The NO-cGMP pathway has been implicated in clitoral and vaginal smooth muscle relaxation based on previous immunochemical, biochemical and physiologic studies. There are limited data from in vivo studies demonstrating enhancement of the genital sexual arousal response by pharmacologic agents influencing the NO-cGMP pathway. The goal of this study was to investigate if sildenafil, a phosphodiesterase type-5 inhibitor, facilitated female genital sexual arousal in an animal model in response to pelvic nerve stimulation (PNS). Using female New Zealand White rabbits, we measured the following parameters before, during and after PNS at 4, 16, and 32 Hz: a) hemoglobin concentration and oxygen saturation in female genital (vaginal, labial, clitoral) tissues by laser oximetry; b) clitoral blood flow by laser Doppler flowmetry; c) vaginal luminal pressure by a balloon catheter pressure transducer; d) vaginal lubrication by tampon. Sildenafil was administered intravenously (0.21 microg/kg, 0.42 microg/kg, 2.1 microg/kg) to achieve a systemic concentration of 5, 10 and 50 nM, respectively. After 20 minutes, physiologic measurements were repeated. Sildenafil (50 nM) caused a significant increase in genital oxyhemoglobin concentration and a significant decrease in genital deoxyhemoglobin concentration. Sildenafil also increased the duration of response following PNS, relative to genital hemoglobin concentration and mean clitoral blood flow. Sildenafil caused a decrease in vaginal luminal pressure and resulted in an increase in vaginal lubrication. These data indicate that the NO-cGMP pathway is involved in the physiologic mechanism of female genital arousal and that sildenafil facilitates this response in an in vivo animal model.