ESSM Newsletter # 40

24 ESSM Today Have you read? Best of the best: Basic research ment (anti-TLR4 antibody) but also with acute blockade of TLR4 (CLI-095). The cavernosal relaxation induced by EFS in tissue precon- tracted with PE in diabetic rats treated with an anti-TLR4 antibody or after incubation with CLI-095 was also significantly increased com- pared to nontreated diabetic animals. Also, higher levels of superoxide were found in corpus cavernosum of diabetic compared to normoglycemic rats, and TLR4 blockade was able to partly prevent this effect. Similarly, nitrite levels, a widely used indirect method to measure nitric oxide, found in lower levels in the diabetic cavernosal tissue was enhanced by treatment with an anti-TLR4 antibody. Tak- ing into consideration these results and the current literature, the authors speculate that activation of TLR4 downstream pathways in the penis due to hyperglycemia may contribute to deficient cavernosal relaxation by possibly affecting the NO-mediated cGMP levels. These findings open research avenues for new ED treatments in the presence of diabetes. Musicki B, Bhunia AK, Karakus S, Burnett AL. S-nitrosylation of NOS pathway mediators in the penis contributes to cavernous nerve injury-induced erectile dysfunction. Int J Impot Res. 2018; 30(3); 108-116 Despite advances in surgical techniques such as nerve-sparing, erectile dysfunction (ED) is still a very common consequence of radical prostatectomy. This complication is mainly associated with cavernous nerve injury with effects observed in the penis at cellular and molecular levels. NO signaling in the penis is mediated through a well recognized signal transduction pathway involving activation of soluble guanylyl cyclase (sGC) and 3,5-cyclic guanosine monophosphate (cGMP)-induced activation of protein kinase G (PKG). It is in- creasingly recognized that NO signaling is also mediated by S-nitrosylation, an alter- native signaling pathway for NO that medi- ates cGMP-independent effects. This group recently demonstrated the importance of transnitrosylation mechanisms in the penis in physiologic NO signaling, such that unchecked nitrosylation decreases NO bioactivity and in- creases oxidative/nitrosative stress. Whether S-nitrosylation is involved in pathologic ef- fects in the penis and exerts deleterious ef- fects with respect to erection preservation under conditions of penile neuropathy is un- known. In the current investigation they used a rat model of cavernous nerve crush injury (BCNI) vs rats submitted to sham surgery. Rats were randomly divided into four groups (n = 9–12/group): Sham + Vehicle, Sham + N-acetyl-cysteine (NAC), BCNI + Vehicle, and BCNI + NAC. NAC, an antioxidant and a denitrosylating agent was given to rats in drinking water starting 2 days before BCNI or sham injury and continuing for 2 weeks after the surgery. After assessment of erec- tile function (intracavernous pressure), pe- nes were collected for measurements of S- nitrosylation by Saville–Griess and TMT-switch assays and PKG-I function by immunoblotting of phospho(P)-VASP-Ser-239. The results showed that ED under conditions of penile neuropathy induced by cavernous nerve injury is mediated in part by S-nitrosylation of eNOS and its downstream signaling mediator sGC and also that denitrosylation in the face of cavernous nerve injury may protect erectile function by preserving NOS signaling path- way function. This novel mechanism for the derangement of NO signaling pathway that promotes ED under conditions of cavernous nerve injury opens new and interesting paths of investigation. Premature ejaculation Xia JD, Chen J, Yang BB, et al. Differences in sympathetic nervous system activity and nmda receptor levels within the hypotha- lamic paraventricular nucleus in rats with differential ejaculatory behaviour. Asian J Androl. 2018; 20(4): 355-359 Lifelong premature ejaculation is a very common sexual dysfunction and has been defined as a neurobiological disorder. The data collected so far indicate that ejacula- tion is predominantly mediated by a spinal control center, which is in turn influenced by the descending inhibitory and excitatory supraspinal sites in the brainstem, hypo- thalamus and preoptic area. Many types of neurotransmitter with inhibitory or excitatory roles, such as serotonin, dopamine, adrena- line, acetylcholine, norepinephrine, oxytocin, gamma‑aminobutyric acid, N‑methyl‑D‑aspar- tic acid (NMDA), and nitric oxide, have been implicated in the central regulation of ejacula- tion reflex. This group had recently found that NMDA receptors in the paraventricular nucleus of the hypothalamus (PVN) facilitate ejacula- tion by enhancing sympathetic nervous sys- tem (SNS) activity. In the present study, in an experimental rat model, they found that male rats with differential ejaculatory behavior had different SNS sensitivities, which correlated with NMDA receptor levels in the PVN, and this supports different levels of NMDA recep- tors in the PVN as contributing to changes in ejaculatory latency during sexual activity. They demonstrated that the density of NMDA recep- tors in the PVN distinguished between three groups (sluggish, normal and rapid ejacula- tors), with the density being the highest in “rapid” ejaculators. This further supports the model of a neurobiological disorder, opening some potential news routes to pharmacologi- cal interventions. Peyronie’s disease Mateus M, Ilg MM, Stebedds WJ, et al. Un- derstanding the role of adenosine recep- tors in the myofibroblast transformation in peyronie’s disease Peyronie’s disease (PD) is a fibrotic disorder characterized by the formation of plaques within the tunica albuginea (TA) of the pe- nis with a poorly understood etiology (which probably accounts for the lack of an effective medical treatment). This fibrotic disorder is characterized by the expression of several cytokines and growth factors, fibrin deposi-