GI motility disorders (Proceedings)
Mechanisms of gastrointestinal smooth muscle contraction have been a longstanding area of research interest. Our laboratory has been particularly interested in the role of myosin light chain phosphorylation in the regulation of contraction.
Mechanisms of gastrointestinal smooth muscle contraction have been a longstanding area of research interest. Our laboratory has been particularly interested in the role of myosin light chain phosphorylation in the regulation of contraction. Those studies have revealed two important findings: 1) Myosin phosphorylation is a key regulatory pathway in gastrointestinal smooth muscle contraction, but steady-state crossbridge cycling rates cannot be predicted by myosin light chain phosphorylation alone. This finding challenged the prevailing four-state kinetic model of smooth muscle contraction, and suggested that there must be additional regulatory mechanisms involved in smooth muscle. 2) Length-dependent activation of gastrointestinal smooth muscle is explained, at least in part, by length-dependent calcium activation and myosin light chain phosphorylation.
Gastrointestinal Motility Disorders
Canine Idiopathic Megaesophagus
Etiology - Most cases of adult-onset megaesophagus have no known etiology and are referred to as acquired idiopathic megaesophagus. The syndrome occurs spontaneously in adult dogs between 7 to 15 years of age without sex or breed predilection. The disorder has been compared erroneously to esophageal achalasia in humans. Achalasia is a failure of relaxation of the lower esophageal sphincter and ineffective peristalsis of the esophageal body. A similar disorder has never been rigorously documented in the dog. Several important differences between idiopathic megaesophagus in the dog and achalasia in humans have been documented. Although the etiology(ies) has not been identified, some studies have suggested a defect in the afferent neural response to esophageal distension similar to what has been reported in congenital megaesophagus.
Clinical Examination - Routine hematology, serum biochemistry, and urinalysis should be performed in all cases to investigate possible secondary causes of megaesophagus (e.g. hypoadrenocorticism). Survey radiographs will be diagnostic for most cases of megaesophagus. Contrast radiographs may be necessary in some cases to confirm the diagnosis, evaluate motility, and exclude foreign bodies or obstruction as the cause of the megaesophagus. Endoscopy will confirm the diagnosis and may further reveal esophagitis, a frequent finding in canine idiopathic megaesophagus. If acquired secondary megaesophagus is suspected, additional diagnostic tests should be considered, for example: serology for nicotinic acetylcholine receptor antibody, ACTH stimulation, serology for antinuclear antibody, serum creatine phosphokinase activity, electromyography and nerve conduction velocity, and muscle and nerve biopsy. Additional medical investigation will be dependent upon the individual case presentation. Hypothyroidism has been cited as an important cause of idiopathic megaesophagus in the dog, although risk factor analysis has not revealed a clear association. Thyroid function testing (e.g., TSH assay, TSH stimulation, free and total thyroid hormones) should be performed in individual suspicious cases.
Treatment - Animals with secondary acquired megaesophagus should be appropriately differentiated from other esophageal disorders and treated. Dogs affected with myasthenia gravis should be treated with pyridostigmine (1.0-3.0 mg/kg PO BID) and/or corticosteroids (prednisone 1.0-2.0 mg/kg PO or SQ BID), dogs affected with hypothyroidism should be treated with levothyroxine (22 µg/kg PO BID), and dogs affected with polymyositis should be treated with prednisone (1.0-2.0 mg/kg PO BID). If secondary disease can be excluded, therapy for the congenital or acquired idiopathic megaesophagus patient should be directed at nutritional management and treatment of aspiration pneumonia. Affected animals should be fed a high-calorie diet, in small frequent feedings, from an elevated or upright position to take advantage of gravity drainage through a non-peristaltic esophagus. Dietary consistency should be formulated to produce the fewest clinical signs. Some animals handle liquid diets quite well, while others do better with solid meals. Animals that cannot maintain adequate nutritional balance with oral intake should be fed by temporary or permanent tube gastrostomy. Gastrostomy tubes can be placed surgically or percutaneously with endoscopic guidance. Smooth muscle prokinetic (e.g., metoclopramide or cisapride) therapy has been advocated for stimulating esophageal peristalsis in affected animals, however metoclopramide and cisapride will not likely have much of an effect on the striated muscle of the canine esophageal body. Bethanechol has been shown to stimulate esophageal propagating contractions in some affected dogs and is therefore a more appropriate prokinetic agent for the therapy of this disorder. Because of the high incidence of esophagitis in canine idiopathic megaesophagus, affected animals should also be medicated with oral sucralfate suspensions (1 g q8h for large dogs 0.5 g q 8h for smaller dogs 0.25 to 0.5 g q8h to q12h for cats).
