Vardenafil enhances clitoral and vaginal blood flow responses to pelvic nerve stimulation in female dogs

Abstract

The relaxation of the smooth muscle in the vagina and clitoris and the increase of blood flow into these organs is thought to be essential in the female sexual response. Vardenafil is a type 5 phosphodiesterase (PDE5) inhibitor that potentiates the nitric oxide (NO)/cGMP pathway facilitating penile smooth muscle relaxation and improving penile erection in men. Although the potentiation of the NO/cGMP pathway through PDE5 inhibitors can clearly enhance blood flow into the penis and is used in the therapy of male sexual dysfunction, there is controversy about the efficacy of these agents in improving female sexual function. The aim of this work was to evaluate the effects of vardenafil on the increase of blood flow into the vagina and clitoris induced by pelvic nerve electrical stimulation (PNES) in a female dog model. Application of PNES produced consistent and frequency-related increased blood flow into the vagina and clitoris of anesthetized female dogs. The magnitude and duration of the blood flow responses to PNES were variable among the different animals but remained stable over time within the same animal. The intravenous administration of vardenafil (1 mg/kg) significantly potentiated the increases in blood flow produced by PNES into the vagina (381.4 and 206.2% of control response at 5 and 10 Hz, respectively, Po0.01, n ¼ 6) and clitoris (379.4 and 238.5% of control response at 5 and 10 Hz, respectively, Po0.01, n ¼ 6) 20 min after administration. The significant enhancement of PNESinduced responses was maintained 50 min (224.5 and 181.0%, Po0.01 in vagina; 294.8 and 258.9%, Po0.05 in clitoris) and 80 min after vardenafil administration (209.5 and 156.9%, Po0.05 in vagina; 268.9 and 194.9%, Po0.05 in clitoris). Here we present a feasible model for research into female sexual function. Our results show that vardenafil effectively potentiates the blood flow responses to PNES in the genitalia of female dogs. These results emphasize the role of the NO/cGMP pathway in the local vasodilatory response in female sexual organs and provide a rationale for testing PDE5 inhibitors, such as vardenafil, as a treatment for certain forms of female sexual dysfunction.

Mechanisms for the Inhibition of Genital Vascular Responses by Antidepressants in a Female Rabbit Model

“…The role of NO in neurogenic relaxation and blood flow control in the clitoris and vagina is supported by substantial evidence (Cellek and Moncada, 1998;Ziessen et al, 2002;Angulo et al, 2003). Our study provides further support for a key role of the NO/cGMP pathway in GVRs since the inhibition of NOS greatly inhibits GVRs to PNES.…”

“…Nitrergic innervation has also been identified in the human vagina and clitoris (Hoyle et al, 1996;Burnett et al, 1997). We have recently shown that the enhancement of the NO/cGMP pathway by the inhibition of type 5 phosphodiesterase potentiates increases in vaginal and clitoral blood flow in response to pelvic nerve electrical stimulation (PNES) in female dogs (Angulo et al, 2003). On the other hand, it has been suggested that the adrenergic system could play a functional antagonistic role to the NO pathway in female sexual responses (Giuliano et al, 2001), as occurs in males.…”

“…Indeed, several techniques are currently used to assess female sexual function by measuring indices of genital blood flow in women (Berman et al, 1999;Sommer et al, 2001). In female animals (rabbits, rats, and dogs), the increase of female genital blood flow in response to pelvic nerve stimulation has recently been suggested as a model of female sexual response (Giuliano et al, 2001;Angulo et al, 2003;Kim et al, 2003).…”

Physiology of Female Sexual Function: Animal Models

“…The stimulation of the paravertebral sympathetic chain reverses the PNS‐induced effect in the rat [32]. In both the rabbit and the dog model, the PDE5 inhibitors sildenafil and vardenafil, respectively, enhanced the PNS‐induced vaginal and clitoral blood flow indicating that the NO/cGMP pathway is involved in the physiological mechanism of female genital arousal [58,61]. The role of the NO/cGMP system in clitoral erection is further indicated by in vitro animal experiments.…”

Zaprinast, a phosphodiesterase type-5 inhibitor, alters paced mating behavior in female rats

“…PDE-5 inhibitors enhance pelvic nerve-stimulated blood flow (e.g., sildenafil, [1]; vardenafil, [23]) although the effects of zaprinast in this model system have yet to be evaluated. Our working model is that the enhanced genital blood flow elicited by zaprinast leads to heightened vaginal sensitivity to mating stimulation manifested behaviorally as a lengthening of contact-return latencies following ejaculation, as exhibited in the present study.…”