Enzyme inhibitor may provide strategy to treat some GI disorders, Jefferson researchers find
(Philadelphia) -- Drugs that block the activity of an enzyme might hold a key to treating chronic and severe disorders such as certain forms of constipation, hemorrhoids, anal fissures, Hirschsprung's disease and other similar gastrointestinal problems.
Researchers led by Satish Rattan, DVM, professor of medicine in the Division of Gastroenterology and Hepatology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, have shown that the enzyme Rho kinase (ROK) plays an important role in maintaining the tone of the internal anal sphincter (IAS), which is crucial for normal bowel functioning. When the IAS tone is too high – or "hypertensive" – the result can be constipation, anal fissures and hemorrhoids. Blocking ROK's activity, they found, could be a viable treatment.
"I would speculate that Rho kinase is not working properly in certain forms of rectum-anal incontinence," Dr. Rattan says. "In the hypertensive sphincter, which is associated with numerous gastrointestinal disorders, Rho kinase is probably working overtime." As a result, he says, "Rho kinase inhibitors would have a role in therapy." Dr. Rattan and his colleagues report their findings in July in the journal Gastroenterology.
The IAS is important for continence and is controlled autonomically (as is all smooth muscle), as opposed to the external sphincter, which as skeletal muscle is voluntary. As a result, IAS dysfunction cannot be easily controlled, and treating a hypertensive IAS can be difficult.
"Surgeons have attempted incisions in the IAS with variable and limited outcomes," says Dr. Rattan. "Botox A has been tried, as has nitroglycerin and calcium channel blockers. All have potential downsides."
Working on a rat model, the researchers examined the effects of a ROK inhibitor, Y 27632, on the hypertensive IAS. They performed a series of tests with varying doses of Y 27632, finding that the inhibitor "causes a dose-dependent fall in the intraluminal pressures in the high pressure zone of the IAS tone," Dr. Rattan explains. Similarly, the ROK inhibitor caused a fall in the IAS tone in in vitro studies.
They also showed that Rho kinase was present in high levels in smooth muscle cells of the IAS. The studies demonstrated that Rho kinase inhibitors are potent smooth muscle inhibitors, causing direct smooth muscle relaxation.
"The next step in the work," says Dr. Rattan, "would be to try these kinds of tests in the hypotensive state of the IAS in animal models first, and then hopefully in humans with some of these conditions."
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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