Colonic Motility Disorders
History - Constipation, obstipation, and megacolon may be observed in cats of any age, sex, or breed, however, most cases are observed in middle aged (mean = 5.8 years), male cats (70% male, 30% female) of Domestic Shorthair (46%), Domestic Longhair (15%), or Siamese (12%) breeding.
Physical Exam - Colonic impaction is a consistent physical examination finding in affected cats. Other findings will depend upon the severity and pathogenesis of constipation. Dehydration, weight loss, debilitation, abdominal pain, and mild to moderate mesenteric lymphadenopathy may be observed in cats with severe idiopathic megacolon. Colonic impaction may be so severe in such cases as to render it difficult to differentiate impaction from colonic, mesenteric, or other abdominal neoplasia. Cats with constipation due to dysautonomia may have other signs of autonomic nervous system failure, such as urinary and fecal incontinence, regurgitation due to megaesophagus, mydriasis, decreased lacrimation, prolapse of the nictitating membrane, and bradycardia. Digital rectal examination should be carefully performed with sedation or anesthesia especially in those cats with recurring bouts of constipation. Pelvic fracture malunion may be detected on rectal examination in cats with pelvic trauma. Rectal examination might also identify other unusual causes of constipation, such as foreign bodies, rectal diverticula, stricture, inflammation, or neoplasia.
Differential Diagnoses - Several authors have emphasized the importance of considering an extensive list of differential diagnoses (e.g. neuromuscular, mechanical, inflammatory, metabolic/endocrine, pharmacologic, environmental, and behavioral causes) for the obstipated cat. A review of published cases, however, suggests that 96% of cases of obstipation are accounted for by idiopathic megacolon (62%), pelvic canal stenosis (23%), nerve injury (6%), or Manx sacral spinal cord deformity (5%).
Pathogenesis - The pathogenesis of idiopathic megacolon has been historically attributed to a primary neurogenic or degenerative neuromuscular disorder. While it seems clear that a small number of cases (11%) result from neurologic disease, the vast majority (>90%) of cases have no evidence of neurologic disease. Some of the idiopathic cases may instead involve disturbances of colonic smooth muscle as suggested by several studies. In vitro isometric stress measurments were performed on colonic smooth muscle segments obtained from cats suffering from idiopathic dilated megacolon. These studies suggested that the disorder of feline idiopathic megacolon is a generalized dysfunction of colonic smooth muscle, and that treatments aimed at stimulating colonic smooth muscle contraction might improve colonic motility.
Therapeutic Plan - The specific therapeutic plan will depend upon the severity of constipation and the underlying cause. Medical therapy may not be necessary with first episodes of constipation. First episodes are often transient and resolve without therapy. Affected animals should always be re-hydrated if dehydration has contributed to the onset of clinical signs. Mild to moderate or recurrent episodes of constipation usually require some medical intervention. These cases may be managed, often on an outpatient basis, with dietary modification, water enemas, oral or suppository laxatives, and/or colonic prokinetic agents. Severe cases of constipation usually require brief periods of hospitalization to correct metabolic abnormalities and to evacuate impacted feces using water enemas, manual extraction of retained feces, or both. Followup therapy in such cases is directed at correcting predisposing factors and preventing recurrence. Subtotal colectomy will become necessary in cats suffering from obstipation or idiopathic dilated megacolon.
