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Enzyme inhibitor may provide strategy to treat some GI disorders, Jefferson researchers find
July 19, 2006Drugs 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."
Thomas Jefferson University
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."
Thomas Jefferson University
Enzyme Inhibitor Current Events and Enzyme Inhibitor News RSSExperimental treatment halts hypoxic-ischemic brain injury in newborns
Inhibiting an enzyme in the brains of newborns suffering from oxygen and blood flow deprivation stops a type of brain damage that is a leading cause of cerebral palsy, mental retardation and death, according to researchers at Cincinnati Children's Hospital Medical Center.
Pitt team finds molecule that regulates heart size by using zebrafish screening model
Using zebrafish, researchers at the University of Pittsburgh have identified and described an enzyme inhibitor that allows them to increase the number of cardiac progenitor cells and therefore influence the size of the developing heart.
Novel enzyme inhibitor paves way for new cancer drug
Combining natural organic atoms with metal complexes, scientists at The Wistar Institute have developed a new type of enzyme inhibitor capable of blocking a biochemical pathway that plays a key role in cancer development.
Chronic kidney disease rises while most people with the condition remain unaware
A growing number of Americans have chronic kidney disease, but most remain unaware of it, hampering efforts to prevent irreversible kidney failure requiring dialysis or a transplant.
Enzyme inhibitor produces stable disease in patients with advanced solid cell cancers
Preliminary trials of a MEK enzyme inhibitor have shown that it is capable of producing long-lasting stable disease in patients with advanced solid cancers. Tests showed that the drug inhibited key targets in the patients' tumours, and now it is being tested in phase II clinical trials.
Scientists discover way to block growth of prostate cancer cells
Scientists have discovered for the first time a specific biochemical pathway by which the sex hormone, androgen, increases levels of harmful chemicals called reactive oxygen species (ROS) in the prostate gland that play a role in the development of prostate cancer.
Pest control research leads to pain control discovery
A newly discovered enzyme inhibitor, identified by researchers originally looking for biological pest controls, may lead to pain relief for sufferers of arthritis and other inflammatory diseases.
Polycystic kidney disease
The National Institutes of Health (NIH) and the PKD Foundation have launched two treatment trials for autosomal dominant polycystic kidney disease (ADPKD).
Defeating the 'superpests'
Scientists have developed a new technique that makes pesticides more effective by removing insects' ability to exhibit resistance.
Blood pressure treatment could cut risk of strokes and heart attacks
A new treatment strategy for hypertension can cut the risk of strokes by around 25 percent and coronary events by around 15 percent according to the preliminary results of a major international trial announced at the American College of Cardiology Late Breaking Clinical Trials II Meeting in Orlando today.
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