January 9, 2012
Experimental ‘Couch Potato Pill’ May Also Prevent Heat Stroke
According to a new study in the journal Nature Medicine, an experimental treatment known as the 'couch potato pill' may also help to prevent heatstroke in people genetically predisposed to it.
The pill first received its name due its ability to mimic the effects of exercise in inactive laboratory mice, eliciting much excitement in the medical community that it might eventually prove useful in activity-disinclined human patients as well.
Dr. Robert Dirkson, the study's chief author and professor of pharmacology and physiology at the University of Rochester Medical Center, noted that such a medication could eventually have some very practical medicinal uses as a prophylactic.
"There is a great need for the training staff of athletic teams, physicians in emergency rooms in places like Phoenix, and soldiers serving in the deserts of the Middle East to have a drug available to give to individuals during a heat-stroke event," explained Dirksen.
"Our study takes an important first step towards developing a new drug therapy that may be part of the standard treatment regimen for heat stroke in the future."
Together with his long-time colleague professor Susan Hamilton of Baylor College of Medicine, Dirksen studied the effects of the drug on mice with a mutation in the RYR1 gene that is associated with malignant hyperthermia.
Mutations in the RYR1 gene respond to heat by causing excessive quantities of calcium to leak out of their cellular storage centers, triggering uncontrolled muscle contractions.
These involuntary contractions in skeletal muscle brought on by the congenital disorder lead to a rapid rise in body temperature. If they persist, the contractions eventually cause the muscle cells to rupture, releasing high amounts of potassium and various proteins into the blood stream. Elevated potassium levels are extremely toxic, typically leading to cardiac arrhythmias and death if not quickly treated.
According to the results of Dirksen and Hamilton's study, the administration of AICAR to affected mice appeared to protect them from such contractions, even when placed under additional heat stress.
Unfortunately, the study indicated that the drug was not successful in treating anesthetic-induced malignant hypothermia which, as the name indicates, is typically the result of anesthetic drugs rather than just heat exposure and genetic predisposition.
The researchers explained that AICAR typically functions by activating an enzyme known as AMPK, the body's so-called metabolic "master switch." One of AMPK's many physiological effects is to regulate muscle activity, yet Dirksen's team found that the drug's ability to protect mice from heat stroke was a result of its direct influence on the protein product of the RYR1 gene rather than on the enzyme master switch. The study indicated that AICAR causes a reduction in calcium leakage from RYR1, thus reducing heat-induced contractions, muscle damage, and death.
"AICAR stops the feed forward cycle that triggers these sustained muscle contractions," explained Hamilton. "We have shown that it acts directly on the ryanodine receptor [RYR1] to decrease the calcium leak. It also protects intracellular calcium stores from depletion and this contributes to the ability of this compound to slow muscle fatigue."
Although people with a genetic predisposition to heat stroke can generally avoid danger by simply avoiding physical activity in extreme heat, many either do not know they suffer from the condition or disregard the advice of medical experts.
"We were attempting to identify an intervention, something that could be used prophylactically to protect these sensitive individuals without significant side effects," said Dr. Hamilton.
While much lab work is still needed before the drug can be considered for therapeutic uses in humans, the team expressed optimism, noting that the work they had already done on mice was very encouraging.
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