The net effect can be too little nitric oxide inside blood vessel walls to help them relax and keep white blood cells and platelets from sticking to them.

"It's taking L-arginine away from the nitric oxide synthase so it can accelerate wound healing but the lack of substrate for nitric oxide synthase leads to vascular constriction and occlusion which causes further tissue damage, " Dr. Ruth Caldwell says. The researchers, who also are studying this process in a model of diabetic retinopathy, want to fully delineate the complex scenario. They already know high levels of the signaling molecule reactive oxygen species is another factor. As with arginase, some reactive oxygen species formation is a good thing but too much causes blood vessel damage.

"Our studies demonstrate that if we inhibit arginase, we also reduce the reactive oxygen species level and vice versa," Dr. Zhang says. "It appears that arginase and nitric oxide synthase influence each other in a positive feedback loop."

Rather than drugs that generally suppress arginase, the researchers want to find new drugs that can restore healthy levels of arginase. "You need arginase. If you don't have it, you are in big trouble," says Dr. William Caldwell. "We want to delineate the events that cause elevation and limit the elevation to prevent the resulting pathology."

The only U.S. Food and Drug Administration approved therapy to intervene in diabetic retinopathy is to use lasers to burn holes in the retina, which reduces the oxygen needs of the tissue by destroying some of it.

In related studies, Dr. William Caldwell, in conjunction with Dr. Maritza Romero, MCG assistant research scientist, has shown that in diabetes blood vessels throughout the body suffer from too much competition for L-arginine and that another amino acid, L-citrulline, as well as statin drugs used to treat cholesterol can prevent unhealthy elevation of arginase.

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