Nitric Oxide Levels Help Cardiac Drugs Work Better

Circulating nitric oxide (NO) can help cardiac drugs improve heart function, but deficiencies could exacerbate heart failure (HF), according to a new study.

Researchers at Case Western Reserve University (CWRU; Cleveland, OH, USA), Duke University (Durham NC, USA), and other institutions conducted a study in mice that focused on one of the most common drug targets in modern medicine, the G protein-coupled receptor (GPCR). When drugs like beta-blockers attach to GPCRs, they influence protein pathways inside the cells. One pathway activates therapeutic G proteins, while a second pathway activates arrestins that can lead to side effects. NO is known to have an established role in receiving signals from GPCRs.

The researchers therefore genetically engineered mice to lack the ability to attach NO to one half of the pathway, the arrestin proteins that can trigger side effects; they found that without NO signaling, the mice could not increase heart rate or pump function. The results suggest HF severity could vary based on NO levels in the body. Low NO levels could cause GPCRs to primarily activate the β-arrestin side of the signaling pathways, excluding the other half that helps the heart respond to stressors.

The researchers confirmed their findings in human tissue samples, collected from hearts involved in transplants. In nearly two-thirds of failing heart samples, the researchers found that NO determined the signaling balance to the β-arrestin pathway. The researchers suggest that with hundreds of GPCRs in the body, managing NO correctly could help existing drugs of all types work with fewer side effects. The study was published on May 3, 2018, in Molecular Cell.

“We have identified a main function of nitric oxide in cellular systems. It likely regulates GPCR signaling across virtually all cell types and tissues. This may bear directly on numerous diseases, as well as the predicted response to therapeutic agents,” said senior author Professor Jonathan Stamler, MD, of CWRU. “Drugs and hormones inevitably regulate both pathways, but if one could shut down the pathway producing side effects, drugs would work better. It is able to use nitric oxide to shut down arrestin-based pathways causing side effects.”

NO has been identified as an important molecule with versatile roles in human physiology, including selective pulmonary vasodilation, bronchodilator, and pulmonary surfactant activities to improve ventilation-perfusion mismatch and hence oxygenation. The clinical effects of NO gas that have been reported include cardio-pulmonary vasodilation, reduction of right heart load, reduction of ischemia, reduction of hypoxemia, inhibition of platelet aggregation, and anti-inflammatory, fungicidal, virocidal, and bactericidal effects, among others.

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