Electrical signals that travel through voltage-gated ion channels orchestrate the timing of heartbeat. In the search for therapies against an inherited form of abnormal heart rhythm caused by mutations in an ion channel-encoding gene, scientists at Columbia University found a cough med could guide the development of future drugs for more common arrhythmias.
The cough suppressant dextromethorphan, available over the counter, could activate a protein called sigma non-opioid receptor 1 (SIGMAR1) to shorten the prolonged heart QT intervals in mice with a potential life-threatening form of inherited arrhythmia called Timothy syndrome.
The drug also showed similar effects in heart muscle cells from patients with two common forms of long QT syndromes, type 1 and type 2, according to results published in the journal Nature Cardiovascular Research. The Columbia team therefore suggests that SIGMAR1 could be a potential target for designing drugs against inherited long QT syndrome.
In a previous study, some members of the Columbia team found that increased CDK5 activity is involved in the cardiac problems of Timothy syndrome. But developing CDK5-specific inhibitors can be challenging as it’s structurally similar to other CDK proteins.
After searching through past studies, the team found SIGMAR1 could be a promising target to inhibit CDK5. To test the theory, the researchers tested several drugs, including dextromethorphan, an FDA-approved SIGMAR1 agonist.
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Similar to a selective SIGMAR agonist, dextromethorphan restored the normal changes in voltage across the cell membrane of heart muscle cells known as cardiomyocytes from patients with Timothy syndrome. The drug normalized the flow of ion current without significantly altering the activity of normal cardiomyocytes, the team reported.
In a mouse model of Timothy syndrome, dextromethorphan significantly shortened the prolonged QT interval as shown on an ECG at both time points of evaluation. Protein analysis found that the expression of many important molecules involved in heart excitation and contraction and other functions was restored to a level comparable to that of control animals.
What’s more, while Timothy syndrome is caused by mutation in a gene encoding the calcium channel, the Columbia team found dextromethorphan showed similar effects in cardiomyocytes from patients with long QT syndrome 1 and 2, which are more common types of arrhythmias caused by mutations in the potassium channel.
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As heart rhythm problems are caused by abnormal electrical signals in cardiomyocytes, scientists have been probing the ion channels for potential solutions. In a recent study, a research team from Duke University designed a gene therapy based on bacterial genes encoding for sodium channels that are similar in humans. In computer models simulating conditions of irregular heartbeats, the therapy returned heart electrical activity back to healthy levels.
Dextromethorphan might not be the best SIGMAR1 agonist option even though it’s readily available on the market, the Columbia researchers said. That’s because the drug is quickly broken down inside the body and can cause nausea, and overdose of dextromethorphan could potentially lead to severe heart events. Nevertheless, dextromethorphan and the SIGMAR1 mechanism could serve as steppingstones for designing drugs for heart arrhythmias, they added.