Whenever prehistoric man felt the sudden need for a muscle-powersurge, his adrenal glands obliged with a burst of adrenaline andnoradrenaline. These hormones, a.k.a. epinephrine andnorepinephrine, gave him a rush of energy.

Between them, adrenaline and noradrenaline divert the blood supplyof a stressed mammal from the workaday chores of digestion to theurgent demands of skeletal muscles and liver, where they turnedglycogen reserves into glucose _ fuel for physical exertion andmental alertness. And stepped-up heart action pumps this high-energyblood to the sites of brain and brawn. They are also responsible forstanding hair on end and heavy breathing.

Medical students know epinephrine and norepinephrine as the "three-F emergency hormones," which fortify the mammalian body to "fight,flight or fornicate." Now there is evidence of a fourth "F" to add tothat equation _ fetal development.

This gestational finding, published in the current issue of Nature,dated April 13, suggests a reason for some unexplained stillbirths: theembryonic genome lacked a gene or genes for synthesizingadrenaline or noradrenaline.

The back-to-back Nature papers have a single senior author,molecular biologist Richard Palmiter. A pioneer constructor oftransgenic mice, he is now at the University of Washington in Seattle.

Death Comes Early To Knockout Mice

One article bears the title, "Noradrenaline is essential for mouse fetaldevelopment." To prove this point, Palmiter and his co-authorsconstructed knockout mice lacking the gene for dopamine b-hydroxylase (DBH), and therefore unable to synthesize adrenaline ornoradrenaline.

In pregnant homozygous females _ those with no DBH gene fromeither parent in their chromosomes _ all pups died unborn. Mothersharboring a single DBH gene gave birth to mixed litters, in whichmost of the homozygous fetuses were stillborn, but an anomalous 5percent survived to adulthood. Presumably, they inherited a leakageof the maternal hormones through the placenta.

To demonstrate that death in mid-gestation resulted from a lack ofnoradrenaline during a crucial period of fetal development, theinvestigators fed the pregnant mice another compound, DOPS, whichis a precursor of noradrenaline. These mothers lapped it up in theirdrinking water, and all of their homozygous offspring survived.

The paper's first author, postdoctoral neuroscientist Steven Thomas,told BioWorld Today how this discovery came to light: "We did notanticipate the result," he said. "It was a surprise to us. When westarted getting some of the mouse pups born," he explained, "the onesthat had both maternal and paternal genes missing were vastly under-represented. Hardly any knockouts were being born. So then westarted studying what was happening in utero."

When he genotyped all 1,375 offspring born to second-generationfemales, all of whom were heterozygous (DBH+/-), 12 percent oftheir homozygous offspring survived to term. Of those, 40 percentdied within 48 hours after birth, and another 20 percent within threeto five weeks.

Only that 5 percent went on to grow up, and they were severelyrunted and growth-delayed.

Normal fetuses (DBH +/+) began synthesizing noradrenaline midwaythrough day 10 of gestation, and adrenaline, three days later. Buttwo-thirds of the DBH -/- fetuses were dead by day 11.5.

Biopsies determined that demise of these DBH-minus pups wasapparently due to heart failure. That finding matched up with the fateof a parallel line of knockout mice, deprived of a different gene, thatfor tyrosine hydroxylase (TH), an enzyme that synthesizes precursorsfor adrenaline and noradrenaline but, unlike DBH, not for dopamine.

Lesson For High-Pressure Pregnant Humans

The first author of Nature's companion paper, post-doctoralneuroscientist Qun-Yong Zhou, managed the TH experiment, withresults nearly identical to the DBH findings. Zhou told BioWorldToday that his and Thomas's experiments have immediate clinicalimplications.

"Pregnant women," he said, "often develop hypertension _ highblood pressure. For this condition, which in its severest form is calledpreeclampsia, they may be treated with drugs such as adrenergicantagonists." Zhou cautioned that these blockers used to excess"might have deleterious effects on embryo development."

Curiously, Thomas noted, half a dozen humans totally deficient in theDBH gene, have been born, and lived to tell the tale. It's a tale ofautonomic failure, he said, "which has two main symptoms: exerciseintolerance and orthostatic hypotension. When they stand up from asitting or lying position, they feel dizzy and faint, or pass out,because they can't maintain their blood pressure."

He added, "It was symptoms like these that made it possible todiscover that their condition was due to the missing DBH enzyme.Judging by our knockout-mouse results, most such humans likely diestillborn."

Zhou observed that "TH deficiency has no living human patient." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.