, since severance of the autonomic nervous system does little to alter motility (38–42).

Endotoxemia has been shown to be involved in the development of POI. In healthy ponies, IV infusion of endotoxin at 0.1 μg/kg body weight (BW) resulted in inhibition of motility in the stomach, left dorsal colon, and small colon. However, no nasogastric reflux was observed. Although motility in the small intestine was increased, its myoelectric pattern was abnormal. Similar effects on motility were observed after IV infusion of prostaglandin E₂ (PGE₂). These findings led to the conclusion that the effects of endotoxin on motility were partially mediated by PGE₂ (8), possibly stimulating alpha-2 adrenergic receptors (43). In a later study, it was shown that a cumulative dose (0.03 mg/kg BW) of endotoxin administered over 1 h resulted in cecal and proximal colonic ileus (44). Intestinal motility was restored when yohimbine (0.75 μg/kg BW) was administered at the same time as the endotoxin. The authors concluded that ileus caused by endotoxemia is at least partially mediated through alpha-2 adrenergic receptors, due to either increased sympathetic nerve activity or circulating catecholamines stimulating alpha-2 adrenergic receptors, modulation of arachidonic acid metabolism to inhibitory prostaglandins via alpha-2 adrenergic receptors, or prevention of opioid-mediated inhibition of intestinal motility via alpha-2 adrenergic receptor blockade. Pretreatment with phenylbutazone, a cyclooxygenase inhibitor, abolished the effects of endotoxin on gastrointestinal motility in horses (45), further implicating a PGE₂ pathway. A platelet-activating-factor (PAF) antagonist also suppressed some of the endotoxin-induced inhibition of motility in horses. Therefore, a PAF may play some role in the development of POI (46).

Since PGE₂ and PAF are both inflammatory mediators, ileus may be triggered by endotoxin but actually induced by inflammation in the intestinal smooth muscle. This inflammation could also affect the cells of Cajal and thus alter normal myoelectric patterns. In a recent investigation in rats, surgical manipulation caused a leukocytic inflammatory response within the intestinal muscularis externa, with suppression of smooth muscle contractions. This suppression of motility was prevented by the administration of adhesion-molecule antibodies, which decreased extravasation of leukocytes. The authors concluded that inflammation must contribute significantly to the development of POI in this model (47). In another study (48), the investigators concluded that ileus might actually be triggered by a primary disturbance of the smooth muscle itself. A portion of equine jejunum was subjected to ischemia for 60 min: Jejunal segments adjacent to the ischemic area had decreased contractility and relaxation when stimulated with an electrical field or with norepinephrine, even though histologically there were no signs of inflammation. When these segments were stained to determine neurotransmitter content, they appeared similar to healthy equine jejunum. Since there was no evidence of inflammation or altered neurotransmitter release, a possible rationalization is that the muscle’s ability to contract may have been affected or that the number of smooth muscle or neuronal receptors had changed (48). In smooth-muscle strips from inflamed rabbit colon, it was demonstrated that a decrease in motilin-induced contractility was caused by a decrease in the number of motilin receptors (49). A study on inflammatory intestine disease in humans showed that substance-P receptors were increased in neurons of the myenteric plexus (50). The effects of inflammation on intestinal smooth muscle or on the enteric nervous system may best explain the development of POI or other forms of ileus common to the horse. Further research to investigate the role of up- or down-regulation of receptors in the myenteric plexus, as well as changes in the smooth muscle, is needed to better understand the pathophysiology of ileus in the horse.

One of the most challenging aspects of POI in horses is the occurrence of cecal impactions, partly because the pathophysiology of cecal motility dysfunction is not known (24,51–53). Cecal impaction occurs more commonly after orthopedic procedures (54). The effects of general anesthesia have been thought to initiate cecal impaction. However, when myoelectric activity was evaluated in horses using 3 different general-anesthetic regimens, effects on intestinal motility disappeared completely within 9 h after anesthesia ended (55). Therefore, general anesthesia appears to be a less likely primary cause of cecal motility dysfunction. On the other hand, horses undergoing orthopedic surgery lasting over 1 h without the administration of phenylbutazone were at much higher risk of developing decreased fecal output (54). Perhaps persistent pain after orthopedic procedures, resulting in sympathetic overstimulation, is a significant contributing factor (24). It was demonstrated that NSAID’s reduced the contractility of equine colonic muscle strips (56). However, flunixin reportedly had no effect on the clearance of radiolabeled markers from the cecum, and induced only an isolated increase in myoelectric activity in the right ventral colon (26). On the other hand, flunixin was administered only as a single dose in this study, and horses developing cecal impactions have usually been treated with NSAIDs for a longer period of time.

