Phosphodiesterase Type 5 Inhibitors Facilitate Noncontact Erections in Male Rats: Site of Action in the Brain and Mechanism of Action

Bernard B. Brodie Department of Neuroscience, University of Cagliari, Monserrato, Cagliari 09042, Italy.
Journal of Sexual Medicine (Impact Factor: 3.15). 09/2009; 6(10):2680-9. DOI: 10.1111/j.1743-6109.2009.01410.x
Source: PubMed


Orally active phosphodiesterase type 5 inhibitors (PDE5i), used in the treatment of erectile dysfunction, facilitate the relaxation of cavernous smooth muscle tissues by reducing the degradation of cyclic guanosine monophosphate.
The aims of this article were to determine whether PDE5i facilitate penile erection and male sexual behavior by acting also on the central nervous system and to investigate their mechanism of action at central level.
PDE5i (sildenafil, vardenafil, and tadalafil) given intraperitoneally (i.p.) (5 mg/kg and 10 mg/kg), intracerebroventricularly (i.c.v.) (10 microg and 50 microg), or into the ventral tegmental area (VTA) (10 microg) were tested in the noncontact erection test in male Sprague-Dawley rats screened for their ability to display or not display this sexual response. Extracellular dopamine was measured in the dialysate obtained from the nucleus accumbens by intracerebral microdialysis on injection of PDE5i into the VTA. MAIN OUTCOME MEASURES. Noncontact erections were counted after intraperitoneal, intracerebroventricular, or intra-VTA treatment with PDE5i. Extracellular dopamine was measured in the dialysate from the nucleus accumbens when sildenafil or vardenafil was given into the VTA. Results. PDE5i induced a significant increase of noncontact erections in male rats displaying this sexual response following intraperitoneal or intracerebroventricular administration at the highest dose tested. However, both doses significantly increased noncontact erections in male rats not displaying this sexual response. Similar results were found when PDE5i were injected into the caudal VTA. Noncontact erections increased concomitantly to a rise in extracellular dopamine in the dialysate from the nucleus accumbens.
The results suggest that PDE5i may increase sexual arousal by acting in the central nervous system. This effect may be mediated (at least in part) by the activation of mesolimbic dopaminergic neurons.

