Female sexual dysfunction is increasingly recognized as a significant and widespread abnormality, contributing to coital pain, decreased libido, and a loss of sexual pleasure. In contrast to the enormous scientific investment in discovering methods to correct male sexual dysfunction, there has been virtually no attention directed at elucidating the fundamental mechanisms accounting for clitoral engorgement, vaginal lubrication, and alterations in vaginal and vulval mucosal blood flows accompanying sexual arousal. Increasing anatomic evidence points to a role for nitric oxide as a mediator of female genital hyperemia, similar to the situation in the male. Topical application of traditional nitric oxide donors to the female genitalia, however, produces profound systemic side effects, including headache and hypotension. What is needed is a potent, but regionally restricted nitric oxide donor, that acts on the local vaginal circulation exclusively. Towards this end, we have developed a nitric oxide pro-drug (DS1) that is restricted from transepithelial flux by virtue of its large hydrodynamic radius. Nitric oxide is released from DS1 and is able to traverse mucosal surfaces and vasodilate underlying arteriolar beds, whereas the pro-drug cannot traverse the epithelium and is confined to the apical mucosa. Nitric oxide that reaches the systemic circulation is immediately inactivated by hemoglobin and therefore does not circulate as a systemic vasodilator. Thus, DS1 represents a true """"""""regional"""""""" vasodilator. We have obtained preliminary data in rats that topical DS1 applied to the vaginal mucosa produces profound and immediate increases in vaginal blood flow, with no effect on systemic blood pressure. Utilizing an anesthetized rat model, we now propose to obtain a pharmacodynamic profile of DS1. We will simultaneously compare the regional blood flow and the mean peripheral arterial pressure in order to verify regional selectivity. Justification of further development towards commercialization will require 1) no decrease in systemic blood pressure, 2) >100 percent increase in vaginal blood flow, and 3) duration of regional hyperemia >30 minutes.
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| Pacher, P; Mabley, J G; Liaudet, L et al. (2003) Topical administration of a novel nitric oxide donor, linear polyethylenimine-nitric oxide/nucleophile adduct (DS1), selectively increases vaginal blood flow in anesthetized rats. Int J Impot Res 15:461-4 |
