Simvastatin linked to protection against endothelial dysfunction in diabetic rats

Almost two years ago, the diabetes arm of the Heart Protection Study, the largest-ever study using a cholesterol-lowering medication, found that diabetics who took a daily dose of the statin drug simvastatin over five years reduced the risk of a first nonlethal heart attack by 37 percent and risk of a first nonfatal or fatal stroke by 24 percent, regardless of their cholesterol or glucose levels.

That is significant, since people with diabetes are two to four times more likely than others to have a coronary event even though their low-density lipid (LDL) cholesterol levels are similar to those in the general population.

Since most patients with diabetes die from some vascular complication, Medical College of Georgia researchers set out to determine the effects of simvastatin on endothelial cell dysfunction, an early pivotal event in atherogenesis and a major cause of the microvascular complications in diabetics. The researchers found that in addition to lowering cholesterol levels, simvastatin also appeared to prevent or reverse vascular injury by vasoprotective means. In a well-established rat model of diabetes, simvastatin protected against the development of diabetes-induced endothelial cell dysfunction in vessels of the heart, kidney, and eye.

Dr. Guochuan Ma, a postdoctoral fellow in the laboratory of Dr. Robert W. Caldwell, presented the promising results on April 2 at Experimental Biology 2005, in San Diego, at the scientific sessions of the American Society for Pharmacology and Experimental Therapeutics.

Endothelial cells make up the inner lining of blood vessels. The stimulation of intact endothelial cells by neurotransmitters, hormones and other substances causes release of a substance that induces relaxation of the underlying vascular smooth muscle. Endothelial dysfunction is characterized by an imbalance between these vasodilators and vasoconstrictors and appears early in diabetes.

The researchers induced diabetes in rats, then treated half of the diabetic rats with simvastatin. After four weeks the untreated rats had high levels of cholesterol and various indicators of endothelial dysfunction in the vessels of the heart, eye, and kidney. The rats that received 5 mg of simvastatin daily showed no or little such damage. Their plasma levels were normal, compared to a 67 percent rise of total cholesterol and 7.5 fold increase of triglycerides in the untreated rats. Unlike the untreated rats, treated rats had no elevation of nitrotyrosine in the retina or lipid peroxidation in the heart and retina. Relaxation of the aorta was normal, as was vascular permeability in all tissues, whereas the untreated diabetic rats had elevations of 2 to 13 times.

Dr. Ma concludes, "The data indicate that simvastatin protects against diabetes induced dysfunction," and Dr. Caldwell says, "The usefulness of statins in the treatment of diabetic patients is being realized."


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