The vessel of life  pg. 2

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

Jeff Reese, M.D., (left) and Robert
Cotton, M.D.
Photo by Joe Howell
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.

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