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    • "These differences are likely to contribute to the different properties of these drugs. Centrally, both Sildenafil and Vardenafil are capable of crossing the blood brain barrier and affecting central PDE-5, which is expressed in different brain areas [24] [25] [26] [27] underlying modulation of behaviors, such as rage, emotion and sexual drive. In a recent animal study [28], we reported that Sildenafil counteracts the inhibitory effects of chronic social subordination on modulation of competitive aggression by restoring both aggressive and sexual behavior in subordinated male mice. "
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    ABSTRACT: Selective phosphodiesterases (PDEs) inhibitors have been widely studied as therapeutic agents for treatment of various human diseases, including cardiotonics, vasodilators, smooth muscle relaxants, antidepressants, antithrombotics, antiasthmatics, and agents for improving learning and memory. Although Sildenafil(®) and Vardenafil(®) have similar chemical formulae, the same target and interact with many of the same residues at the active site of phosphodiesterse-5 (PDE-5), they exhibit both in vitro and in vivo some important functional differences that could differentially affect behavior. Therefore we assessed whether repeated and chronic administration of Vardenafil and Sildenafil at a dose based upon human treatment can differentially affect aggressive, social, emotional and sexual behavior. To this aim, the effects of Sildenafil (10mg/kg) or Vardenafil (2mg/kg) (t.i.w., for 5 weeks) were observed in CD1 subordinate male mice in a low aggression and social subordination context. The results show that Sildenafil increased competitive aggression, environmental and social exploration, and reduced anxiety like behaviors as compared to controls, whereas Vardenafil had a significant major effect on appetitive and consummatory aspect of sexual behavior. This demonstrates that Sildenafil and Vardenafil, although being structurally and functionally similar, are characterized by different neuro-behavioral actions and can have differential therapeutic potentials.
    Behavioural brain research 07/2013; 253(253). DOI:10.1016/j.bbr.2013.07.004 · 3.03 Impact Factor
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    • "Increasing the duration of NO signaling by preventing cGMP breakdown is the main mechanism of action for the successful PDE-5 inhibitor class of drugs which currently are used as first-line treatment of ED [4]. Interestingly, recent studies have shown that these drugs have other beneficial effects such as stimulation of bone marrow endothelial progenitor cell function [5-9], inhibition of smooth muscle cell apoptosis [10,11], preservation/restoration of function in post-prostatectomy settings [12,13] and activation of mesolimbic dopaminergic neurons in the CNS to promote sexual behavior [14]. "
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    ABSTRACT: While PDE5 inhibitors have revolutionized treatment of ED, approximately 30% of patients are non-responsive. A significant cause of this is vascular and smooth muscle dysfunction, as well as nerve atrophy. Autologous administration of bone marrow mononuclear cells (BMMC) has been performed in over 2000 cardiac patients without adverse effects, for stimulation of angiogenesis/regeneration. Despite its ease of access, and dependence on effective vasculature for function, comparatively little has been perform in terms of BMMC therapy for ED. Here we outline the rationale for use of autologous BMMC in patients with ED, as well as provide early safety data on the first use of this procedure clinically.
    Journal of Translational Medicine 06/2013; 11(1):139. DOI:10.1186/1479-5876-11-139 · 3.93 Impact Factor
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    • "A group of vehicle-treated SE rats (n ¼9) was used as a reference for optimal sexual performance under physiological conditions. Dosages of Turnera diffusa and sildenafil were selected based on previous observations (Estrada- Reyes et al., 2009; Sanna et al., 2009). All solutions were administered in a volume of 2 mL/kg of body weight. "
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    ABSTRACT: ETHNOPHARMACOLOGICAL RELEVANCE: Turnera diffusa Wild has been used in folk medicine by its aphrodisiac and tranquilizing properties. Previously we experimentally showed the aphrodisiac effect of a chemically characterized aqueous extract of T. diffusa in male rats. However, the mechanism of action underlying such effects has not been studied. STUDY AIMS: As part of our systematic studies of pharmacological properties of T. diffusa, we aimed to analyze whether the increased sexual motivation and the augmented sexual performance of sexually sluggish (SL) male rats treated with T. diffusa involves the NO pathway. Additionally we analyzed whether such effects were exerted at the level of the brain or the spinal cord. Finally, anxiety levels and ambulatory activity were also evaluated. MATERIAL AND METHODS: T. diffusa (10-40mg/kg) and sildenafil citrate (10mg/kg) with or without a nonspecific inhibitor of NO synthase, Nω-nitro-L-arginine methyl esther (L-NAME, 12.5mg/kg) were evaluated in SL rats, in a standard sexual behavior test and in the fictive ejaculation model in spinal cord transected and urethane-anaesthetized SL rats. Anxiety levels or ambulation were assessed in the burying behavior and open-field tests. RESULTS: T. diffusa and sildenafil (both at 10mg/kg) facilitated expression of male sexual behavior by shortening mainly ejaculation latency. Treatments also facilitated the number of discharges in the ejaculatory motor pattern as well as the number of ejaculatory motor patterns and its associated penile erections. L-NAME prevented the pro-sexual effects of treatments on both experimental models. Besides, the extract of T. diffusa (10mg/kg) produced an anxiolytic-like effect in male rats without affecting ambulation. CONCLUSIONS: Findings from the present work support the notion that pro-sexual effect of the aqueous extract of T. diffusa in rats involves the participation of NO pathway, mainly at central level. The anxiolytic-like effect of T. diffusa is an advantage to its use for improving sexual performance.
    Journal of ethnopharmacology 01/2013; 146(1). DOI:10.1016/j.jep.2012.12.025 · 3.00 Impact Factor
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