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Genetic Disorder May Hold Key to Heat Stroke Cure
Date:4/3/2008

Some antioxidants may protect people like athletes, soldiers from fatal temperature rise

THURSDAY, April 3 (HealthDay News) -- The key to curing heat stroke may have been found in a genetic disorder that causes people under general anesthesia to suffer a deadly rise in body temperature, according to a new report.

The findings, published in the April 4 issue of Cell, also suggest that certain antioxidants may help protect people genetically prone to heat stroke.

Excessive heat exposure has caused 8,000 deaths in the United States since 1979, more than hurricanes, tornadoes, floods and earthquakes combined, according to the U.S. Centers for Disease Control and Prevention. Ongoing U.S. military operations in desert environments overseas have piqued interest in heat stroke prevention and cure.

"Along with cardiac abnormalities, heat stroke is a major culprit in unexpected sudden deaths of otherwise fit, young athletes and soldiers," study co-author Robert T. Dirksen, an associate professor of pharmacology and physiology at the University of Rochester Medical Center, in New York, said in a prepared statement. "With a better knowledge of these mechanisms, we can begin to better diagnose and treat both disorders, and hopefully, save some lives."

Researchers at four universities and the U.S. Army linked the development of heat stroke and the genetic and protein defects that cause malignant hyperthermia (MH), an inherited condition that occurs in one in about 10,000 adult patients undergoing general anesthesia. During MH bouts, the acid content of a patient's blood and tissues becomes altered and heart rate increases, causing muscle rigidity and a rapid rise in body temperature that can result in kidney failure and potentially fatal heart arrhythmias.

MH reactions can be treated with the drug dantrolene, which causes muscles to relax, the researchers said.

The researchers genetically engineered mice with a known mutation seen in human MH disease. As expected, these mice died when exposed to anesthesia, but they also exhibited the same life-threatening symptoms when briefly exposed to heat stress at 105 degrees Fahrenheit.

This established a link between the mutation, located in a gene that codes for ryanodine receptor proteins, and heat stroke. Ryanodine receptors are channels for calcium to be released into the muscle cell to cause contraction. The mutated calcium channel, the researchers suggested, may allow too much calcium through in response to heat and cause extreme muscle contractions.

"It has long been debated as to whether some cases of heat stroke and exercise-induced muscle breakdown in humans are related to malignant hyperthermia as well," Henry Rosenberg, president of the Malignant Hyperthermia Society of the United States, said in a prepared statement. "This study defines a biochemical pathway that might very well clarify the relationship between anesthesia-induced malignant hyperthermia and heat stroke. This opens new avenues for the study of the not-uncommon problem of heat stroke and exercise-induced muscle breakdown and the risk for malignant hyperthermia."

The team's findings also noted increased calcium ion leakage from the mutated ryanodine receptors during heat stress. The leak contributed to the calcium channels becoming extremely heat sensitive and muscles contracting uncontrollably in response to anesthesia or heat, the researchers said.

The calcium leak also caused a profound increase in free radical production. Free radicals are molecules that can destroy sensitive cell components and hasten cell death. Free radicals are largely created as a side effect when structures within all human cells, the mitochondria, use oxygen to convert food into energy. Disease processes tend to create more free radicals than the body's naturally occurring antioxidants can handle.

The researchers found that including the antioxidant N-acetylcysteine (NAC) in the mice's water supply, though, greatly decreased their sensitivity to heat stress. NAC is being tested in clinical trials involving patients with cystic fibrosis, where disease creates free radicals that severely damage lung tissue.

"We found that destructive cycles of calcium leakage and excess free radical production damage mitochondria and contribute to the deterioration of muscle function in aged animals," Dirksen said. "In successfully constructing the first mouse model of human MH, we unwittingly generated the first animal model of heat stroke that will undoubtedly be tremendously useful in better understanding these disorders and in accelerating the design of safe and effective treatments for both conditions."

More information

The U.S. Centers for Disease Control and Prevention has more about protecting yourself from extreme heat.



-- Kevin McKeever



SOURCE: University of Rochester Medical Center, news release, April 3, 2008


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