The Harry M. Zweig Memorial Fund for Equine Research

Are ERG K+ Channels in Equine GI Smooth Muscle
Molecular Targets for Prokinetic Drugs?

Dr. Robert F. Gilmour and Dr. J. Brett Woodie

The main functions of the gastrointestinal (GI) tract are digestion and absorption of nutrients. Coordinated movement of the intestinal tract is necessary to perform these functions in all species, and critical in the horse. This coordinated movement, called intestinal motility, is an intrinsic function of the smooth muscle in the bowel wall that is subject to regulation by the nervous system.

Advances in anesthetic and surgical techniques have allowed horses exhibiting signs of intestinal distress or colic to have severe, potentially fatal bowel lesions corrected on the operating table. Unfortunately, post-operative complications are still a tremendous risk in these patients. It has been estimated that as many as 40% of equine deaths following abdominal surgery result from post-operative ileus, the loss of adequate intestinal motility.

Pharmaceutical companies are not committed to developing drugs to treat post-operative ileus or other intestinal problems in horses, because the size of the potential market is too small to offset research and development costs in a timely manner. As a result, veterinarians must decide which drugs designed to increase intestinal motility in the human population are likely to be both safe and effective in horses. This challenge is tremendous. The dietary requirements and GI anatomy of horses are vastly different from those of humans. Furthermore, drugs that increase intestinal motility have been shown to work via different mechanisms of action in different regions of the intestinal tract and different species. Finally, almost nothing is known about which drug receptors are present in the equine gut. Therefore, even when we know how a drug increases coordinated motility in guinea pig small intestine and human large intestine, we are unlikely to know if any of the receptors for the drug (drug targets) are present in the equine bowel.

Two drugs that have been shown to be effective treatments for post-operative ileus in horses are not currently available to veterinarians in the United States. The human-label prokinetic agent cisapride was used successfully to treat ileus in horses before it was withdrawn from the market as the result of an unacceptable incidence of cardiac toxicity in human patients. Domperidone (Motilium) has been marketed worldwide since 1978 and used successfully to treat post-operative ileus in horses, although it is still under investigation in the U.S. Recently, domperidone was also reported to have significant cardiotoxic potential.

The cardiac toxicity of cisapride and domperidone has been associated with antagonism of one class of ion channels that allow potassium to exit cardiac muscle cells. These channels are known as ERG channels. Recently, we have shown that similar potassium channels are expressed in the equine intestine, and that drugs that specifically block the cardiac channels increase coordinated contraction in isolated pieces of horse intestine. On this basis, we hypothesize that these ERG channels may actually be an important mechanism of action for the therapeutic effects of cisapride and domperidone. If this is the case, ongoing efforts to find drugs that prevent or cure post-operative ileus without blocking ERG channels will be unsuccessful, and new drug discovery paradigms designed to selectively target the potassium channels in equine GI smooth muscle over those in heart will be necessary.

To test our working hypothesis, we will use electrophysiological techniques to study the interactions of cisapride and domperidone with ion channels in equine GI smooth muscle. We will also perform a series of experiments designed to rule in and rule out other potential mechanisms of drug action. If our data suggest that the ERG potassium channels in equine gut are an important drug target, we will compare their properties to those of the ERG potassium channels in heart, in order to assess the potential for development of tissue-specific ERG antagonists. Alternatively, we may identify other important receptors used by the drugs that combat post-operative ileus. In either case, the information gained will help clinicians make rational choices about treatment of post-operative ileus with existing human-label drugs and drugs currently under development for use in humans.