By David N. Leff

A peculiar, non-functional pit or dimple graces the abdomen of every man, woman and child on earth. This bellybutton, or navel, recalls the fact that before being born, we spent many months connected to our pregnant mothers by a long, slender tube. This umbilical cord ran from the fetal veins and arteries to the placenta — a filling station for nutrients and oxygen-enriched blood.

Meanwhile, the fetal lungs, though fully formed long before birth, remained collapsed, cut off from their future action of swapping oxygen for carbon dioxide in the blood.

Bypassing those latent lungs, the fetal vein ran up the middle of the cord, wrapped round and round by two spiral fetal arteries.

Within the first 30 minutes after birth, the umbilical cord shuts down spontaneously, with a sudden contraction of its arterial smooth muscle layer. "This is a temperature-sensitive mechanism," observed pediatric cardiologist Page Anderson, of Duke University Medical Center, in Durham, N.C. "When the baby is delivered," he told BioWorld Today, "and the cord is exposed to normal temperatures, there's a cascade of events that produce constriction of those umbilical vessels."

He added: "In the hospital, we clamp or tie the cord, to make sure there's no excessive blood loss."

Meanwhile, deep inside the newborn infant's chest, another suddenly redundant blood vessel is also shutting down. This stubby, muscular artery, the ductus arteriosus (DA), connects the main pulmonary artery to the descending aorta. It serves as the conduit that bypasses the lungs, while moving venous blood to the placenta. A typical DA is five to seven millimeters in diameter, and slightly longer.

With no delivery-room obstetrician on hand to shut it down, the DA has to rely on its newborn body's own metabolic mechanism to effect closure.

"In human babies," Anderson observed, "it takes a matter of hours. First, there is smooth-muscle contraction, which markedly decreases the DA channel's diameter. This is followed by a piling up of endothelial cells within the lumen to ensure that even if the smooth muscle relaxed, there would be no channel."

Underlying this process are the prostaglandins, ubiquitous substances with myriad functions. Here they stimulate smooth-muscle relaxation. At birth, the fetal prostaglandin level drops, permitting constriction of the ductus. What remains after its closure becomes a mere ligament.

By then the long-dormant lungs have inflated to take over their lifelong job of oxygenating arterial blood.

But in six of every 10,000 full-term births, the ductus arteriosus refuses to quit the stage, and stays open — in direct competition with blood flow from the now active lungs. That incidence is even higher in prematurely born neonates.

"In the preterm infants," Anderson observed, "the normal patterning that would result in ductus closure hasn't had the time to take place in utero. So when those preemies are born, the DA doesn't close, and they can be subject to pulmonary edema, heart failure and a decrease in blood flow to the rest of the body."

A Murmur Betrays Wide-Open Ductus

Again, unlike the umbilical cord, this patent (wide open) ductus arteriosus (PDA) is not visible to the obstetrician's eye at birth. If a full-term newborn has trouble breathing, a suspicion of PDA is readily confirmed by an audible heart murmur — the harsh, rasping sound that bespeaks turbulence of blood flow someplace in the circulation.

"Before going home from the hospital at one or two days of age," Anderson said, "someone would listen to the baby's heart." He described three degrees of therapy for this potentially lethal congenital heart defect:

The drug of choice in a preterm infant is indomethacin, better known as an arthritis painkiller and all-around anti-inflammatory. It also interferes with an enzyme, cyclooxygenase, which promotes the synthesis of prostaglandins, and thus allows the ductus to close. But it produces severe side effects.

"Blue babies," Anderson continued, "who evince hypoxia, cyanosis, obstruction of blood flow to their lungs, receive intravenous infusions of prostaglandin to reopen their closed ductus.

"It relaxes the smooth muscle of the PDA, allowing blood to flow from the aorta into the pulmonary artery by way of the duct, and thus permitting its oxygenation. This temporizing measure," he pointed out, "keeps a blue baby alive until surgery can repair the underlying defect that made it blue.

"Surgery used to be far more common before indomethacin was introduced," Anderson pointed out. "But blue babies now have corrective open-heart surgery at two, three, four or five days of age." He continued: "This neonatal cardiovascular surgery has become common in the sense that the most common time for children to die of congenital heart disease is in the first month of life."

Molecular Scalpel Dissects Prostaglandin Role

Anderson is a co-author of a report in today's Nature, dated Nov. 6, 1997. Its title: "The prostaglandin receptor E4 triggers remodeling of the cardiovascular system at birth." Its senior author is molecular biologist Beverly Koller, at the University of North Carolina, in Chapel Hill.

"Dr. Koller set off down this road," Anderson recalled, "with the idea of doing this molecular approach to dissect out the mechanism by which prostaglandins affect the body, through their multiple receptors. Her approach," he went on, "was to remove expression of the four individual isoforms of the prostaglandin receptor in knockout mice, beginning with E4."

In one typical experiment, mice lacking the E4 gene failed to close their ductus, resulting in lung edema and death. This suggested to the research team that "the neonatal drop in prostaglandin E2 that triggers ductal closure is sensed through their E4 receptor."

However, knockout fetuses gestating in utero did not die. As Anderson commented, "The first thought by a pediatric cardiologist would be that if you had a knockout of this receptor, you would have had premature closure of the ductus arteriosus in utero, and death — embryonic or fetal lethal. But the actual opposite occurred, in that the animals survived and did well. Then, at their birth, because of the DA being persistently patent, it points out that there has to be another system that we are not aware of." *

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