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Physiologist North: Exploring the many faces of vasopressin

One of life's lessons, often learned in college, is that you don't really buy beer, you sort of rent it. Consumption of a Foster's lager, imported from Down Under in generous 25-ounce cans—which Dartmouth physiologist William North, Ph.D., would probably call "Australian thimbles"—leads sooner rather than later to urinary urgency. That college student may also learn in a science class that this phenomenon is due not so much to the major but inert component of beer—water—as to its biologically active ingredient, ethanol. Of the many effects that ethanol exerts on the brain, among the less desirable is its ability to suppress the secretion of the antidiuretic hormone vasopressin, which regulates urine formation.

Up from Down Under: Bill North was born in New South Wales and received his Ph.D. from the University of Queensland. He came to the United States in 1972 with the idea of staying for three years. After two years at the Mount Sinai School of Medicine in New York City, he joined DMS physiologist Heinz Valtin, M.D., in Hanover for what was to be a one-year stay. That one year has been parlayed into a quarter-century.

At the time, Valtin's laboratory was developing the nowworld- famous Brattleboro rat as an animal model to study human diabetes insipidus. The Brattleboro rat is born with a permanent problem somewhat similar to the temporary one in a Foster's drinker, in that it does not produce enough vasopressin to allow it to conserve its body water. Much of the life of these animals is taken up by trying to consume enough water at one end to make up for losses at the other. North began studying methods to extract and assay vasopressin as well as oxytocin and neurophysins, peptides found in association with vasopressin.

DMS physiologist Bill North has been at Dartmouth since 1974, studying the neuropeptide vasopressin.
Photo: Flying Squirrel Graphics

Marker: In the late 1970s, North ran across a paper on the possibility that vasopressin might constitute a useful marker for small-cell carcinoma of the lung. The paper's authors had arrived at their conclusion through mathematical extrapolations, which purported to show that tumors weighing several grams could be detected by measuring plasma vasopressin. By the time a tumor is that size, however, it can be detected by many other means and it is usually too late for effective intervention. The investigators concluded that vasopressin was thus not an effective plasma marker for small-cell carcinoma.

But when North went over the calculations, he found an apparent error of several thousandfold. He got some mathematically savvy colleagues to confirm his suspicion, and recalculation indicated the possibility of detecting tumors of less than a few milligrams —a much more favorable stage in tumor growth for meaningful treatment. North went on to use not only vasopressin but also neurophysins as plasma tumor markers. Such was his enthusiasm for the subject that medical students dubbed him "Dr. Neurophysin." Although he continued to make many other fundamental contributions to the basic biochemistry and physiology of the neurohypophyseal hormones, the possibility of their use as tumor markers was a concept that gradually came to dominate his research.

Synthesis: When North first came to Dartmouth, vasopressin was thought to be synthesized only in the hypothalamus. Today it is known to be made in the ovaries, uterus, adrenal gland, lungs, and gastrointestinal epithelium as well. Moreover, its physiological effects are not limited to antidiuresis at the level of the renal collecting duct.

The hormone's name, vasopressin, was originally chosen because of its potent effects at vasoconstriction —narrowing of the blood vessels. It also serves as a neurotransmitter in the central nervous system, where it plays a role in the secretion of adrenocorticotropic hormone (ACTH) as well as in the regulation of cardiovascular and visceral functions and of body temperature, all via central mechanisms. In addition, through effects on both coagulation factors and platelets, it plays a role in the blood-clotting mechanism.

Vasopressin is synthesized in breast tumors as well as smallcell tumors, types of cancer that share few other characteristics except that both arise from epithelial cells. Other common types of lung cancer do not produce vasopressin, but some tumors unrelated to breast or small-cell do produce it.

Early on, skeptics suggested that the tumor cells may simply accumulate vasopressin synthesized in other sites instead of actually producing it themselves. However, North proved that the vasopressin gene is indeed expressed in the tumor cells. He was able to identify tumor-specific surface antigens that resulted from this gene expression, and he showed that these antigens could serve as targets for tumor immunodiagnosis. These antigens are also likely targets for tumor immunotherapy.

Peptides: What role do vasopressin and other related peptides play in tumor biology? Says North, "The simplistic answer is that they probably function as growth factors; in fact, vasopressin and other neuropeptides have been shown to promote the growth of breast cancer. However, I believe that these peptides may subsume many other functions in tumor cells, just as we now know they have many different physiological roles. For example, we have found all four known vasopressin receptors in these tumors, and each activates a different molecular train of events. One type of vasopressin receptor may inhibit cell growth, even as another promotes it. Moreover, tumors also produce many other neuropeptides, which probably also have important functions that have not yet been elucidated, and which might also be used as tumor markers.

"I don't think that vasopressin is necessarily the most important peptide in the world," North admits, even though it is the most intensively studied of all the neuropeptides. "Chemists have run amok," he explains, "in synthesizing new vasopressin agonists and antagonists, including some exciting antagonists that are not peptides."

In fact, he says, "an effective vasopressin antagonist might turn out to be either an effective anticancer drug or a chemopreventive agent for tumors that depend on its availability."

Roger P. Smith, Ph.D.

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