Loss of intestinal motility is the leading cause of equine deaths following abdominal surgery.
Effective Drug Therapy for Postoperative Ileus Remains Elusive
Loss of intestinal motility is the leading cause of equine deaths following abdominal surgery.
When horses show signs of intestinal distress or colic, they may have potentially fatal bowel lesions. Thanks to modern advances in anesthetic and surgical techniques, these lesions usually can be corrected. Postoperative complications, however, put horses at high risk: the cause of as many as 90 percent of equine deaths after abdominal surgery is postoperative ileus, the loss of adequate intestinal motility.
Intestinal motility is a series of coordinated movements of the smooth muscle in the bowel wall that are regulated by nerves and muscles in the intestinal tract. Intestinal motility is critical for proper digestion—to get the digestive enzymes mixed into the food to break it down, to stir up the nutrients and push them to the intestinal wall where they are absorbed, and then to propel the contents of the intestines through the digestive tract.
Even though there is such a high risk of postoperative ileus, the development of drugs to treat the condition in horses is not a priority for pharmaceutical companies because the potential market is too small to warrant the high costs of research and development, explains Robert J. Gilmour, PhD, a professor of physiology.
"Thus, veterinarians may turn to drugs that increase intestinal motility in humans," Gilmour says, "but whether these medications are safe and effective for horses is uncertain because the dietary requirements and the GI anatomy of horses are vastly different. Furthermore, so-called prokinetic drugs that increase intestinal motility have been shown to work via different mechanisms of action in different regions of the intestinal tract and in different species."
To further confound the problem, researchers don't know whether the equine gut has the same drug receptors (drug targets) as other mammals. Thus, even if a drug works well in humans or guinea pigs, for example, there is no way of knowing at the present time if the drug is appropriate for horses.
With a new grant from the Harry M. Zweig Memorial Fund, Gilmour plans to learn more about two drugs that have been shown to be effective for postoperative ileus, even though neither one is currently available in the United States. One of them—cisapride—has been withdrawn from the market because of its high incidence of toxicity to the heart in humans. The other—domperidone (Motilium)—also carries some risk to hearts and is still under investigation in this country.
Gilmour seeks to understand the mechanisms by which these drugs increase intestinal motility. Preliminary studies by Gilmour and his colleagues suggest that the same mechanism that damages the heart could be exactly what is therapeutic for improving the coordinated contractions in the horse intestines.
"In other words, we know that these drugs are toxic to cardiac muscle because they block what are called ERG channels (a class of ion channels) and by doing so don't allow potassium to exit the muscle cells," Gilmour explains.
Gilmour, in collaboration with Drs. Lisa Freeman and James Lillich at Kansas State University, has recently shown that similar potassium channels are expressed in the equine intestine and drugs that specifically block the cardiac channels increase coordinated contraction in isolated pieces of horse intestine. As a result, Gilmour hypothesizes that blocking these ERG channels may be an important mechanism of cisapride and domperidone in enhancing the motility of the GI smooth muscle.
"If this is the case, ongoing efforts to find drugs that prevent or cure postoperative ileus without blocking ERG channels will be unsuccessful until new drug paradigms are designed that selectively target the potassium channels in the equine GI smooth muscle but not the smooth muscle in the heart," he says.
Along with assistant professor of large animal surgery J. Brett Woodie, Gilmour will study the interactions of cisapride and domperidone with ion channels in equine GI smooth muscle. They'll also perform a series of experiments to determine other potential mechanisms of these drugs. Depending on what he learns, Gilmour may compare the ERG potassium channels in the equine gut with those in the heart to see if a drug might target one without affecting the other. He also will seek to identify if there are other important receptors used by these two drugs that help relieve postoperative ileus.
"In either case, the information we gain will help veterinarians make rational choices about treating postoperative ileus with medications currently available for human use as well as drugs currently under development," Gilmour concludes.
