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August 5, 2020

Nitric oxide reduces risk of stroke in aneurysm patients

By Ann Wang | October 21, 2009

Researchers working at the Hopkins School of Medicine have developed a novel treatment for a common, often fatal, condition that strikes down patients days after an aneurysm.

About 30 percent of patients who suffer from subarachnoid hemorrhage (SAH) - bleeding into the area between the brain and the beginning of the spinal cord - as a result of a ruptured aneurysm go on to develop vasospasm, where vessels contract and constrict. Four to fourteen days after hemorrhage, the blood vessels going to the brain become inflamed and dangerously constricted. The narrow vessels cut off the brain's supply of oxygen and put patients at a high risk for stroke. Vasospasm is the primary cause of death in patients who have suffered SAH.

A research team led by Rafael Tamargo of the Department of Neurosurgery has shown that nitric oxide, delivered to the brain in small polymers, greatly decreases the risk of vasospasm after SAH in a mouse model.

"One of the most difficult problems that we face is that we can fix an aneurysm that has ruptured. Then I saw one third of patients developed this problem of vasospasm, and we didn't have a way to treat it," Tamargo, who is a neurosurgeon and specializes in aneurysms, said. Nitric oxide, which has the chemical formula NO and is not to be confused with the more notorious nitrous oxide, or laughing gas, is a gas normally produced and used in the body as a rapidly-diffusing signaling molecule. For example, nitric oxide dilates blood vessels by signaling the surrounding smooth muscle to relax, and is used by the immune system to combat bacterial infections.

Tamargo's previous research found that the root cause of vasospasm is not narrowing blood vessels as once believed, but instead an inflammation of the brain. The spastic and constricting vessels are just one symptom of inflammation. "One of the things I've been doing is trying to find drugs that will both inhibit the inflammation and dilate the vessels," Tamargo said. "That's how we became interested in nitric oxide. It's a very good drug for both."

Nitric oxide reduces the risk of vasospasm in two ways. First, it dilates vessels around the brain, increasing blood flow. Second, it inhibits white blood cells, decreasing inflammation.

Tamargo's research team developed a method to introduce nitric oxide locally in order to minimize side effects. Nitric oxide is incorporated into small polymers which are delivered to the brain via a small opening where the skull meets the neck. Cerebrospinal fluid then carries the drug throughout the brain.

The team found that mice who suffered SAH and then were treated with the nitric oxide polymers had fewer constricted blood vessels, lower inflammation and higher activity overall than a control group that had undergone a sham operation.

However, the researchers were curious about another aspect of the disorder. 30 percent of patients develop vasospasm after SAH, and another 40 percent develop constricted blood vessels that do not progress to vasospasm. What made some people more susceptible than others? It turns out people with the haptoglobin2-2 genotype develop vasospasm with a much greater frequency.

Humans, unlike most other animals, have two types of a protein that helps recycle hemoglobin, called haptoglobin. When red blood cells die and release hemoglobin, haptoglobin binds the free hemoglobin and takes it to the liver for recycling. The two alleles are haptoglobin-1 and haptoglobin-2. The second form binds hemoglobin more weakly than the first.

After an aneurysm, many dead red blood cells at the site of the aneurysm must be recycled. If haptoglobin cannot keep up, the excess hemoglobin causes inflammation, leading to vasospasm. When mice that had two copies of the human haptoglobin-2 gene were treated with nitric oxide, they had more dilated vessels, less inflammation and more activity. These results showed that nitric oxide is a potent drug even in the worst cases.

There are many obstacles to overcome before nitric oxide delivery can be considered as a therapy for humans. Tamargo says drug companies have no interest in developing a drug that must be administered through an opening in the brain.

"I'm looking for drugs that we can give systemically without using the control released polymers," Tamango said. The researchers' ultimate goal is to use their results to treat human patients.

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