Essential hypertension (EH) is a common disease that has nosymptoms and no known cause, but is potentially lethal. Yet thisidiopathic, silent high blood pressure is readily diagnosed and easilykept at bay for a lifetime by oral drugs with minimal side effects, anda moderately sane lifestyle.

EH usually makes itself known to its unsuspecting sufferer during aphysical examination. Its definition _ blood pressure of 160 over 95millimeters of mercury in a resting, supine adult _ is statisticalrather than physiological. It reflects an average danger signal, not thethreshold of actual danger.

Of all patients found to have high blood pressure, only 10 percentsuffer from hypertension related to a specific diseased organ systemin the body. The whopping 90 percent receives a diagnosis of EH.

Like so many diseases of advancing age, EH tends to run in families.Molecular geneticist Oliver Smithies cited a recent expert estimate tothe effect that "roughly two-thirds of familial tendencies in bloodpressure are due to genetic factors; the other one-third to a familialcollection of social environmental patterns, such as whether you eat alot of salt, whether life is stressful, or whether you sit home andwatch TV all the time for exercise."

Smithies, a professor of pathology at the University of NorthCarolina, Chapel Hill, points out that "these lifestyles are transmittersin families, just as well as genes are."

Stretching The Heart Signals The Pressure

The genes involved in high blood pressure, Smithies told BioWorldToday, are many, varied and little explored. That is, EH is amultigenic disorder.

"Our point of view at this stage," he said, "is that our studies havebeen directed toward finding what effects altering specific genes canhave on blood pressure." The first gene on which he and his co-authors tested this approach is reported in today's issue of Science,dated Feb. 3. Its title: "Genetic Decreases in Atrial NatriureticPeptide and Salt-Sensitive Hypertension."

The precursor of the gene that expresses atrial natriuretic peptide(ANP), Smithies explained, "is located in the right side of the heart,the right atrium, which receives the blood from the venous system.In that chamber are a lot of cells containing granules."

He continued: "When the atrium is stretched at all, its distentionsignals these granules to release their cargo of ANP into thecirculation. ANP, a 28-amino-acid peptide, thereupon interacts withvascular receptors to relax blood vessels, and with renal receptors,which cause kidneys to excrete salt _ sodium. These effects thuslower blood pressure."

What makes the atrium distend, Smithies went on, "is an increase inthe volume of blood coming back from the peripheral circulation.And what makes the blood volume rise is its absorption of dietarysalt and water from the intestines."

What if the gene that controls the release of ANP from those atrialcell granules is defective or missing? Smithies and the first author ofthe Science paper, post-doc Simon John, set out to answer thisquestion by creating knockout mice without that pro-ANP precursorgene. By mating their altered offspring, they obtained three sets ofgenetically assorted animals. One batch was homozygous (-/-),totally lacking the pro-ANP precursor gene. A second group,heterozygous (+/-), had one normal gene, rather than two, inchromosomes. The wild-type (+/+) third cohort was completelynormal.

True to this inheritance pattern, as Science reported, five +/+ wild-type mice had both atria packed with more than 100 nanograms permilligram in each chamber. The +/- heterozygotes, with one geneinstead of two, weighed in with half the quantity, about 50 ng/mg.And nine -/- mice, with no genes at all, had no ANP in their heartchambers.

At first, these rodents all consumed a standard diet of mouse chowcontaining 0.5 percent salt. The +/+ and +/- mice had similarnormotensive arterial blood pressures _ about 116 mm of mercury,measured by tail-cuff pressure gauge. As expected, the -/- knockouts,bereft of ANP, registered "significantly higher" blood pressures _in the 124 range.

Later, after two weeks on a salt ration increased to 2 percent, themutant homozygotes' readings went up from 124 to a hypertensive156, while their heterozygous +/- and wild-type +/+ littermates bothshrugged off the added salt burden by staying close to their originalnormal pressures.

"In human populations," Smithies observed, "a complete absence ofANP is probably exceedingly rare. But reduced levels may not be souncommon. So we fed their murine counterparts, the heterozygous+/- mice, with reduced ANP expression, a much higher salt diet intheir chow _ 8 percent. With their diminished but not absent ANP,they developed hypertension. The +/+ wild-types could handle theextra sodium load without a rise in blood pressure.

"These results say that we should look in our different populations ofpatients for differences in the human gene," Smithies said. "Thoseindividuals whose genetic alterations are in the direction ofdecreasing function can be expected to be patients whose bloodpressure would be improved by being very careful with salt intake intheir diet."

One population in particular, Smithies pointed out, "has thatproblem. Our black population as a whole has more salt-sensitivehypertension than the white population."

Tracking Multigenic EH, Gene By Gene

He and his team are moving now from ANP to three other genes thatappear to be closely tied to hypertension, all in the renin-angiotensinsystem. Renin is an enzyme produced in the kidney that convertsangiotensinogen to angiotensin I, thence to angiotensin II. This raisesblood pressure by constricting blood vessels. Inhibition of thatcascade prevents or reduces hypertension.

In the early 1980s, California Biotechnology Inc., of MountainView, synthesized recombinant human atrial natriuretic peptide, andtrade-named it Auriculin. The company, now Scios Nova Inc., hasAuriculin in advanced clinical trials for treating acute renal failureand kidney transplantation. (See BioWorld Today, Nov. 17, 1993, p.2.)

"If Smithies has knocked out ANP in mice," said Scios-Nova'sacting director of pharmacology, biochemist Andrew Protter, "andyou see disturbance in salt regulation as well as in blood pressure, Ithink that would be consistent with the critical role that ANP plays inthese processes."

Protter told BioWorld Today: "What we think of as ANP isincredibly natriuretic, very sensitive to salt loads _ that's thestimulus for its release. So Smithies' findings are very much inkeeping with our current understanding of how ANP works, how it'sregulated, and its activities." n

-- David N. Leff Science Editor

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