By David N. Leff
At almost any hour of the day or night, a TV commercial urges its male viewers with erectile dysfunction, "Ask your doctor if Viagra is right for you."
"Viagra is an extremely successful drug, but not all men can take it," observed reproductive physiologist Thomas Mills, at the Medical College of Georgia in Augusta. "For some situations," he pointed out, "it's contraindicated. For example, men taking certain antihypertensive medications can't use it.
"There are several possible problems with Viagra," Mills cautioned. "Since it prolongs vasodilation, it may be additive with some drugs prescribed for high blood pressure. These also can lead to hypotension. Blood pressure goes down, down, down - and the guy can get in trouble that way.
"Viagra is fine," he summed up, "but it's not for everybody. It gives satisfaction in maybe 60 percent to 70 percent of men. But in situations such as severe diabetes or prostate surgery, the effectiveness is less. So Viagra is not the total, final answer to erectile dysfunction. Also it's very expensive."
Mills is senior author of an article in the January issue of Nature Medicine. Its title: "Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway." It reports on in vivo experiments with a Japanese compound called Y-27632.
"The basic science finding in this paper," Mills told BioWorld Today, "is that we've discovered, I think, a pretty strong vasoconstrictive pathway operating in the erectile tissue, which keeps the penis in a flaccid state. By inhibiting that with this Y-27632 drug, the pressure goes up, and we stimulate erection.
"Viagra works by prolonging the effects of cGMP - cyclic guanosine monophosphate. Our Y-27632 compound has nothing to do with NO or with cGMP. It is strictly an inhibitor of the vasoconstrictive pathways - unrelated to Viagra's vasorelaxation pathway.
"Y-27632," he explained, "is a small, proprietary molecule, belonging to the Welfide Corp. of Osaka, Japan. This compound is quite different from the other treatments that have been used to generate erection, agents that either increase nitric oxide [NO] with cyclic GMP or prolong NO's erectile effects."
Blood Flow Orchestrates Erectility
The coital drama of penile erection plays out on a stage called the corpus cavernosum. This consists of two parallel columns of spongy, vascular tissue - bounded by smooth-muscle cells - and lying along the back of the penis. When this organ is at rest, or flaccid, the corpus is relatively empty of blood. When called upon to perform, these tissues fill with arterial blood, pumped in under pressure to impart rigidity - and erection.
With Viagra, as in the unassisted, normal state, NO actuates that arterial pressure. Welfide's compound blocks the rho-kinase enzyme, causing the smooth-muscle cells to rally round and impart contractility - hence erectility - to the flaccid member.
Mills tells how: "Rho-kinase," he explained, "is one of those switching molecules that has a variety of cellular functions. In this penile context it functions to phosphorylate the muscle cells' myosin light chain. This turns off that chain's phosphatase activity. By doing so it slows the breakdown of myosin light chain phosphate, so it can combine with actin to keep things in the contracted state."
In Osaka, Welfide developed Y27632 in conjunction with its program of anti-hypertensive drug discovery. In Augusta, Ga., Mills and his co-authors tested it for erectile dysfunction, as an alternative to Viagra. Mills recalled the serendipitous chain of events:
"The chairman of my department, R. Clinton Webb, was at the University of Michigan. He's a world authority on hypertension, and its control from a basic science standpoint. He had received this experimental drug from Welfide. Webb became chairman of physiology at the Medical College of Georgia, so when he came to town he brought Y-27632 with him for his studies.
"In discussing this with Webb," Mills went on, "we thought we would try it in the penis, because these drugs act as vasodilators, and that's what the erectile process is. I've been doing the basic science of erection for 10 years or so, and have developed a pretty good rat model for these studies. So we injected this stuff into the animals' erectile tissue, and it was one of those really neat moments when you see an event happen that was totally unexpected. And I think we knew we were on to something when we saw it."
To begin with, they inserted cannulas into the carotid and corpus cavernosum arteries of heavily anesthetized rats. Then, after treating them with an inhibitor of NO production to exclude any Viagra-like effect, they injected the Welfide compound into the corpus cavernosal tissues. This produced "a significant dose-dependent increase in intracavernosal arterial pressure, which plateaued within four minutes, and lasted some 15 minutes."
From Shooting It In To Daubing It On
Mills cited two key factors that will decide the future of Y-27632 as a competitor to Viagra:
"First of all," he said, "the drug belongs to Welfide Corp. Whether or not they're going to try to develop this indication clinically is up to them. They have expressed interest in our results. The other factor," Mills pointed out, "has to do with the route of administration. Injection therapy is something that's available now. Prostaglandin E1 is a common treatment for erectile dysfunction. Men self-inject this by needle into the shaft of the penis and it works very well. In fact the quality of the resulting erection is probably the best of all the various treatments on the market.
"Viagra," he continued, "is competitive with our compound because Viagra is taken orally. Our drug is no improvement; it has to be injected. So we are currently investigating," he disclosed, "topical application of the Y compound, in an ointment. We're not ready to publish it yet, but we've done preliminary in vivo studies in our rats and it appears to be active when given topically. So that's a big plus."
Mills presented his up-to-date data at the end of November to the Ninth World Meeting on Impotence in Perth, Australia. "There was really a lot of interest shown," he recalled. "In fact, our research was adjudged the best basic science paper presented at the meeting. I suspect that other labs are going to get into this now. But I think," he concluded, "we're ahead at the present point in time."