Therapeutic stimulation of penile nitric oxide synthase (NOS) and related pathways

The advent of a novel oral treatment for erectile dysfunction appears to have reduced the urgency for seeking alternative therapeutic innovations. However, the currently available therapies can be viewed as simply palliative, requiring on-demand access and having a significant failure rate. Therefore, additional approaches for patients unresponsive to any type of medical treatment require investigation. The modulation of the synthesis of nitric oxide (NO), the main mediator of penile erection, is an attractive target for such an approach. Models for human erectile dysfunction related to aging, diabetes and endocrine disorders have been characterized in the rat. The affected animals exhibit a reduced erectile response to electrical stimulation of the cavernosal nerve and/or a loss of spontaneous erectile reflexes. In virtually all cases, the content and/or enzyme activity of penile NOS is significantly reduced, or NO synthesis may be insufficient to overcome the relatively poor compliance of the penile corpora cavernosa smooth muscle (aging). This led to the proposal that the stimulation of penile NO synthesis may be a viable therapy for erectile dysfunction. The upregulation of penile NOS activity may be achieved by: a) increase in NOS substrate concentration, b) stimulation of NOS activity through related pathways or c) blockade of endogenous NOS inhibitors. We have shown that approach a ameliorated the erectile dysfunction of aging rats by elevating intracavernosal NOS substrate through long-term oral administration of high doses of L-arginine. Evidence supporting approach b is based on our recent discovery that the main stimulating pathway for NOS, the NMDA receptor, is present in the penis. However, NMDA receptor antagonists unpredictably trigger cavernosal relaxation in vitro in a NO-independent pathway. Finally, in the case of approach c we have found that a protein inhibitor of NOS (PIN) is expressed in the corpora cavernosa. Penile NOS content may be pharmacologically increased by: d) induction of NOS expression, and e) gene therapy with NOS cDNA. Approach d applied to the penis ameliorated erectile dysfunction in aging rats, but may be clinically unfeasible because of the risk of side effects. Our laboratory cloned the inducible and neuronal NOS isoforms expressed in the penis (PiNOS and PnNOS, respectively), and showed that approach e, based on gene transfer of PiNOS into the rat corpora cavernosa improved the erectile response. Since PnNOS is a nNOS variant different from the one expressed in the CNS, gene therapy with PnNOS is promising in combination with viral vectors and tissue-specific promoters. The aim is to achieve a long-lasting increase in penile NOS that is responsive to sexual stimulation. Following validation in animal models, oral L-arginine, intracavernosal antagonists of NMDA receptor and PIN, and intracavernosal or systemic PnNOS, may eventually translate to clinical trials.