Newly mapped enzyme could yield new treatments for female sexual dysfunction

PHILADELPHIA -- New research from the University of Pennsylvania and other institutions indicates that the enzyme arginase II, which can short-circuit a biochemical pathway leading to sexual arousal in men, is also present in the female genitalia and represents a promising target for new drugs to treat sexual dysfunction in women.

Scientists from Penn, Temple University and Boston University have mapped out arginase II's three-dimensional structure, easing the job of creating drugs to disable it. Their results will appear in the Aug. 5 issue of the journal Biochemistry, and were published this week on the journal's Web site.

"Existing treatments have shown little success in treating female sexual dysfunction," said lead author David W. Christianson, professor of chemistry at Penn. "Given the relative failure of remedies such as Viagra, the identification of a new target for the possible treatment of female sexual dysfunction represents an important advance."

In 2001 Christianson and his colleagues reported that arginase II is present in the human penis. In studies with female rabbits, described in the current paper, the researchers have found the same enzyme in the genitalia of female mammals.

Christianson's group also found that administration of a powerful arginase inhibitor enhanced smooth muscle relaxation and blood flow in the female rabbits' genitalia, fostering sexual arousal.

"Ever since the enzyme nitric oxide synthase was identified in the female genitalia six years ago, we've been very interested in learning whether arginase might play a role in female sexual dysfunction," Christianson said. "More importantly, we've wondered whether arginase inhibitors could enhance smooth muscle relaxation in the female genitalia, leading to sexual arousal. It now appears that this may be the case."

Healthy sexual function in both genders relies on a biochemical cascade as carefully orchestrated as any courtship ritual. At one critical step in that pathway, nitric oxide synthase converts arginine, one of the 20 natural amino acids, into citrulline and nitric oxide. The latter product causes rapid relaxation of smooth muscle in male and female genitalia, allowing the thousands of tiny vessels there to swell with blood.

Arginase can derail this reaction by sequestering arginine and breaking it down into compounds unrelated to those physiologically responsible for arousal, depriving the genitalia of the nitric oxide needed for sexual function.

In both men and women, sexual dysfunction occurs when this enzyme-mediated pathway goes awry, impeding blood flow in and out of the genitalia. Sexual difficulty often manifests itself as a side effect of heart disease, hypertension, diabetes and the use of medications such as antidepressants.

Christianson is joined in the research by Evis Cama and Hyunshun Shin at Penn; Diana M. Colleluori, Frances A. Emig and David E. Ash of Temple University; and Soo Woong Kim, Noel N. Kim and Abdulmaged M. Traish of Boston University. Their work was supported by the National Institutes of Health.