By David N. Leff

"When ya gotta go, ya gotta go!"

This informal rule of conduct expresses the truism that the urge to pass water - to urinate - simply cannot be denied.

A historic case in point concerns one of Renaissance Europe's greatest astronomers, the Danish stargazer Tycho Brache (1546-1601). Late in life he was appointed astronomer royal to the emperor Rudolph II, who ran the Holy Roman Empire from his palace in Prague, Bohemia. At a royal banquet, Brache indulged mightily in wine (alcohol being a bladder stimulant), and felt a strong urge to urinate. But fearing to show disrespect to his monarch by a temporary absence from the royal presence, he kept his seat until his overdistended bladder ruptured. Brache's death ensued a few days later.

Nowadays, of course, this form of noblesse oblige is definitely dated. Instead, its opposite, incontinence - involuntary voiding of the bladder - afflicts more than 110 million men and women worldwide. One in 11 Americans suffers from the embarrassingly overactive-bladder disorder, due to various etiologies, from benign and malignant prostate gland enlargement to old age.

Indeed, large numbers of elderly, incontinent, individuals are placed in nursing homes just to spare caregivers the nuisance of coping with their disorder.

To be sure, there are more than half a dozen prescription drugs on the market - some in TV commercials - to treat adult urinary incontinence, but all of them have their drawbacks. "The current treatments for overactive bladder," observed neuropharmacologist Anthony Ford, "have very profound side effects from salivary glands and so on, producing dry mouth, dry skin and dry eye. These approaches," he continued, "typically involve medications, such as anticholinergics, which block acetylcholine receptors throughout the body."

Pain, Peeing Share Same Neurons

Ford is head of genitourinary research at Roche Bioscience in Palo Alto, Calif. His unit's agenda is to elucidate the underlying mechanism of bladder dysfunction, with a view toward developing medications that will treat the basic disorder rather than just its urinary manifestations. These include - besides that sudden urgency, undue storage and untoward spillage - frequency of urination, day and night.

Ford is senior author of a progress report in the current issue of Nature, dated Oct. 26, 2000, titled: "Urinary bladder hyporeflexia and reduced pain-related behavior in P2X3-deficient mice."

He and his co-authors discovered a previously unknown mechanism that controls this bladder misbehavior. "It's based on a recently cloned protein receptor called P2X3," he told BioWorld Today, "which binds the neurotransmitter ATP [adenosine triphosphate], the energy source for most chemical reactions in each human cell. Our finding suggests that P2X3 plays a pivotal role in receiving signals from the urinary bladder.

"First, we genetically engineered knockout [KO] mice," Ford recounted, "that had their P2X3 gene removed, and therefore were born, and developed, without expression of this receptor.

"The first thing we were interested in looking at," he recounted, "were responses to simple noxious stimuli - for example, touch and mild pain, the classical reflexive reactions - and also to the injection of small amounts of irritant substances into their paws. Normal wild-type animals responded in a particular way that showed they were perceiving a noxious insult. But in the P2X3-lacking KO mice, we could see that there was a reduction in their responsiveness to such kinds of stimuli.

"One of the things we have an interest in here," Ford went on, "is interpreting the pain reaction of these sensory neurons in the context of visceral organ functions - notably in the bladder. For this kind of study we implanted a small catheter into the body of the mouse bladder, which at rest is the size of a small pea. When we infused saline solution at relatively slow filling rates, it gradually distended the bladder. Then we could record pressure changes and the volumes of contraction produced as the micturition response. And what we found in these P2X3-deletion mice was the volume that was required to elicit this micturition response was about twice the size of the volume in the wild-type animal. In other words, they were urinating half as frequently, so the interval between urinations was twice as long."

In effect, their P2X3-induced incontinence was cured by knocking out that receptor. "This," Ford observed, "points toward inhibitory drugs, something we're very keen to pursue from a chemical standpoint. We have some small-molecule leads that do inhibit this particular protein selectively. Obviously it will take a while before these are turned into real drug candidates through preclinical and clinical testing.

"But the feeling is," he added, "that in the patients who have this sensory dysfunction, the overactive bladder, the thresholds have fallen so that they now respond to small changes in volume. Therefore, if we can eliminate some of this signaling by chemically inhibiting ATP from activating P2X3, hopefully we can raise these thresholds again. So I think a P2X3 antagonist may allow us to selectively create such a drug-discovery situation."

From Infant Bed-Wetting To Adult Embarrassment

Urinary incontinence affects young as well as old - but transiently. Bed-wetting - nocturnal enuresis - occurs in 30 percent of children under 4 years of age, but declines to 10 percent by age six, 3 percent by 12 years, and 1 percent at 18.

Ford finds that "nocturnal enuresis is an interesting area. When the bladder fills," he pointed out, "the increasing level of sensory neurons gives rise to an excitatory discharge to the bladder. That is the micturition reflex - which is slow to develop in children with nocturnal enuresis.

"One of the things that has been described by pediatricians specialized in this area," he observed, "is that the slow maturation of the sensory control mechanism sometimes causes problems in adult life. That is," he concluded, "children who fail to control urinary function, and have this delayed development of continence, often in later life are most likely to develop the bladder and urgency syndrome of incontinence."

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