Certain classes of drugs can induce ileus. Activation of presynaptic alpha-2 adrenergic receptors within the enteric nervous system inhibited ACh release from cholinergic neurons, thereby suppressing intestinal contractions in normal ponies (26). In horses, IV administration of xylazine, an alpha-2 adrenergic agonist, resulted in a significant reduction of duodenal (57), jejunal (58), and cecal and colonic motility (55,58), and detomidine, a more-potent alpha-2 adrenergic agonist, was also more potent in suppressing motility in the duodenum and large intestine (24,57).

The effect of butorphanol, an opioid agonist-antagonist, on equine intestinal motility is controversial. In one study, butorphanol decreased MMC activity in the jejunum but did not affect the pelvic flexure (59), whereas in another study, butorphanol had no effect on either gastric or duodenal activity (9). Thus, it appears that there is variability in the response of different intestine segments to opioids. When xylazine and butorphanol were given to horses as a combination, duodenal motility was decreased for up to 1 h (57); however, this decrease in motility, may have contributed to the xylazine or to a synergistic effect of the 2 drugs.

Metabolic abnormalities, such as hypokalemia, hypocalcemia, and uremia, have been implicated in the pathophysiology of ileus in humans and other animals, but little to no information is available on horses (24). In sheep and cattle, experimentally induced hypocalcemia depressed intestinal mechanical activity. As calcium levels progressively dropped, mechanical activity also decreased, until stasis occurred (3). Analysis of serum ionized-calcium concentrations in 147 horses with either nonstrangulating obstruction of the colon or infarction of the small intestine, cecum, or colon showed that all of these animals had low calcium levels before and after surgery (60). The importance of extracellular and intracellular calcium for intestinal smooth-muscle contraction has been described for other species (18,19,61).

2. Prokinetic drugs for the treatment of ileus

Cholinomimetics

Cholinomimetic or parasympathomimetic agents increase ACh either by stimulating ACh receptors (directly acting parasympathomimetic agents) or by inhibiting cholinesterase (indirectly acting parasympathomimetic agents) (62).

Bethanechol chloride, a directly acting parasympathomimetic agent, is a muscarinic-receptor agonist that causes contraction of smooth-muscle cells in the gastrointestinal and urinary tracts (43). In healthy horses, bethanechol (0.025 mg/kg BW, IV) significantly hastened gastric emptying of liquid and solid-phase radiolabeled markers (63). The only side effect reported in this investigation was increased salivation. In another study on normal horses, bethanechol (0.025 mg/kg BW, IV) hastened cecal emptying and increased myoelectric activity in the ileum, cecum, and right ventral colon (26). In these latter horses, however, side effects included both increased salivation and mild abdominal pain. In an equine model of POI, bethanechol accelerated the passage of orally administered plastic beads being used as transit markers and improved myoelectric activity in the stomach, jejunum, ileum, and large and small colon. However, bethanechol did not improve gastroduodenal coordination (36). Salivation is the most common side effect noted, but some animals seem to tolerate it well.

Neostigmine methylsulfate, an indirectly acting parasympathomimetic agent, is a cholinesterase inhibitor that prolongs the activity of ACh by retarding its breakdown at the synaptic junction (43,62). Neostigmine has been shown to delay gastric emptying and decrease jejunal myoelectric activity, but to enhance pelvic flexure activity in healthy ponies (32,58). In another study, neostigmine improved cecal emptying and increased mechanical and myoelectric activity in the ileum, cecum, and right ventral colon (26). Although neostigmine has been beneficial in the treatment of reflux esophagitis in humans, it has also increased gastric secretion, delayed gastric emptying, and caused abdominal pain. Therefore, it is not frequently used in humans (62). Based on clinical impressions, neostigmine can effectively reduce POI in the horse, especially when the large colon is involved. In a survey that evaluated the use of prokinetic therapy, neostigmine (5 to 10 mg, IM or SC) was the most commonly selected prokinetic for treatment of large colon impactions (64). However, monitoring the patient for any adverse effects is advised (40).

Adrenergic antagonists

Alpha-2 antagonists are sympatholytic agents that block alpha-2 receptors within the enteric nervous system and allow release of ACh from cholinergic neurons (65). Yohimbine increased myoelectric activity in the right ventral colon and cecum of healthy ponies, but it did not significantly affect cecal emptying time (26). Although yohimbine was moderately successful in improving myoelectric and mechanical activity in an equine model of POI, normal motility was not restored (36). Based on reports in the literature, little is known about the effectiveness of yohimbine for treatment of equine POI. Further research is required before recommending it for use as a prokinetic drug in horses.

Phenoxybenzamine (200 mg diluted in 500 mL sodium chloride) was administered, IV, and repeated (if no improvement of clinical signs occurred) to 12 horses that had developed ileus either after surgery for colic or secondary to inflammatory intestinal disease. In all 12 horses, the amount of nasogastric reflux decreased in proportion to increases in the dose of phenoxybenzamine (66); however, as there were no control animals, it could not be determined if the improvement was due to the phenoxybenzamine or from time and other supportive therapy.

