Die Reduktion des Nachhyperpolarisationspotenzials nach einer Abfolge von Aktionspotenzialen in der CA1 Region im akuten Epilepsiemodell der Ratte

Eine langanhaltende Depolarisation von hippokampalen CA1-Neuronen induziert Aktionspotenzialsalven, welche von einem Nachhyperpolarisationspotenzial (AHP) gefolgt werden. Nach Auslösung akuter epileptiformer Entladungen mit Gabazin konnte gezeigt werden, dass die AHP-Amplitude signifikant gesenkt wurde. Durch Blockierung glutamaterger Transmission wurde eine AHP-Suppression nicht gezeigt. Eine AHP-Reduktion konnte auch nach Applikation der Proteinkinaseblocker H9 und -89 nicht gesehen werden. Die Ursache liegt in der Aktivierung von Proteinkinasen, am wahrscheinlichsten durch Proteinkinase A

Hyperpolarization-Activated Cyclic Nucleotide-Gated Non-selective (HCN) Ion Channels Regulate Human and Murine Urinary Bladder Contractility

Purpose: Hyperpolarization-activated cyclic nucleotide gated non-selective (HCN) channels have been demonstrated in the urinary bladder in various species. Since they play a major role in governing rhythmic activity in pacemaker cells like in the sinoatrial node, we explored the role of these channels in human and murine detrusor smooth muscle.Methods: In an organ bath, human and murine detrusor smooth muscle specimens were challenged with the HCN channel blocker ZD7288. In human tissue derived from macroscopically tumor-free cancer resections, the urothelium was removed. In addition, HCN1-deficient mice were used to identify the contribution of this particular isoform. Expression of HCN channels in the urinary bladder was analyzed using histological and ultrastructural analyses as well as quantitative reverse transcriptase polymerase chain reaction (RT-PCR).Results: We found that the HCN channel blocker ZD7288 (50 μM) both induced tonic contractions and increased phasic contraction amplitudes in human and murine detrusor specimens. While these responses were not sensitive to tetrodotoxin, they were significantly reduced by the gap junction inhibitor 18β-glycyrrhetic acid suggesting that HCN channels are located within the gap junction-interconnected smooth muscle cell network rather than on efferent nerve fibers. Immunohistochemistry suggested HCN channel expression on smooth muscle tissue, and immunoelectron microscopy confirmed the scattered presence of HCN2 on smooth muscle cell membranes. HCN channels seem to be down-regulated with aging, which is paralleled by an increasing effect of ZD7288 in aging detrusor tissue. Importantly, the anticonvulsant and HCN channel activator lamotrigine relaxed the detrusor which could be reversed by ZD7288.Conclusion: These findings demonstrate that HCN channels are functionally present and localized on smooth muscle cells of the urinary bladder. Given the age-dependent decline of these channels in humans, activation of HCN channels by compounds such as lamotrigine opens up the opportunity to combat detrusor hyperactivity in the elderly by drugs already approved for epilepsy

Sling Surgery for Female Incontinence

The pelvic floor is at an increased risk of damage during the lifespan of women. Pregnancy, vaginal delivery, aging, menopause, previous pelvic surgery, and lifestyle factors have a negative influence on the connective tissue and muscular components of the pelvic floor leading to urinary incontinence (UI). Pregnancy and vaginal delivery have been identified as the most important risk factors for incontinence. Cystocele, rectocele, uterine, vault prolapse, and/or incontinence can occur due to lacerations of the connective tissue support at different levels. Moreover, muscular damage of the levator complex can lead to widening of the levator hiatus, giving way to the descent of pelvic organs resulting in UI. Although some genetic abnormalities have been identified, their clinical implications remain unclear. Diagnostic evaluations should be performed in accordance with established evidence-based guidelines. Although short-term results of single-incision midurethral slings indicate similar efficacy to conventional midurethral slings, their long-term outcome is still not determined. Scientists continue to investigate the exact causes of stress UI as well as the optimum substitute material using the best surgical reconstructive approach. The recent European Association of Urology consensus statement underlines an imperative requirement for an optimal solution using minimal amount of material related to the indication and higher competence of surgeons for this surgery. High-quality trials with a longer follow-up are currently an unmet need.status: publishe