Phosphodiesterase Type 5 Inhibitors Facilitate Noncontact Erections in Male Rats: Site of Action in the Brain and Mechanism of Action
ABSTRACT 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.
SourceAvailable from: Riccardo Volpi[Show abstract] [Hide abstract]
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; DOI:10.1016/j.bbr.2013.07.004 · 3.22 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Great burdock (Arctium lappa) is an edible vegetable that is also used as herbal medicines in many countries. Traditionally, burdock is used to slow aging, cure male impotence and in beauty care. However, the relevant mechanisms and scientific proof of its actions have not yet been elucidated. The expansion of the corpora cavernosum smooth muscle cells of the penis is the main regulating factor of erection, and the nitric oxide-soluble guanylyl cyclase-cyclic guanine monophosphate (NO-sGC-cGMP) pathway plays an important role in maintaining expansion of the corpora cavernosum. The current study aims are to investigate the effects of burdock extract on a rabbit's corpora cavernosum. The effects of burdock on the protein expression in the cavernosum tissues and smooth muscle cells were investigated, and the changes in cGMP level were determined via enzyme-linked immunosorbent assay kit analysis. Our results showed that burdock extract increased the expression of neuronal nitric oxide synthase, cGMP-dependent kinase, sGCα1 and sGCβ1 in the smooth muscle cells and tissues of the corpora cavernosum, while the expression of phosphodiesterase-5 was inhibited. Additionally, cGMP levels become elevated in the smooth muscles after treatment with burdock extract. In summary, our data suggest that burdock can facilitate in the relaxation of the corpora cavernosum; however, the benefits of burdock in treating erectile dysfunction remain to be resolved.Fooyin Journal of Health Sciences 08/2010; 2(3):98-104. DOI:10.1016/S1877-8607(11)60006-4
[Show abstract] [Hide abstract]
ABSTRACT: Of the numerous neuropeptides identified in the central nervous system, only a few are involved in the control of sexual behavior. Among these, the most studied are oxytocin, adrenocorticotropin, α-melanocyte stimulating hormone and opioid peptides. While opioid peptides inhibit sexual performance, the others facilitate sexual behavior in most of the species studied so far (rats, mice, monkeys and humans). However, evidence for a sexual role of gonadotropin-releasing hormone, corticotropin releasing factor, neuropeptide Y, galanin and galanin-like peptide, cholecystokinin, substance P, vasoactive intestinal peptide, vasopressin, angiotensin II, hypocretins/orexins and VGF-derived peptides are also available. Corticotropin releasing factor, neuropeptide Y, cholecystokinin, vasopressin and angiotensin II inhibit, while substance P, vasoactive intestinal peptide, hypocretins/orexins and some VGF-derived peptide facilitate sexual behavior. Neuropeptides influence sexual behavior by acting mainly in the hypothalamic nuclei (i.e., lateral hypothalamus, paraventricular nucleus, ventromedial nucleus, arcuate nucleus), in the medial preoptic area and in the spinal cord. However, it is often unclear whether neuropeptides influence the anticipatory phase (sexual arousal and/or motivation) or the consummatory phase (performance) of sexual behavior, except in a few cases (e.g., opioid peptides and oxytocin). Unfortunately, scarce information has been added in the last 15 years on the neural mechanisms by which neuropeptides influence sexual behavior, most studied neuropeptides apart. This may be due to a decreased interest of researchers on neuropeptides and sexual behavior or on sexual behavior in general. Such a decrease may be related to the discovery of orally effective, locally acting type V phosphodiesterase inhibitors for the therapy of erectile dysfunction.Progress in Neurobiology 07/2013; DOI:10.1016/j.pneurobio.2013.06.006 · 10.30 Impact Factor