Phenothiazines, a group of peripheral alpha-adrenergic antagonists, are used in humans for treatment of POI with variable success (65). Acepromazine was shown to reduce myoelectric activity in the equine small intestine, but intestinal transit of fluids became more rapid (67). Based on clinical impressions, acepromazine was thought to reduce POI (40), but there was no solid scientific evidence to support this theory.

Benzamides

Benzamides possess 5-hydroxytryptamine (5-HT, serotonin) antagonist and agonist properties on 5-HT₃ and 5-HT₄ receptors, respectively (65). Their prokinetic activity seems to result from neuronal 5-HT₄ agonism, enhancing cholinergic transmission in the myenteric plexus (37).

Metoclopramide has the 5-HT receptor properties described above. It also has an antagonistic effect on dopaminergic DA₂ receptors and obstructs the inhibitory effect of dopamine on gastrointestinal smooth muscle (68). In a model of POI in the horse, continuous infusion of metoclopramide restored coordinated gastroduodenal activity and gastrointestinal ingesta transit. However, the presence of dopamine receptors in the equine gastrointestinal tract has not been documented (29). Unfortunately, horses showed transient excitement after the administration of metoclopramide (36). Similar side effects, such as sweating, excitement, and restlessness, have been well documented in humans (65). In a retrospective study in other horses, the clinical use of metoclopramide (administered as a continuous infusion at 0.04 mg/kg BW/h) was evaluated after small-intestinal resection and anastomosis. Although horses treated with metoclopramide had decreased total volume, duration, and rate of gastric reflux, the previously reported side effects were again noted (69). In another study, metoclopramide increased contractility of smooth-muscle strips from the equine pyloric antrum, duodenum, and jejunum (70). When used as a pretreatment, metoclopramide has also been shown to improve gastric emptying in horses receiving endotoxin (71). The prokinetic capacity of metoclopramide appears substantial, but its potential side effects for clinical use have to be considered.

Cisapride is a substituted benzamide that is devoid of antidopaminergic properties. Therefore, it is unlikely to cause the same undesirable side effects as metoclopramide (72). In an experimental model of POI in ponies and in a clinical trial on horses, cisapride was effective in reestablishing motility after small-intestinal anastomosis and enterotomy (73). Similar to metoclopramide, cisapride restored gastric emptying that had been delayed by endotoxin administration (74). The only side effect observed in horses after cisapride treatment in a clinical setting was periodic mild abdominal pain (73). In humans, cisapride has been shown to have adverse cardiac effects, including ventricular dysrrhythmias, syncopal episodes, and lengthening of the electrocardiographic QT intervals. These effects have been related to prolongation of the action-potential duration through blockage of potassium channels, with a resulting delay in cardiac repolarization (68). No such reports of side effects have been made for the horse.

Erythromycin

Erythromycin estolate is a 14-member macrolide antibiotic used almost exclusively in equine practice to treat diseases caused by Rhodococcus equi in juvenile animals (75). In horses and humans, antimicrobial doses of erythromycin occasionally induce severe colitis and other undesirable side effects (76–78). In healthy horses, low doses of erythromycin lactobionate (0.1 and 1 mg/kg BW, IV) decreased the emptying time of radiolabeled markers from the stomach (63). Cecal emptying in ponies receiving erythromycin lactobionate, IV, was dose dependent (79). Studies in other species also demonstrated that the prokinetic effects of erythromycin were often dose related (80,81). A dose of 0.01 mg/kg BW, infused over a period of 1 h, had no effect on cecal emptying, while a similar infusion at a dose of 1 mg/kg BW maximized equine cecal activity. The onset and rate of cecal emptying were more rapid when erythromycin, 0.1 mg/kg BW, was administered as a bolus rather than a slow infusion. The total amount of erythromycin lactobionate needed to create an increase in ileocecocolic myoelectric activity in the horse was as little as 500 μg (79). Erythromycin lactobionate increased the contractility of both circular and longitudinal smooth-muscle strips from the equine jejunum. In strips from the pyloric antrum, it increased the contractility of longitudinal muscle, but inhibited the contractility of circular muscle. These responses were consistent with the passage of ingesta from the stomach into the small intestine (70). Recently, it was shown that erythromycin lactobionate displaces motilin from motilin receptors in the equine duodenum, jejunum, cecum, and pelvic flexure (82). When the effect of erythromycin lactobionate, 0.5 mg/kg BW, IV, was evaluated in horses during the first 24 h after a ventral-midline celiotomy, myoelectric activity increased in the ileum and pelvic flexure, but not in the cecum. When reevaluated with the same dose 8 d after surgery, the cecum was responsive. The prokinetic effects of erythromycin reported in healthy horses were not the same in horses with gastrointestinal disease (83). A different study showed that distension and subsequent decompression of a segment of equine jejunum resulted in inflammation. When testing the response of circular smooth muscle strips from distended jejunum to erythromycin, contractions were weaker than in control strips (35). It seems that in several species, the response to erythromycin in healthy subjects is different from that in subjects with gastrointestinal disease. Interestingly, the ability of erythromycin lactobionate to bind to the equine motilin receptor is not affected by ischemia or distension of the jejunum (84). Therefore, the decreased response to erythromycin may be associated with down-regulation of motilin receptors, which has been reported in rabbits with chemically induced colitis (49). It has been demonstrated recently, that distension of equine jejunum results in a decrease of motilin receptors when compared with sham-operated segments of jejunum, which seems to be partly due to a decrease in motilin receptor synthesis (84). Prolonged administration of erythromycin can also result in down-regulation of motilin receptors (85).

