It’s the “vessel of life,” according to Jeff Reese, M.D., associate professor of Pediatrics at Vanderbilt University Medical Center.
In the fetus, the ductus arteriosus (DA) is a temporary vascular shunt that routes blood from the pulmonary artery to the aorta, bypassing the uninflated lungs. After the birth of a healthy baby, its work is done. It constricts within 24-36 hours after delivery, and “remodels” into a fibrous ligament during the next several weeks.
For Reese the bottom line is simple: “You have to have it as a fetus. It should close as a newborn.”
But in up to 40 percent of premature babies, the DA doesn’t close properly, resulting in patent ductus arteriosus (PDA), one of the most common congenital heart diseases. The negative effects of PDA are twofold: it conveys excess blood through the open ductus causing lung injury, and it diverts normal blood flow away from the peripheral circulation, causing ischemia, which can damage the body’s organs from lack of oxygen and nutrients.
About 25,000 babies undergo surgery to close the DA every year in the United States, but because of the risks involved it is employed only as a last resort. A drug called indomethacin can also close the shunt, but it also can cause ischemia by constricting other blood vessels.
“We’ve learned over the 30 years that we’ve used indomethacin what the right dose is, not to give it too fast and how many days it needs to be given to get the ductus to constrict but not hurt other vessels, and even with that knowledge, there is still a narrow therapeutic window where children have organ injury because of it,” Reese says.
In an effort to discover a safer and more successful drug therapy, Reese is researching what makes the DA tick – what keeps it open in the fetus, what makes it close in the newborn, and what makes it permanently remodel into a ligament.
Researchers already know that the DA is particularly reactive to oxygen – it closes when the newborn starts to breathe. But too much oxygen can be toxic.
“We’d like to know the underlying pathways that makes the ductus so much more sensitive to oxygen than other blood vessels, and instead of giving oxygen to the vessel, we’d like to be able to activate the downstream mediator – a calcium channel or potassium channel or some other regulatory enzyme that is used by the oxygen sensor – and trigger it without giving too much oxygen,” Reese explains.
The first breakthrough in Reese’s lab was the discovery of a mouse model of PDA in prostaglandin-deficient mice in 2000. Indomethacin works by blocking prostaglandins, signaling molecules involved in inflammation. A follow-up study using prolonged exposure to prostaglandin inhibitors showed that a specific window of sensitivity to prostaglandin effects exists during DA development.
In order to better study the mechanisms of DA reactivity and directly observe its response to various compounds or a change in study conditions, Reese uses a technique called cannulated microvessel myography.
First, he dissects the mouse DA and mounts it in a custom-made perfusion chamber where the DA is pressurized to levels that match fetal arterial blood pressure. Then compounds are added under various oxygen conditions to determine whether they cause the vessel to constrict or dilate. A videomicroscope and specialized software automatically record and measure the change in diameter of the vessel as different compounds are added.
These dynamic studies have already yielded results that could change the way neonatologists practice.
An ulcer connection
Robert Cotton, M.D., professor of Pediatrics at Vanderbilt and former director of the Division of Neonatology, was investigating the use of cimetidine (an ulcer drug that blocks the histamine H2 receptor involved in acid secretion) to prevent oxygen-induced lung injury.
In a clinical study published in 2006, Cotton and his colleagues reported that cimetidine did not reduce the incidence of lung injury. There was, however, an increased incidence of PDA in babies who received the drug. That suggested that the H2 receptor may be important in closing the ductus arteriosus.
Cotton was aware of Reese’s lab work, and asked him to test cimetidine in the mouse models. They found that giving the drug to an isolated ductus causes it to relax and open wider. In addition, vessels that were bathed in cimetidine did not undergo the normal contractile response to oxygen, similar to what was observed in the clinical trial.
More importantly, the researchers determined that other types of H2 blockers that – unlike cimetidine — don’t block metabolic enzymes did not relax the ductus or prevent oxygen-induced constriction.
“It’s clear that the use of cimetidine in premature babies puts them at bigger risk for having a PDA because they’re on a drug that could cause relaxation of the ductus,” Cotton says. “So now we have a reason to be selective in which drugs we choose to use in preemies, and we have insight into why premature babies (given) certain H2 blockers may have a PDA.
“There are unintended consequences of many drugs,” he continues. “We have a system now where we can go to the perfusion bath and say ‘Does this drug that we currently use unexpectedly cause relaxation of the ductus?’”
Reese thinks that studies like this will be crucial to understanding the underlying mechanisms of PDA.
“We need to be conscientious of other drugs that cause the ductus to relax and be better physicians at the bedside by not inadvertently giving a patient a drug that will cause it to partially relax,” he says. “If we could avoid all of the relaxors and give a specific therapy to the vessel to get it to close, I think we’ll be much better off.”
Though the exact therapies that will cause DA constriction are still unclear, Reese has a few leads.
“Our hunch is that there will be a combination of drugs that do a good job at getting it to close,” he says. “Indomethacin or its sister compounds will be one of those, but we need to have other drugs in our arsenal to fully complete the job. We need new pathways to work on.”