Gastrointestinal Prokinetic Agents
Previous studies of feline colonic smooth muscle function have suggested that stimulation of colonic smooth muscle contraction might improve colonic motility in cats affected with idiopathic dilated megacolon. Unfortunately, many of the currently available gastrointestinal prokinetic agents have not proved useful in the therapy of feline constipation either because of significant side effects (e.g., bethanechol) or because the prokinetic effect is limited to the proximal gastrointestinal tract (e.g., metoclopramide, domperidone, erythromycin). The 5-HT4 serotonergic agonists (e.g., cisapride, prucalopride, tegaserod, mosapride) appear to have the advantage of stimulating motility from the gastroesophageal sphincter to the descending colon with relatively few side effects.
Cisapride increases gastroesophageal sphincter pressure, promotes gastric emptying, and enhances small intestinal and colonic propulsive motility. Cisapride enhances colonic propulsive motility through activation of colonic neuronal or smooth muscle 5-HT receptors in a number of animal species. In vitro studies have shown that cisapride stimulates feline colonic smooth muscle contraction, although it has not yet been conclusively shown that cisapride stimulates feline colonic propulsive motility in vivo. A large body of anecdotal experience suggests that cisapride is effective in stimulating colonic propulsive motility in cats affected with mild to moderate idiopathic constipation; cats with long-standing obstipation and megacolon are not likely to show much improvement with cisapride therapy. Cisapride was widely used in the management of feline colonic motility disorders throughout most of the 1990's, until it was withdrawn from the American, Canadian and certain Western European countries in July of 2000 following reports of untoward cardiac side effects in human patients. Cisapride causes QT interval prolongation and slowing of cardiac repolarization via blockade of the rapid component of the delayed rectifier potassium channel (IKr). This effect may result in a fatal ventricular arrhythmia referred to as torsades de pointes. Similar effects have been characterized in canine cardiac Purkinje fibers, but in vivo effects have not yet been reported in dogs or cats. The withdrawal of cisapride has created a clear need for new G.I. prokinetic agents although cisapride continues to be available from compounding pharmacies throughout the United States and other countries.
Tegaserod is a potent partial non-benzamide agonist at 5-HT4 receptors and a weak agonist at 5-HT1D receptors. Tegaserod has definite prokinetic effects in the canine colon, but its effects in the feline colon are not known. Intravenous doses of tegaserod (0.03-0.3 mg/kg) accelerate colonic transit in dogs during the first hour after intravenous administration. Tegaserod at doses of 3-6 mg/kg PO has also been shown to normalize intestinal transit in opioid-induced bowel dysfunction in dogs, suggesting it could prove useful in other disorders of intestinal ileus or pseudo-obstruction. Eventually, tegaserod was also shown to prolong the QT interval and delay cardiac repolarization as had been reported with cisapride. Tegaserod was marketed under the tradename of Zelnorm in the United States in September 2002 and subsequently removed from American and other markets in 2006.
Prucalopride is a potent 5-HT4 receptor agonist that stimulates giant migrating contractions (GMC's) and defecation in the dog and cat. Prucalopride also appears to stimulate gastric emptying in the dog. In lidamidine-induced delayed gastric emptying in dogs, prucalopride (0.01-0.16 mg/kg) dose-dependently accelerates gastric emptying of dextrose solutions. Prucalopride has not yet been marketed in the United States or elsewhere.
Misoprostol is a prostaglandin E1 analogue that reduces the incidence of nonsteroidal anti-inflammatory drug-induced gastric injury. The main side effects of misoprostol therapy are abdominal discomfort, cramping, and diarrhea. Studies in dogs suggest that prostaglandins may initiate a giant migrating complex pattern and increase colonic propulsive activity. In vitro studies of misoprostol show that it stimulates feline and canine colonic smooth muscle contraction. Given its limited toxicity, misoprostol may be useful in cats (and dogs) with severe refractory constipation.
Ranitidine and nizatidine, classic histamine H2 receptor antagonists, may also stimulate canine and feline colonic motility. These drugs stimulate contraction apparently through inhibition of tissue acetylcholinesterase and accumulation of acetylcholine at the motor endplate. It's not yet clear how effective these drugs are in vivo, although both drugs stimulate feline colonic smooth muscle contraction in vitro. Cimetidine and famotidine, members of the same classification of drug, are without this effect.
References available upon request