The prokinetic activity of erythromycin is very specific to 14-membered macrolides (86,87). Erythromycin-A and several erythromycin derivatives were evaluated in vitro for their antimicrobial properties and their ability to induce gastrointestinal motility in rabbit duodenal muscle strips. One derivative, 8,9-anhydroerythromycin-A 6,9-hemiketal propargyl bromide, was 2890 times more potent in inducing gastrointestinal motility than was erythromycin-A and had no antimicrobial properties (87). Clinical use of these derivatives for their prokinetic activity should prevent the development of antimicrobial resistance and other undesirable side effects associated with erythromycin. In the equine patient with ileus, erythromycin may be a useful prokinetic drug. Currently, it is most commonly used for treatment of cecal impactions (64). However, before making any assumptions, it is important to further elucidate the mechanism of action of erythromycin in the horse. Additional studies, including clinical trials, are needed.

Dopamine antagonists

Domperidone is a selective peripheral dopamine (DA₂ receptor) antagonist (24,73). In a preliminary study in which using an experimental model of POI in ponies was used, domperidone, given at 0.2 mg/kg BW, IV, was effective in restoring transit time, electromechanical activity, and coordination of gastric and intestinal cycles (73). No further information about domperidone as a prokinetic agent is available at this time, and further research is needed before it is used clinically in horses.

Lidocaine

Lidocaine may act by inhibiting the sympathetic response, blocking the effects of endotoxin, restoring intestinal coordination, or decreasing inflammation (70). However, when comparing the effect of lidocaine with the use of a placebo in clinical cases with an intestinal order requiring surgical intervention, no significant difference was detected between groups (88). In the treatment of POI, lidocaine, 0.05 mg/kg BW, was the most common first choice, using a continuous infusion with or without a 1.3 mg/kg BW loading dose (64). However, the exact mechanism of lidocaine’s action is still unknown and further research is required to evaluate its efficacy.

Conclusion

The complex physiology of equine gastrointestinal motility has been discussed. The horse always has MMC’s, regardless of whether fed or fasted, in contrast to other species where a clear differentiation in myoelectric activity exists. Despite the extensive research that has been done to measure equine transit of intraluminal contents, it does not always correlate with myoelectric and mechanical activity. Consequently, combining all 3 methods seems to provide the most accurate way to evaluate motility.

Regulation of intestinal motility depends on complex networking between sympathetic, parasympathetic, and enteric nervous system. Recently, a lot of research has been conducted on the neural regulation of equine motility, especially with a view to understanding the role of the enteric nervous system. Despite these efforts, much is still extrapolated from what is known for humans. Further scientific investigation of the neural regulation of equine motility is required.

Shock; electrolyte imbalances; hypoalbuminemia; peritonitis; endotoxemia; and distension, ischemia, or inflammation of the intestinal tract have all been implicated as contributing to the pathophysiology of ileus in the horse. Treatment of ileus should consist first of supportive therapy, like IV fluids, anti-inflammatory drugs, etc, to eliminate as many ileus-contributing factors as possible, before even considering the use of prokinetic drugs.

Among the different prokinetic drugs available for use in horses, bethanechol was shown to promote motility in both small and large intestine; but, due to loss of gastroduodenal coordination, it appears to be safer to use it for large intestinal problems only. Neostigmine appears to be most useful for problems of the large intestine, especially for large colon problems. Erythromycin lactobionate seems to be effective in promoting motility in both small and large intestine, at least in healthy horses, but clinically it is used more often for large intestinal problems. Metoclopramide, used as a continuous infusion, seems most promising for small intestinal problems, but the extrapyramidal side effects have to be considered. Cisapride showed good results for promoting gastric emptying and small intestinal motility, but it is not sold anymore in Canada due to potential cardiac side effects in humans. Lidocaine, as a continuous infusion, is also used most commonly for small intestinal problems, but not enough is known about its efficacy. CVJ