Rho kinase inhibitors cause a fall in the internal anal sphincter tone

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, at 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, which is crucial for normal bowel functioning. When the internal anal sphincter 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, " 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." Rattan and his colleagues report their findings in the journal Gastroenterology.

The internal anal sphincter is important for continence and is controlled autonomically, as opposed to the external sphincter, which as skeletal muscle is voluntary. As a result, internal anal sphincter dysfunction cannot be easily controlled, and treating a hypertensive internal anal sphincter can be difficult.

" Surgeons have attempted incisions in the internal anal sphincter with variable and limited outcomes," says 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 internal anal sphincter. 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 internal anal sphincter tone," Rattan explains. Similarly, the ROK inhibitor caused a fall in the internal anal sphincter tone in in vitro studies.

They also showed that Rho kinase was present in high levels in smooth muscle cells of the internal anal sphincter. The studies demonstrated that Rho kinase inhibitors are potent smooth muscle inhibitors, causing direct smooth muscle relaxation.

Source: Thomas Jefferson University, 2006


Link: Xapedia - Medical Encyclopedia